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Arcot A, Gallagher K, Goldstein JA, Gernand AD. The relationship between maternal glucose concentrations, gestational diabetes mellitus, placental weight, and placental vascular malperfusion lesions: a retrospective study of a U.S. pregnancy cohort. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.05.14.25327646. [PMID: 40463560 PMCID: PMC12132164 DOI: 10.1101/2025.05.14.25327646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/16/2025]
Abstract
Background Gestational diabetes mellitus (GDM) is associated with increased placental weight and the presence of placental malperfusion lesions, likely related to high blood glucose. The relationship between high glucose without overt GDM, and placental characteristics is not well understood. Objective To examine the relationships between glucose challenge test (GCT) concentrations, GDM, and placental characteristics associated with GDM. Methods We conducted a secondary analysis of medical record data from singleton placentas sent to pathology at Northwestern Memorial Hospital (2011-2022; n=11,585). Data included maternal demographic variables, GCT concentrations, GDM diagnosis, placental weight, and vascular malperfusion lesions (accelerated villous maturation, increased syncytial knots, delayed villous maturation, and increased perivillous fibrin deposition). We classified GCT <140 mg/dL as pass and ≥140 mg/dL as fail. We categorized glucose groups into pass GCT/no GDM , fail GCT/no GDM , and GDM . We used linear and Poisson regression models to examine the association between GCT concentrations or groups with placental outcomes, adjusting for maternal age, race and ethnicity, parity, gestational age at delivery, and infant sex. Results Of placentas sent to pathology, 5% were from pregnancies with GDM and 17% from those who failed the GCT but did not get diagnosed with GDM. Compared to the pass GCT/no GDM group, the adjusted mean placental weight was heavier by 13.6 grams [95% CI: 8.8, 18.3] in the fail GCT/no GDM and 22.0 grams [13.8, 30.2] in the GDM group. Patients diagnosed with GDM had a 36% [2%, 81%] increased adjusted risk of delayed villous maturation compared to the pass GCT/no GDM . The risk of the other lesions was not statistically significantly different between groups. Conclusion GDM and high glucose concentrations without GDM were associated with heavier placentas; patients with GDM had a higher risk of delayed villous maturation.
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Affiliation(s)
- Amrita Arcot
- The Pennsylvania State University Department of Nutritional Sciences, University Park, PA 16802
| | - Kelly Gallagher
- The Pennsylvania State University Ross and Carol Nese College of Nursing, University Park, PA 16802
| | - Jeffery A. Goldstein
- Northwestern University Feinberg School of Medicine Department of Pathology, Chicago, Illinois 60611
| | - Alison D. Gernand
- The Pennsylvania State University Department of Nutritional Sciences, University Park, PA 16802
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Shamsad A, Gautam T, Singh R, Banerjee M. Genetic and epigenetic alterations associated with gestational diabetes mellitus and adverse neonatal outcomes. World J Clin Pediatr 2025; 14:99231. [DOI: 10.5409/wjcp.v14.i1.99231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/03/2024] [Accepted: 10/31/2024] [Indexed: 12/20/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disorder, recognised during 24-28 weeks of pregnancy. GDM is linked with adverse newborn outcomes such as macrosomia, premature delivery, metabolic disorder, cardiovascular, and neurological disorders. Recent investigations have focused on the correlation of genetic factors such as β-cell function and insulin secretary genes (transcription factor 7 like 2, potassium voltage-gated channel subfamily q member 1, adiponectin etc.) on maternal metabolism during gestation leading to GDM. Epigenetic alterations like DNA methylation, histone modification, and miRNA expression can influence gene expression and play a dominant role in feto-maternal metabolic pathways. Interactions between genes and environment, resulting in differential gene expression patterns may lead to GDM. Researchers suggested that GDM women are more susceptible to insulin resistance, which alters intrauterine surroundings, resulting hyperglycemia and hyperinsulinemia. Epigenetic modifications in genes affecting neuroendocrine activities, and metabolism, increase the risk of obesity and type 2 diabetes in offspring. There is currently no treatment or effective preventive method for GDM, since the molecular processes of insulin resistance are not well understood. The present review was undertaken to understand the pathophysiology of GDM and its effects on adverse neonatal outcomes. In addition, the study of genetic and epigenetic alterations will provide lead to researchers in the search for predictive molecular biomarkers.
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Affiliation(s)
- Amreen Shamsad
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Tanu Gautam
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
| | - Renu Singh
- Department of Obstetrics and Gynecology, King George’s Medical University, Lucknow 226003, Uttar Pradesh, India
| | - Monisha Banerjee
- Molecular and Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow 226007, Uttar Pradesh, India
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Mittal R, Prasad K, Lemos JRN, Arevalo G, Hirani K. Unveiling Gestational Diabetes: An Overview of Pathophysiology and Management. Int J Mol Sci 2025; 26:2320. [PMID: 40076938 PMCID: PMC11900321 DOI: 10.3390/ijms26052320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 02/14/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Gestational diabetes mellitus (GDM) is characterized by an inadequate pancreatic β-cell response to pregnancy-induced insulin resistance, resulting in hyperglycemia. The pathophysiology involves reduced incretin hormone secretion and signaling, specifically decreased glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), impairing insulinotropic effects. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), impair insulin receptor substrate-1 (IRS-1) phosphorylation, disrupting insulin-mediated glucose uptake. β-cell dysfunction in GDM is associated with decreased pancreatic duodenal homeobox 1 (PDX1) expression, increased endoplasmic reticulum stress markers (CHOP, GRP78), and mitochondrial dysfunction leading to impaired ATP production and reduced glucose-stimulated insulin secretion. Excessive gestational weight gain exacerbates insulin resistance through hyperleptinemia, which downregulates insulin receptor expression via JAK/STAT signaling. Additionally, hypoadiponectinemia decreases AMP-activated protein kinase (AMPK) activation in skeletal muscle, impairing GLUT4 translocation. Placental hormones such as human placental lactogen (hPL) induce lipolysis, increasing circulating free fatty acids which activate protein kinase C, inhibiting insulin signaling. Placental 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) overactivity elevates cortisol levels, which activate glucocorticoid receptors to further reduce insulin sensitivity. GDM diagnostic thresholds (≥92 mg/dL fasting, ≥153 mg/dL post-load) are lower than type 2 diabetes to prevent fetal hyperinsulinemia and macrosomia. Management strategies focus on lifestyle modifications, including dietary carbohydrate restriction and exercise. Pharmacological interventions, such as insulin or metformin, aim to restore AMPK signaling and reduce hepatic glucose output. Emerging therapies, such as glucagon-like peptide-1 receptor (GLP-1R) agonists, show potential in improving glycemic control and reducing inflammation. A mechanistic understanding of GDM pathophysiology is essential for developing targeted therapeutic strategies to prevent both adverse pregnancy outcomes and the progression to overt diabetes in affected women.
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Affiliation(s)
| | | | | | | | - Khemraj Hirani
- Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (K.P.); (J.R.N.L.); (G.A.)
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4
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Hari Gopal S, Alenghat T, Pammi M. Early life epigenetics and childhood outcomes: a scoping review. Pediatr Res 2025; 97:1305-1314. [PMID: 39289593 DOI: 10.1038/s41390-024-03585-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 08/28/2024] [Accepted: 09/07/2024] [Indexed: 09/19/2024]
Abstract
Epigenetics is the study of changes in gene expression, without a change in the DNA sequence that are potentially heritable. Epigenetic mechanisms such as DNA methylation, histone modifications, and small non-coding RNA (sncRNA) changes have been studied in various childhood disorders. Causal links to maternal health and toxin exposures can introduce epigenetic modifications to the fetal DNA, which can be detected in the cord blood. Cord blood epigenetic modifications provide evidence of in-utero stressors and immediate postnatal changes, which can impact both short and long-term outcomes in children. The mechanisms of these epigenetic changes can be leveraged for prevention, early detection, and intervention, and to discover novel therapeutic modalities in childhood diseases. We report a scoping review of early life epigenetics, the influence of maternal health, maternal toxin, and drug exposures on the fetus, and its impact on perinatal, neonatal, and childhood outcomes. IMPACT STATEMENT: Epigenetic changes such as DNA methylation, histone modification, and non-coding RNA have been implicated in the pathophysiology of various disease processes. The fundamental changes to an offspring's epigenome can begin in utero, impacting the immediate postnatal period, childhood, adolescence, and adulthood. This scoping review summarizes current literature on the impact of early life epigenetics, especially DNA methylation on childhood health outcomes.
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Affiliation(s)
- Srirupa Hari Gopal
- Dept. of Pediatrics, Division of Neonatology, Baylor College of Medicine & Texas Children's Hospital, Houston, TX, USA.
| | - Theresa Alenghat
- Division of Immunobiology and Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Mohan Pammi
- Dept. of Pediatrics, Division of Neonatology, Baylor College of Medicine & Texas Children's Hospital, Houston, TX, USA
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Lee J, Lee NK, Moon JH. Gestational Diabetes Mellitus: Mechanisms Underlying Maternal and Fetal Complications. Endocrinol Metab (Seoul) 2025; 40:10-25. [PMID: 39844628 PMCID: PMC11898322 DOI: 10.3803/enm.2024.2264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 12/18/2024] [Accepted: 12/23/2024] [Indexed: 01/24/2025] Open
Abstract
Gestational diabetes mellitus (GDM) affects over 10% of all pregnancies, both in Korea and worldwide. GDM not only increases the risk of adverse pregnancy outcomes such as preeclampsia, preterm birth, macrosomia, neonatal hypoglycemia, and shoulder dystocia, but it also significantly increases the risk of developing postpartum type 2 diabetes mellitus and cardiovascular disease in the mother. Additionally, GDM is linked to a higher risk of childhood obesity and diabetes in offspring, as well as neurodevelopmental disorders, including autistic spectrum disorder. This review offers a comprehensive summary of clinical epidemiological studies concerning maternal and fetal complications and explores mechanistic investigations that reveal the underlying pathophysiology.
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Affiliation(s)
- Jooyeop Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Armed Forces Yangju Hospital, Yangju, Korea
| | - Na Keum Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Joon Ho Moon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Tortelote GG. The Impact of Gestational Diabetes on Kidney Development: is There an Epigenetic Link? Curr Diab Rep 2024; 25:13. [PMID: 39690358 DOI: 10.1007/s11892-024-01569-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/03/2024] [Indexed: 12/19/2024]
Abstract
PURPOSE OF REVIEW This review explores the mechanisms through which gestational diabetes mellitus GDM impacts fetal kidney development, focusing on epigenetic alterations as mediators of these effects. We examine the influence of GDM on nephrogenesis and kidney maturation, exploring how hyperglycemia-induced intrauterine stress can reduce nephron endowment and compromise renal function via dysregulation of normal epigenetic mechanisms. RECENT FINDINGS In addition to metabolic impacts, emerging evidence suggests that GDM exerts its influence through epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA expression, which disrupt gene expression patterns critical for kidney development. Recently, specific epigenetic modifications observed in offspring exposed to GDM were implicated in aberrant activation or repression of genes essential for kidney development. Key pathways influenced by these epigenetic changes, such as oxidative stress response, inflammatory regulation, and metabolic pathways, are discussed to illustrate the broad molecular impact of GDM on renal development. Finally, we consider potential intervention strategies that could mitigate the adverse effects of GDM on kidney development. These include optimizing maternal glycemic control, dietary modifications, dietary supplementation, and pharmacological agents targeting epigenetic pathways. Through a comprehensive synthesis of current research, this review underscores the importance of early preventive strategies to reduce the burden of kidney disease in individuals exposed to GDM and highlights key epigenetic mechanisms altered during GDM that impact kidney development.
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Affiliation(s)
- Giovane G Tortelote
- Section of Pediatric Nephrology, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA, 70112, USA.
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7
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Cao W, Wang H, Zhao S, Liu J, Liu E, Zhang T, Li N, Gao M, Li J, Yu Z, Hu G, Leng J, Yang X. Long-term risk of overweight in offspring of Chinese women with gestational diabetes defined by IADPSG's but not by WHO's criteria. Prim Care Diabetes 2024; 18:448-457. [PMID: 38777723 DOI: 10.1016/j.pcd.2024.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/19/2024] [Accepted: 05/11/2024] [Indexed: 05/25/2024]
Abstract
AIMS To examine long-term risk of overweight in offspring of women with gestational diabetes mellitus (GDM) defined by the International Association of Diabetes and Pregnancy Study Group (IADPSG)'s criteria but not by the 1999 World Health Organization (WHO)'s criteria. METHODS We followed up 1681 mother-child pairs for 8 years in Tianjin, China. Overweight in children aged 1-5 and 6-8 were respectively defined as body mass index-for-age and -sex above the 2 z-score and 1 z-score curves of the WHO's child growth standards. Logistic regression was performed to obtain odds ratios (ORs) and 95% confidence intervals (CIs) of hyperglycemia indices at oral glucose tolerance test and GDMs defined by different criteria for offspring overweight at different ages. RESULTS Offspring of women with fasting plasma glucose ≥5.1 mmol/L were at increased risk of overweight at 6-8 years old (OR:1.45, 95% CI: 1.09-1.93). GDM defined by the IADPSG's criteria only was associated with increased risk of childhood overweight at 6-8 years old (1.65, 1.13-2.40), as compared with non-GDM by either of the two sets of criteria. CONCLUSIONS Newly defined GDM by the IADPSG's criteria increased the risk of offspring overweight aged 6-8 years.
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Affiliation(s)
- Weihan Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Hui Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Tianjin Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin 300070, China
| | - Shumin Zhao
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Jin Liu
- Department of Child Health, Tianjin Women and Children's Health Center, Tianjin 300070, China
| | - Enqing Liu
- Department of Child Health, Tianjin Women and Children's Health Center, Tianjin 300070, China
| | - Tao Zhang
- Department of Child Health, Tianjin Women and Children's Health Center, Tianjin 300070, China
| | - Ninghua Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Ming Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China
| | - Jing Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Tianjin Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin 300070, China
| | - Zhijie Yu
- Population Cancer Research Program and Department of Pediatrics, Dalhousie University, Halifax 15000, Canada
| | - Gang Hu
- Chronic Disease Epidemiology Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
| | - Junhong Leng
- Department of Child Health, Tianjin Women and Children's Health Center, Tianjin 300070, China.
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Environment, Nutrition and Public Health, Tianjin 300070, China; Tianjin Center for International Collaborative Research on Environment, Nutrition and Public Health, Tianjin 300070, China.
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8
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Anunciado-Koza RVP, Yin H, Bilodeau CL, Cooke D, Ables GP, Ryzhov S, Koza RA. Interindividual differences of dietary fat-inducible Mest in white adipose tissue of C57BL/6J mice are not heritable. Obesity (Silver Spring) 2024; 32:1144-1155. [PMID: 38616328 PMCID: PMC11132930 DOI: 10.1002/oby.24020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 02/01/2024] [Accepted: 02/20/2024] [Indexed: 04/16/2024]
Abstract
OBJECTIVE Differences in white adipose tissue (WAT) expression of mesoderm-specific transcript (Mest) in C57BL6/J mice fed a high-fat diet (HFD) are concomitant with and predictive for the development of obesity. However, the basis for differences in WAT Mest among mice is unknown. This study investigated whether HFD-inducible WAT Mest, as well as susceptibility to obesity, is transmissible from parents to offspring. METHODS WAT biopsies of mice fed an HFD for 2 weeks identified parents with low and high WAT Mest for breeding. Obesity phenotypes, WAT Mest, hepatic gene expression, and serum metabolites were determined in offspring fed an HFD for 2 weeks. RESULTS Offspring showed no heritability of obesity or WAT Mest phenotypes from parents but did show hepatic and serum metabolite changes consistent with their WAT Mest. Importantly, retired male breeders showed WAT Mest expression congruent with initial WAT biopsies even though HFD exposure occurred early in life. CONCLUSIONS Disparity of HFD-induced Mest in mice is not heritable but, rather, is reestablished during each generation and remains fixed from an early age to adulthood. Short-term HFD feeding reveals variation of WAT Mest expression within isogenic mice that is positively associated with the development of obesity.
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Affiliation(s)
| | - Haifeng Yin
- MaineHealth Institute for Research, Scarborough, Maine, USA
| | | | - Diana Cooke
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Gene P. Ables
- Orentreich Foundation for the Advancement of Science, Inc., Cold Spring, New York, USA
| | - Sergey Ryzhov
- MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
- Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts, USA
| | - Robert A. Koza
- MaineHealth Institute for Research, Scarborough, Maine, USA
- Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, Maine, USA
- Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
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Yi Y, Wang T, Xu W, Zhang SH. Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring. World J Diabetes 2024; 15:378-391. [PMID: 38591094 PMCID: PMC10999040 DOI: 10.4239/wjd.v15.i3.378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 12/30/2023] [Accepted: 02/06/2024] [Indexed: 03/15/2024] Open
Abstract
Gestational diabetes mellitus (GDM) is a pregnancy-related complication characterized by abnormal glucose metabolism in pregnant women and has an important impact on fetal development. As a bridge between the mother and the fetus, the placenta has nutrient transport functions, endocrine functions, etc., and can regulate placental nutrient transport and fetal growth and development according to maternal metabolic status. Only by means of placental transmission can changes in maternal hyperglycemia affect the fetus. There are many reports on the placental pathophysiological changes associated with GDM, the impacts of GDM on the growth and development of offspring, and the prevalence of GDM in offspring after birth. Placental epigenetic changes in GDM are involved in the programming of fetal development and are involved in the pathogenesis of later chronic diseases. This paper summarizes the effects of changes in placental nutrient transport function and hormone secretion levels due to maternal hyperglycemia and hyperinsulinemia on the development of offspring as well as the participation of changes in placental epigenetic modifications due to maternal hyperglycemia in intrauterine fetal programming to promote a comprehensive understanding of the impacts of placental epigenetic modifications on the development of offspring from patients with GDM.
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Affiliation(s)
- Yan Yi
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - Tao Wang
- Clinical Molecular Immunology Center, Yangtze University, Jingzhou 434023, Hubei Province, China
| | - Wei Xu
- Department of Ultrasonography, The First Affiliated Hospital of Yangtze University, Jingzhou 434000, Hubei Province, China
| | - San-Hong Zhang
- Department of Pediatric, Xiantao First People’s Hospital, Xiantao 433000, Hubei Province, China
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10
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Thornton JM, Shah NM, Lillycrop KA, Cui W, Johnson MR, Singh N. Multigenerational diabetes mellitus. Front Endocrinol (Lausanne) 2024; 14:1245899. [PMID: 38288471 PMCID: PMC10822950 DOI: 10.3389/fendo.2023.1245899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 12/27/2023] [Indexed: 02/01/2024] Open
Abstract
Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, "developmental programming", has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health.
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Affiliation(s)
- Jennifer M. Thornton
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Nishel M. Shah
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Karen A. Lillycrop
- Institute of Developmental Sciences, University of Southampton, Southampton General Hospital, Southampton, United Kingdom
| | - Wei Cui
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Mark R. Johnson
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Natasha Singh
- Department of Academic Obstetrics & Gynaecology, Chelsea & Westminster NHS Foundation Trust, London, United Kingdom
- Department of Metabolism, Digestion & Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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11
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Derakhshan M, Kessler NJ, Hellenthal G, Silver MJ. Metastable epialleles in humans. Trends Genet 2024; 40:52-68. [PMID: 38000919 DOI: 10.1016/j.tig.2023.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/20/2023] [Accepted: 09/21/2023] [Indexed: 11/26/2023]
Abstract
First identified in isogenic mice, metastable epialleles (MEs) are loci where the extent of DNA methylation (DNAm) is variable between individuals but correlates across tissues derived from different germ layers within a given individual. This property, termed systemic interindividual variation (SIV), is attributed to stochastic methylation establishment before germ layer differentiation. Evidence suggests that some putative human MEs are sensitive to environmental exposures in early development. In this review we introduce key concepts pertaining to human MEs, describe methods used to identify MEs in humans, and review their genomic features. We also highlight studies linking DNAm at putative human MEs to early environmental exposures and postnatal (including disease) phenotypes.
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Affiliation(s)
- Maria Derakhshan
- London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
| | - Noah J Kessler
- Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK
| | | | - Matt J Silver
- London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK; Medical Research Council (MRC) Unit The Gambia at the London School of Hygiene and Tropical Medicine, Fajara, Banjul, The Gambia.
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12
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Lizárraga D, Gómez-Gil B, García-Gasca T, Ávalos-Soriano A, Casarini L, Salazar-Oroz A, García-Gasca A. Gestational diabetes mellitus: genetic factors, epigenetic alterations, and microbial composition. Acta Diabetol 2024; 61:1-17. [PMID: 37660305 DOI: 10.1007/s00592-023-02176-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023]
Abstract
Gestational diabetes mellitus (GDM) is a common metabolic disorder, usually diagnosed during the third trimester of pregnancy that usually disappears after delivery. In GDM, the excess of glucose, fatty acids, and amino acids results in foetuses large for gestational age. Hyperglycaemia and insulin resistance accelerate the metabolism, raising the oxygen demand, and creating chronic hypoxia and inflammation. Women who experienced GDM and their offspring are at risk of developing type-2 diabetes, obesity, and other metabolic or cardiovascular conditions later in life. Genetic factors may predispose the development of GDM; however, they do not account for all GDM cases; lifestyle and diet also play important roles in GDM development by modulating epigenetic signatures and the body's microbial composition; therefore, this is a condition with a complex, multifactorial aetiology. In this context, we revised published reports describing GDM-associated single-nucleotide polymorphisms (SNPs), DNA methylation and microRNA expression in different tissues (such as placenta, umbilical cord, adipose tissue, and peripheral blood), and microbial composition in the gut, oral cavity, and vagina from pregnant women with GDM, as well as the bacterial composition of the offspring. Altogether, these reports indicate that a number of SNPs are associated to GDM phenotypes and may predispose the development of the disease. However, extrinsic factors (lifestyle, nutrition) modulate, through epigenetic mechanisms, the risk of developing the disease, and some association exists between the microbial composition with GDM in an organ-specific manner. Genes, epigenetic signatures, and microbiota could be transferred to the offspring, increasing the possibility of developing chronic degenerative conditions through postnatal life.
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Affiliation(s)
- Dennise Lizárraga
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Bruno Gómez-Gil
- Laboratory of Microbial Genomics, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Teresa García-Gasca
- Laboratory of Molecular and Cellular Biology, Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Avenida de las Ciencias s/n, 76230, Juriquilla, Querétaro, Mexico
| | - Anaguiven Ávalos-Soriano
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico
| | - Livio Casarini
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via G. Campi 287, 41125, Modena, Italy
| | - Azucena Salazar-Oroz
- Maternal-Fetal Department, Instituto Vidalia, Hospital Sharp Mazatlán, Avenida Rafael Buelna y Dr. Jesús Kumate s/n, 82126, Mazatlán, Sinaloa, Mexico
| | - Alejandra García-Gasca
- Laboratory of Molecular and Cell Biology, Centro de Investigación en Alimentación y Desarrollo, Avenida Sábalo Cerritos s/n, 82112, Mazatlán, Sinaloa, Mexico.
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13
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Nair S, Ormazabal V, Carrion F, Handberg A, McIntyre H, Salomon C. Extracellular vesicle-mediated targeting strategies for long-term health benefits in gestational diabetes. Clin Sci (Lond) 2023; 137:1311-1332. [PMID: 37650554 PMCID: PMC10472199 DOI: 10.1042/cs20220150] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 07/23/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023]
Abstract
Extracellular vesicles (EVs) are critical mediators of cell communication, playing important roles in regulating molecular cross-talk between different metabolic tissues and influencing insulin sensitivity in both healthy and gestational diabetes mellitus (GDM) pregnancies. The ability of EVs to transfer molecular cargo between cells imbues them with potential as therapeutic agents. During pregnancy, the placenta assumes a vital role in metabolic regulation, with multiple mechanisms of placenta-mediated EV cross-talk serving as central components in GDM pathophysiology. This review focuses on the role of the placenta in the pathophysiology of GDM and explores the possibilities and prospects of targeting the placenta to address insulin resistance and placental dysfunction in GDM. Additionally, we propose the use of EVs as a novel method for targeted therapeutics in treating the dysfunctional placenta. The primary aim of this review is to comprehend the current status of EV targeting approaches and assess the potential application of these strategies in placental therapeutics, thereby delivering molecular cargo and improving maternal and fetal outcomes in GDM. We propose that EVs have the potential to revolutionize GDM management, offering hope for enhanced maternal-fetal health outcomes and more effective treatments.
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Affiliation(s)
- Soumyalekshmi Nair
- Translational Extracellular Vesicle in Obstetrics and Gynae-Oncology Group, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Australia
| | - Valeska Ormazabal
- Department of Pharmacology, Faculty of Biological Sciences, University of Concepcion, Concepción, Chile
| | - Flavio Carrion
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - Aase Handberg
- Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - H David McIntyre
- Mater Research, Faculty of Medicine, University of Queensland, Mater Health, South Brisbane, Australia
| | - Carlos Salomon
- Translational Extracellular Vesicle in Obstetrics and Gynae-Oncology Group, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Australia
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
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14
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Muñoz-Islas E, Vargas-Balderas DI, Hernandez I, Vazquez-Mora JA, Acosta-González RI, Jiménez-Andrade JM. Long-term effects of streptozotocin-induced gestational diabetes mellitus on mechanical sensitivity and intraepidermal nerve fibers in female and male mice offspring. Neurosci Lett 2023; 812:137402. [PMID: 37507046 DOI: 10.1016/j.neulet.2023.137402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023]
Abstract
While the long-term complications of gestational diabetes mellitus (GDM) in the cardiovascular, endocrine, and central nervous systems from offspring have been widely studied, less is known about the long-term outcomes of GDM on the peripheral nervous system. Thus, here we assessed the mechanical sensitivity and density of nerve fibers of the hind paw from middle-aged offspring born from dams with GDM. GDM was induced by the intraperitoneal administration of streptozotocin (STZ) in mouse dams. Mechanical sensitivity in male and female offspring was bi-weekly evaluated from week 18 to week 40 of age. At 40 weeks old, offspring were sacrificed and glabrous hind paw skin was processed for immunohistochemistry to determine the density of intraepidermal CGRP and PGP9.5 positive nerve fibers. Offspring mice born from STZ-treated dams had significantly greater mechanical sensitivity from 18 to 40 weeks of age compared to offspring born from vehicle-treated dams (control group). The density of intraepidermal CGRP+ and PGP9.5+ nerve fibers were significantly lower in the hind paw skin of female but not male offspring, born from STZ-treated dams versus the control group. These results suggest that GDM has long-term sex-dependent complications on the nociceptive system. Further studies are necessary to elucidate the mechanisms underlying the GDM-induced long-term consequences.
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Affiliation(s)
- Enriqueta Muñoz-Islas
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico.
| | | | - Ivanna Hernandez
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Juan Antonio Vazquez-Mora
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Rosa Issel Acosta-González
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
| | - Juan Miguel Jiménez-Andrade
- Unidad Académica Multidisciplinaria Reynosa-Aztlán, Universidad Autónoma de Tamaulipas, Reynosa, Tamaulipas, Mexico
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15
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Linares-Pineda T, Peña-Montero N, Fragoso-Bargas N, Gutiérrez-Repiso C, Lima-Rubio F, Suarez-Arana M, Sánchez-Pozo A, Tinahones FJ, Molina-Vega M, Picón-César MJ, Sommer C, Morcillo S. Epigenetic marks associated with gestational diabetes mellitus across two time points during pregnancy. Clin Epigenetics 2023; 15:110. [PMID: 37415231 PMCID: PMC10324212 DOI: 10.1186/s13148-023-01523-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/23/2023] [Indexed: 07/08/2023] Open
Abstract
An adverse intrauterine or periconceptional environment, such as hyperglycemia during pregnancy, can affect the DNA methylation pattern both in mothers and their offspring. In this study, we explored the epigenetic profile in maternal peripheral blood samples through pregnancy to find potential epigenetic biomarkers for gestational diabetes mellitus (GDM), as well as candidate genes involved in GDM development. We performed an epigenome-wide association study in maternal peripheral blood samples in 32 pregnant women (16 with GDM and 16 non-GDM) at pregnancy week 24-28 and 36-38. Biochemical, anthropometric, and obstetrical variables were collected from all the participants. The main results were validated in an independent cohort with different ethnic origin (European = 307; South Asians = 165). Two hundred and seventy-two CpGs sites remained significantly different between GDM and non-GDM pregnant women across two time points during pregnancy. The significant CpG sites were related to pathways associated with type I diabetes mellitus, insulin resistance and secretion. Cg01459453 (SELP gene) was the most differentiated in the GDM group versus non-GDM (73.6 vs. 60.9, p = 1.06E-11; FDR = 7.87E-06). Three CpG sites (cg01459453, cg15329406, and cg04095097) were able to discriminate between GDM cases and controls (AUC = 1; p = 1.26E-09). Three differentially methylated positions (DMPs) were replicated in an independent cohort. To conclude, epigenetic marks during pregnancy differed between GDM cases and controls suggesting a role for these genes in GDM development. Three CpGs were able to discriminate GDM and non-GDM groups with high specificity and sensitivity, which may be biomarker candidates for diagnosis or prediction of GDM.
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Affiliation(s)
- Teresa Linares-Pineda
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
- Departamento de Bioquímica y Biología Molecular 2, Universidad de Granada, Granada, Spain
| | - Nerea Peña-Montero
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
| | - Nicolás Fragoso-Bargas
- Department of Endocrinology Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Carolina Gutiérrez-Repiso
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 29029, Madrid, Spain
| | - Fuensanta Lima-Rubio
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
| | - María Suarez-Arana
- Departamento de Obstetricia y Ginecología, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Regional Universitario de Málaga, 29009, Málaga, Spain
| | - Antonio Sánchez-Pozo
- Departamento de Bioquímica y Biología Molecular 2, Universidad de Granada, Granada, Spain
| | - Francisco J Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
- Department of Endocrinology Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
- Departamento de Medicina y Dermatología, Universidad de Málaga, 29010, Málaga, Spain
| | - María Molina-Vega
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain
| | - María José Picón-César
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain.
| | - Christine Sommer
- Department of Endocrinology Morbid Obesity and Preventive Medicine, Oslo University Hospital, Oslo, Norway
- Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Sonsoles Morcillo
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga-IBIMA_Plataforma Bionand, Hospital Universitario Virgen de la Victoria, 29010, Málaga, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Instituto de Salud Carlos III, 29029, Madrid, Spain.
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16
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Rodolaki K, Pergialiotis V, Iakovidou N, Boutsikou T, Iliodromiti Z, Kanaka-Gantenbein C. The impact of maternal diabetes on the future health and neurodevelopment of the offspring: a review of the evidence. Front Endocrinol (Lausanne) 2023; 14:1125628. [PMID: 37469977 PMCID: PMC10352101 DOI: 10.3389/fendo.2023.1125628] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 06/12/2023] [Indexed: 07/21/2023] Open
Abstract
Maternal health during gestational period is undoubtedly critical in shaping optimal fetal development and future health of the offspring. Gestational diabetes mellitus is a metabolic disorder occurring in pregnancy with an alarming increasing incidence worldwide during recent years. Over the years, there is a growing body of evidence that uncontrolled maternal hyperglycaemia during pregnancy can potentially have detrimental effect on the neurodevelopment of the offspring. Both human and animal data have linked maternal diabetes with motor and cognitive impairment, as well as autism spectrum disorders, attention deficit hyperactivity disorder, learning abilities and psychiatric disorders. This review presents the available data from current literature investigating the relationship between maternal diabetes and offspring neurodevelopmental impairment. Moreover, possible mechanisms accounting for the detrimental effects of maternal diabetes on fetal brain like fetal neuroinflammation, iron deficiency, epigenetic alterations, disordered lipid metabolism and structural brain abnormalities are also highlighted. On the basis of the evidence demonstrated in the literature, it is mandatory that hyperglycaemia during pregnancy will be optimally controlled and the impact of maternal diabetes on offspring neurodevelopment will be more thoroughly investigated.
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Affiliation(s)
- Kalliopi Rodolaki
- First Department of Pediatrics, “Aghia Sophia” Children’s Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Vasilios Pergialiotis
- First Department of Obstetrics and Gynecology, Alexandra Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikoleta Iakovidou
- Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Theodora Boutsikou
- Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Zoe Iliodromiti
- Neonatal Department, Aretaieio Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Kanaka-Gantenbein
- First Department of Pediatrics, “Aghia Sophia” Children’s Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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17
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Pradhan J, Mallick S, Mishra N, Tiwari A, Negi VD. Pregnancy, infection, and epigenetic regulation: A complex scenario. Biochim Biophys Acta Mol Basis Dis 2023:166768. [PMID: 37269984 DOI: 10.1016/j.bbadis.2023.166768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 03/23/2023] [Accepted: 04/17/2023] [Indexed: 06/05/2023]
Abstract
A unique immunological condition, pregnancy ensures fetus from maternal rejection, allows adequate fetal development, and protects against microorganisms. Infections during pregnancy may lead to devastating consequences for pregnant women and fetuses, resulting in the mother's death, miscarriage, premature childbirth, or neonate with congenital infection and severe diseases and defects. Epigenetic (heritable changes in gene expression) mechanisms like DNA methylation, chromatin modification, and gene expression modulation during gestation are linked with the number of defects in the fetus and adolescents. The feto-maternal crosstalk for fetal survival during the entire gestational stages are tightly regulated by various cellular pathways, including epigenetic mechanisms that respond to both internal as well outer environmental factors, which can influence the fetal development across the gestational stages. Due to the intense physiological, endocrinological, and immunological changes, pregnant women are more susceptible to bacterial, viral, parasitic, and fungal infections than the general population. Microbial infections with viruses (LCMV, SARS-CoV, MERS-CoV, and SARS-CoV-2) and bacteria (Clostridium perfringens, Coxiella burnetii, Listeria monocytogenes, Salmonella enteritidis) further increase the risk to maternal and fetal life and developmental outcome. If the infections remain untreated, the possibility of maternal and fetal death exists. This article focused on the severity and susceptibility to infections caused by Salmonella, Listeria, LCMV, and SARS-CoV-2 during pregnancy and their impact on maternal health and the fetus. How epigenetic regulation during pregnancy plays a vital role in deciding the fetus's developmental outcome under various conditions, including infection and other stress. A better understanding of the host-pathogen interaction, the characterization of the maternal immune system, and the epigenetic regulations during pregnancy may help protect the mother and fetus from infection-mediated outcomes.
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Affiliation(s)
- Jasmin Pradhan
- Laboratory of Infection Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
| | - Swarupa Mallick
- Laboratory of Infection Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
| | - Neha Mishra
- Laboratory of Infection Immunology, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
| | - Aman Tiwari
- Vidya Devi Negi, Infection Immunology Laboratory (2i-Lab), Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Punjab 140306, India
| | - Vidya Devi Negi
- Vidya Devi Negi, Infection Immunology Laboratory (2i-Lab), Department of Biological Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Punjab 140306, India.
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18
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Alsharairi NA. Exploring the Diet-Gut Microbiota-Epigenetics Crosstalk Relevant to Neonatal Diabetes. Genes (Basel) 2023; 14:genes14051017. [PMID: 37239377 DOI: 10.3390/genes14051017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/24/2023] [Accepted: 04/28/2023] [Indexed: 05/28/2023] Open
Abstract
Neonatal diabetes (NDM) is a rare monogenic disorder that presents as hyperglycemia during the first six months of life. The link between early-life gut microbiota dysbiosis and susceptibility to NDM remains uncertain. Experimental studies have demonstrated that gestational diabetes mellitus (GDM) could develop into meconium/gut microbiota dysbiosis in newborns, and thus, it is thought to be a mediator in the pathogenesis of NDM. Epigenetic modifications have been considered as potential mechanisms by which the gut microbiota and susceptibility genes interact with the neonatal immune system. Several epigenome-wide association studies have revealed that GDM is associated with neonatal cord blood and/or placental DNA methylation alterations. However, the mechanisms linking diet in GDM with gut microbiota alterations, which may in turn induce the expression of genes linked to NDM, are yet to be unraveled. Therefore, the focus of this review is to highlight the impacts of diet, gut microbiota, and epigenetic crosstalk on altered gene expression in NDM.
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Affiliation(s)
- Naser A Alsharairi
- Heart, Mind & Body Research Group, Griffith University, Gold Coast, QLD P.O. Box 4222, Australia
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19
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Lecorguillé M, McAuliffe FM, Twomey PJ, Viljoen K, Mehegan J, Kelleher CC, Suderman M, Phillips CM. Maternal Glycaemic and Insulinemic Status and Newborn DNA Methylation: Findings in Women With Overweight and Obesity. J Clin Endocrinol Metab 2022; 108:85-98. [PMID: 36137169 PMCID: PMC9759168 DOI: 10.1210/clinem/dgac553] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 08/26/2022] [Indexed: 11/07/2022]
Abstract
CONTEXT Maternal dysglycaemia and prepregnancy obesity are associated with adverse offspring outcomes. Epigenetic mechanisms such as DNA methylation (DNAm) could contribute. OBJECTIVE To examine relationships between maternal glycaemia, insulinemic status, and dietary glycemic indices during pregnancy and an antenatal behavioral-lifestyle intervention with newborn DNAm. METHODS We investigated 172 women from a randomized controlled trial of a lifestyle intervention in pregnant women who were overweight or obese. Fasting glucose and insulin concentrations and derived indices of insulin resistance (HOMA-IR), β-cell function (HOMA-%B), and insulin sensitivity were determined at baseline (15) and 28 weeks' gestation. Dietary glycemic load (GL) and index (GI) were calculated from 3-day food diaries. Newborn cord blood DNAm levels of 850K CpG sites were measured using the Illumina Infinium HumanMethylationEPIC array. Associations of each biomarker, dietary index and intervention with DNAm were examined. RESULTS Early pregnancy HOMA-IR and HOMA-%B were associated with lower DNAm at CpG sites cg03158092 and cg05985988, respectively. Early pregnancy insulin sensitivity was associated with higher DNAm at cg04976151. Higher late pregnancy insulin concentrations and GL scores were positively associated with DNAm at CpGs cg12082129 and cg11955198 and changes in maternal GI with lower DNAm at CpG cg03403995 (Bonferroni corrected P < 5.99 × 10-8). These later associations were located at genes previously implicated in growth or regulation of insulin processes. No effects of the intervention on cord blood DNAm were observed. None of our findings were replicated in previous studies. CONCLUSION Among women who were overweight or obese, maternal pregnancy dietary glycemic indices, glucose, and insulin homeostasis were associated with modest changes in their newborn methylome. TRIAL REGISTRATION ISRCTN29316280.
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Affiliation(s)
- Marion Lecorguillé
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland
| | - Fionnuala M McAuliffe
- UCD Perinatal Research Centre, School of Medicine, National Maternity Hospital, University College Dublin, Dublin, Ireland
| | - Patrick J Twomey
- School of Medicine, University College Dublin, Dublin, Republic of Ireland
| | - Karien Viljoen
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland
| | - John Mehegan
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland
| | - Cecily C Kelleher
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland
| | - Matthew Suderman
- MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Catherine M Phillips
- School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin 4, Republic of Ireland
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20
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Ibrahim HIM. Epigenetic Regulation of Obesity-Associated Type 2 Diabetes. Medicina (B Aires) 2022; 58:medicina58101366. [PMID: 36295527 PMCID: PMC9607337 DOI: 10.3390/medicina58101366] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Obesity is becoming more widespread, and epidemics of this condition are now considered present in all developed countries, leading to public health concerns. The dramatic increases in obesity, type 2 diabetes mellitus (T2DM), and related vascular difficulties are causing a public health crisis. Thus, it is imperative that these trends are curbed. Understanding the molecular underpinnings of these diseases is crucial to aiding in their detection or even management. Thus, understanding the mechanisms underlying the interactions between environment, lifestyle, and genetics is important for developing effective strategies for the management of obesity. The focus is on finding the vital role of epigenetic changes in the etiology of obesity. Genome and epigenome-wide approaches have revealed associations with T2DM. The epigenome indicates that there is a systematic link between genetic variants and environmental factors that put people at risk of obesity. The present review focuses on the epigenetic mechanism linked with obesity-associated T2DM. Although the utilization of epigenetic treatments has been discussed with reference to certain cancers, several challenges remain to be addressed for T2DM.
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Affiliation(s)
- Hairul Islam Mohamed Ibrahim
- Department of Biological Science, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia;
- Division of Microbiology and Immunology, Pondicherry Centre for Biological Science and Educational Trust, Puducherry 605004, India
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21
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Dias S, Willmer T, Adam S, Pheiffer C. The role of maternal DNA methylation in pregnancies complicated by gestational diabetes. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2022; 3:982665. [PMID: 36992770 PMCID: PMC10012132 DOI: 10.3389/fcdhc.2022.982665] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022]
Abstract
Diabetes in pregnancy is associated with adverse pregnancy outcomes and poses a serious threat to the health of mother and child. Although the pathophysiological mechanisms that underlie the association between maternal diabetes and pregnancy complications have not yet been elucidated, it has been suggested that the frequency and severity of pregnancy complications are linked to the degree of hyperglycemia. Epigenetic mechanisms reflect gene-environment interactions and have emerged as key players in metabolic adaptation to pregnancy and the development of complications. DNA methylation, the best characterized epigenetic mechanism, has been reported to be dysregulated during various pregnancy complications, including pre-eclampsia, hypertension, diabetes, early pregnancy loss and preterm birth. The identification of altered DNA methylation patterns may serve to elucidate the pathophysiological mechanisms that underlie the different types of maternal diabetes during pregnancy. This review aims to provide a summary of existing knowledge on DNA methylation patterns in pregnancies complicated by pregestational type 1 (T1DM) and type 2 diabetes mellitus (T2DM), and gestational diabetes mellitus (GDM). Four databases, CINAHL, Scopus, PubMed and Google Scholar, were searched for studies on DNA methylation profiling in pregnancies complicated with diabetes. A total of 1985 articles were identified, of which 32 met the inclusion criteria and are included in this review. All studies profiled DNA methylation during GDM or impaired glucose tolerance (IGT), while no studies investigated T1DM or T2DM. We highlight the increased methylation of two genes, Hypoxia‐inducible Factor‐3α (HIF3α) and Peroxisome Proliferator-activated Receptor Gamma-coactivator-Alpha (PGC1-α), and the decreased methylation of one gene, Peroxisome Proliferator Activated Receptor Alpha (PPARα), in women with GDM compared to pregnant women with normoglycemia that were consistently methylated across diverse populations with varying pregnancy durations, and using different diagnostic criteria, methodologies and biological sources. These findings support the candidacy of these three differentially methylated genes as biomarkers for GDM. Furthermore, these genes may provide insight into the pathways that are epigenetically influenced during maternal diabetes and which should be prioritized and replicated in longitudinal studies and in larger populations to ensure their clinical applicability. Finally, we discuss the challenges and limitations of DNA methylation analysis, and the need for DNA methylation profiling to be conducted in different types of maternal diabetes in pregnancy.
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Affiliation(s)
- Stephanie Dias
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
| | - Tarryn Willmer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Sumaiya Adam
- Department of Obstetrics and Gynecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- Diabetes Research Center, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa
- Centre for Cardio-Metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Department of Obstetrics and Gynecology, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
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22
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de Souza MLM, Borçoi AR, Dutra BAB, Dos Santos Vieira T, Mendes SO, Nascimento IAA, Quaioto BR, Olinda AS, Cunha ER, Freitas FV, Pinheiro JA, Dos Santos JG, Sorroche BP, Arantes LMRB, Sartório CL, da Silva AMA. Lifestyle and NR3C1 exon 1F gene methylation is associated with changes in glucose levels and insulin resistance. Life Sci 2022; 309:120940. [PMID: 36108769 DOI: 10.1016/j.lfs.2022.120940] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 08/03/2022] [Accepted: 09/05/2022] [Indexed: 10/31/2022]
Abstract
AIMS the present study aimed to investigate how glucose and insulin levels may be associated with changes in NR3C1 gene methylation levels in adults. MAIN METHODS 375 volunteers users of the Brazilian Public Unified Health System (SUS) were recruited to assess socioeconomic status, lifestyle, anthropometric data, blood glucose and serum cortisol levels, insulin resistance, and NR3C1 gene methylation assessment. Factors associated with glucose levels and insulin resistance were investigated using multivariate analysis GLzM at 5 % significance (p < 0.05). KEY FINDINGS our results verified that glucose levels and insulin resistance were directly related to NR3C1 gene methylation and age, while not being overweight and obese and no tobacco consumption were indirectly related to glucose levels and insulin resistance. SIGNIFICANCE habits and lifestyle may influence NR3C1 gene regulation, revealing the complexity of environmental impacts on NR3C1 methylation. Furthermore, associated risk factors must be taken into account in epigenetic studies as they directly interfere with blood glucose levels and insulin resistance.
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Affiliation(s)
| | - Aline Ribeiro Borçoi
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | | | - Tamires Dos Santos Vieira
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | | | | | - Barbara Risse Quaioto
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | - Amanda Sgrancio Olinda
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | - Ester Ribeiro Cunha
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | - Flávia Vitorino Freitas
- Department of Pharmacy and Nutrition, Universidade Federal do Espírito Santo, Alegre, ES, Brazil
| | - Julia Assis Pinheiro
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
| | | | - Bruna Pereira Sorroche
- Molecular Oncology Research Center, Hospital do Câncer de Barretos, Barretos, São Paulo, Brazil
| | | | - Carmem Luíza Sartório
- Biotechnology/Renorbio Postgraduate Program, Universidade Federal do Espírito Santo, Vitória, ES, Brazil
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23
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Ormazabal V, Nair S, Carrión F, Mcintyre HD, Salomon C. The link between gestational diabetes and cardiovascular diseases: potential role of extracellular vesicles. Cardiovasc Diabetol 2022; 21:174. [PMID: 36057662 PMCID: PMC9441052 DOI: 10.1186/s12933-022-01597-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022] Open
Abstract
Extracellular vesicles are critical mediators of cell communication. They encapsulate a variety of molecular cargo such as proteins, lipids, and nucleic acids including miRNAs, lncRNAs, circular RNAs, and mRNAs, and through transfer of these molecular signals can alter the metabolic phenotype in recipient cells. Emerging studies show the important role of extracellular vesicle signaling in the development and progression of cardiovascular diseases and associated risk factors such as type 2 diabetes and obesity. Gestational diabetes mellitus (GDM) is hyperglycemia that develops during pregnancy and increases the future risk of developing obesity, impaired glucose metabolism, and cardiovascular disease in both the mother and infant. Available evidence shows that changes in maternal metabolism and exposure to the hyperglycemic intrauterine environment can reprogram the fetal genome, leaving metabolic imprints that define life-long health and disease susceptibility. Understanding the factors that contribute to the increased susceptibility to metabolic disorders of children born to GDM mothers is critical for implementation of preventive strategies in GDM. In this review, we discuss the current literature on the fetal programming of cardiovascular diseases in GDM and the impact of extracellular vesicle (EV) signaling in epigenetic programming in cardiovascular disease, to determine the potential link between EV signaling in GDM and the development of cardiovascular disease in infants.
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Affiliation(s)
- Valeska Ormazabal
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia.,Faculty of Biological Sciences, Pharmacology Department, University of Concepcion, Concepción, Chile
| | - Soumyalekshmi Nair
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia
| | - Flavio Carrión
- Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile
| | - H David Mcintyre
- Mater Research, Faculty of Medicine, University of Queensland, Mater Health, South Brisbane, Australia
| | - Carlos Salomon
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine + Biomedical Sciences, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia. .,Departamento de Investigación, Postgrado y Educación Continua (DIPEC), Facultad de Ciencias de la Salud, Universidad del Alba, Santiago, Chile.
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24
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Hjort L, Novakovic B, Cvitic S, Saffery R, Damm P, Desoye G. Placental DNA Methylation in pregnancies complicated by maternal diabetes and/or obesity: State of the Art and research gaps. Epigenetics 2022; 17:2188-2208. [PMID: 35950598 DOI: 10.1080/15592294.2022.2111755] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
SUMMARYMaternal diabetes and/or obesity in pregnancy are undoubtedly associated with later disease-risk in the offspring. The placenta, interposed between the mother and the fetus, is a potential mediator of this risk through epigenetic mechanisms, including DNA methylation. In recent years, multiple studies have identified differentially methylated CpG sites in the placental tissue DNA in pregnancies complicated by diabetes and obesity. We reviewed all published original research relevant to this topic and analyzed our findings with the focus of identifying overlaps, contradictions and gaps. Most studies focused on the association of gestational diabetes and/or hyperglycemia in pregnancy and DNA methylation in placental tissue at term. We identified overlaps in results related to specific candidate genes, but also observed a large research gap of pregnancies affected by type 1 diabetes. Other unanswered questions relate to analysis of specific placental cell types and the timing of DNA methylation change in response to diabetes and obesity during pregnancy. Maternal metabolism is altered already in the first trimester involving structural and functional changes in the placenta, but studies into its effects on placental DNA methylation during this period are lacking and urgently needed. Fetal sex is also an important determinant of pregnancy outcome, but only few studies have taken this into account. Collectively, we provide a reference work for researchers working in this large and evolving field. Based on the results of the literature review, we formulate suggestions for future focus of placental DNA methylation studies in pregnancies complicated by diabetes and obesity.
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Affiliation(s)
- Line Hjort
- Dept. of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark.,Novo Nordisk Foundation Center for Basic Metabolic Research, Environmental Epigenetics Group, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Boris Novakovic
- Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.,Dept. of Pediatrics, Melbourne University, Melbourne, VIC, Australia
| | - Silvija Cvitic
- Department of Pediatrics and Adolescent Medicine, Research Unit of Analytical Mass Spectrometry, Cell Biology and Biochemistry of Inborn Errors of Metabolism, Medical University of Graz, Austria
| | - Richard Saffery
- Murdoch Children's Research Institute, Royal Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia.,Dept. of Pediatrics, Melbourne University, Melbourne, VIC, Australia
| | - Peter Damm
- Dept. of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark.,Dept of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Gernot Desoye
- Dept. of Obstetrics, Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark.,Dept. of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
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25
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Sekine T, Tsuchiya K, Uchinuma H, Horiuchi S, Kushima M, Otawa S, Yokomichi H, Miyake K, Akiyama Y, Ooka T, Kojima R, Shinohara R, Yamagata Z, The Yamanashi Adjunct Study of the Japan Environment, Children’s Study Group. Association between maternal gestational diabetes mellitus and high-sensitivity C-reactive protein levels in 8-year-old children: The Yamanashi Adjunct Study of the Japan Environment and Children's Study (JECS). J Diabetes Investig 2022; 13:1444-1447. [PMID: 35348295 PMCID: PMC9340882 DOI: 10.1111/jdi.13796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/19/2022] [Accepted: 03/22/2022] [Indexed: 11/29/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is one of the most common pregnancy-related complications; it is associated with adverse pregnancy outcomes and metabolic disorders in offspring, consistent with the concept of the developmental origins of health and disease. This cohort study of women without diabetes (n = 761), who were part of the Yamanashi Adjunct Study of the Japan Environment and Children's Study, aimed to explore the associations between maternal GDM and their offspring's level of high-sensitivity C-reactive protein (hsCRP), a biomarker of inflammatory and cardiovascular diseases. We analyzed the associations between GDM and the offspring's hsCRP levels using a multiple logistic regression model. A mother with GDM significantly increased the risk for high hsCRP level by 4.07-fold (≥2.0 mg/L) in the child. As such, maternal GDM was significantly associated with increased serum hsCRP levels in 8-year-old children.
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Affiliation(s)
- Tetsuo Sekine
- Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuo CityJapan
| | - Kyoichiro Tsuchiya
- Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuo CityJapan
| | - Hiroyuki Uchinuma
- Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuo CityJapan
| | - Sayaka Horiuchi
- Center for Birth Cohort StudiesUniversity of YamanashiChuo CityJapan
| | - Megumi Kushima
- Center for Birth Cohort StudiesUniversity of YamanashiChuo CityJapan
| | - Sanae Otawa
- Center for Birth Cohort StudiesUniversity of YamanashiChuo CityJapan
| | - Hiroshi Yokomichi
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
| | - Kunio Miyake
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
| | - Yuka Akiyama
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
| | - Tadao Ooka
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
| | - Reiji Kojima
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
| | - Ryoji Shinohara
- Center for Birth Cohort StudiesUniversity of YamanashiChuo CityJapan
| | - Zentaro Yamagata
- Center for Birth Cohort StudiesUniversity of YamanashiChuo CityJapan
- Department of Health SciencesSchool of MedicineUniversity of YamanashiChuo CityJapan
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26
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Ku MS, Pan WC, Huang YT, Hsieh WS, Hsu YH, Chen PC, Liu CY. Associations between prenatal exposure to perfluoroalkyl substances, hypomethylation of MEST imprinted gene and birth outcomes. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 304:119183. [PMID: 35331797 DOI: 10.1016/j.envpol.2022.119183] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 03/15/2022] [Accepted: 03/17/2022] [Indexed: 06/14/2023]
Abstract
Prenatal perfluoroalkyl substance (PFAS) exposure has been linked to adverse birth outcomes, but the underlying mechanism has yet to be elucidated. DNA methylation changes in mesoderm-specific transcript (MEST) imprinted gene may be a mechanism of the prenatal exposure effects of PFASs on fetal growth. The aim was to investigate the prenatal PFASs exposure effects on DNA methylation changes in MEST imprinted gene involved in fetal growth. Among 486 mother-infant pairs from the Taiwan Birth Panel Study, PFASs and DNA methylation levels at 5 CpG sites of MEST promoter region were measured in cord blood. Univariable and multivariable linear regressions were performed to estimate the associations between prenatal PFAS exposure, MEST DNA methylation levels, and child birth outcomes. Mediation analysis was performed to examine the potential pathway of MEST methylation between PFASs and birth outcomes. We found that higher prenatal perfluorooctyl sulfonate (PFOS) exposure was significantly associated with lower methylation levels at 5 CpG sites of MEST promoter region (an adjusted β range: -1.56, -2.22). Significant negative associations were also found between MEST methylation levels and child birth weight. Furthermore, the associations between PFOS and perfluorooctanoic acid (PFOA) exposure and MEST methylation levels were more profound in girls than in boys. The mediated effect of average MEST methylation level between PFOS exposure and birth weight was 18.3 (95% CI = 2.1, 40.2; p = 0.014). The direct effect of PFOS exposure to birth weight independent to average MEST methylation level was -93.2 (95% CI = -170.5, -17.8; p = 0.018). In conclusion, our results suggest that prenatal PFAS exposure, especially PFOS, is associated with lower methylation levels at MEST promoter region, which not only leverages the role of imprinted gene in ensuring the integrity of fetal growth but also provides a potential mechanism for evaluating the prenatal exposure effect.
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Affiliation(s)
- Mei-Sheng Ku
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wen-Chi Pan
- Institute of Environmental and Occupational Health Sciences, National Yang-Ming University, Taipei, Taiwan
| | - Yen-Tsung Huang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Wu-Shiun Hsieh
- Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Yi-Hsiang Hsu
- Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, 02131, USA; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, 02215, USA; Broad Institute of MIT and Harvard, Boston, MA, 02142, USA
| | - Pau-Chung Chen
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan
| | - Chen-Yu Liu
- Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.
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27
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Louise J, Deussen AR, Koletzko B, Owens J, Saffery R, Dodd JM. Effect of an antenatal diet and lifestyle intervention and maternal BMI on cord blood DNA methylation in infants of overweight and obese women: The LIMIT Randomised Controlled Trial. PLoS One 2022; 17:e0269723. [PMID: 35749371 PMCID: PMC9231808 DOI: 10.1371/journal.pone.0269723] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 05/23/2022] [Indexed: 11/18/2022] Open
Abstract
Background
To investigate the effect of an antenatal diet and lifestyle intervention, and maternal pre-pregnancy overweight or obesity, on infant cord blood DNA methylation.
Methods
We measured DNA methylation in 645 cord blood samples from participants in the LIMIT study (an antenatal diet and lifestyle intervention for women with early pregnancy BMI ≥25.0 kg/m2) using the Illumina 450K BeadChip array, and tested for any differential methylation related to the intervention, and to maternal early pregnancy BMI. We also analysed differential methylation in relation to selected candidate genes.
Results
No CpG sites were significantly differentially methylated in relation to either the diet and lifestyle intervention, or with maternal early pregnancy BMI. There was no significant differential methylation in any of the selected genes related to the intervention, or to maternal BMI.
Conclusion
We found no evidence of an effect of either antenatal diet and lifestyle, or of maternal early pregnancy BMI, on cord blood DNA methylation.
Clinical trials registration
ACTRN12607000161426
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Affiliation(s)
- Jennie Louise
- Discipline of Obstetrics & Gynaecology and The Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- * E-mail:
| | - Andrea R. Deussen
- Discipline of Obstetrics & Gynaecology and The Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
| | - Berthold Koletzko
- Division of Metabolic and Nutritional Medicine, Dept. Paediatrics, Dr. von Hauner Children’s Hospital, LMU—Ludwig-Maximilian-Universität, Munich, Germany
| | - Julie Owens
- Deputy Vice-Chancellor’s Research Office, Deakin University, Geelong, Australia
| | - Richard Saffery
- Epigenetics Group, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Jodie M. Dodd
- Discipline of Obstetrics & Gynaecology and The Robinson Research Institute, The University of Adelaide, Adelaide, South Australia, Australia
- Department of Perinatal Medicine, Women’s and Babies Division, The Women’s and Children’s Hospital, Adelaide, South Australia, Australia
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28
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Wang WJ, Huang R, Zheng T, Du Q, Yang MN, Xu YJ, Liu X, Tao MY, He H, Fang F, Li F, Fan JG, Zhang J, Briollais L, Ouyang F, Luo ZC. Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood. Front Endocrinol (Lausanne) 2022; 13:875180. [PMID: 35721735 PMCID: PMC9204344 DOI: 10.3389/fendo.2022.875180] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/21/2022] [Indexed: 12/03/2022] Open
Abstract
Gestational diabetes mellitus (GDM) "program" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.
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Affiliation(s)
- Wen-Juan Wang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Clinical Skills Center, School of Clinical Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Rong Huang
- Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Tao Zheng
- Department of Obstetrics and Gynecology, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Qinwen Du
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Department of Obstetrics and Gynecology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meng-Nan Yang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Ya-Jie Xu
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Xin Liu
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Min-Yi Tao
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Hua He
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Fang Fang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Fei Li
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Laurent Briollais
- Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Fengxiu Ouyang
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
| | - Zhong-Cheng Luo
- Ministry of Education-Shanghai Key Laboratory of Children’s Environmental Health, Early Life Health Institute, and Department of Pediatrics, Xinhua Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China
- Lunenfeld-Tanenbaum Research Institute, Prosserman Centre for Population Health Research, Department of Obstetrics and Gynecology, Mount Sinai Hospital, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
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29
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Lu S, Wang J, Kakongoma N, Hua W, Xu J, Wang Y, He S, Gu H, Shi J, Hu W. DNA methylation and expression profiles of placenta and umbilical cord blood reveal the characteristics of gestational diabetes mellitus patients and offspring. Clin Epigenetics 2022; 14:69. [PMID: 35606885 PMCID: PMC9126248 DOI: 10.1186/s13148-022-01289-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/13/2022] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is a common pregnancy-specific disease and is growing at an alarming rate worldwide, which can negatively affect the health of pregnant women and fetuses. However, most studies are limited to one tissue, placenta or umbilical cord blood, usually with one omics assay. It is thus difficult to systematically reveal the molecular mechanism of GDM and the key influencing factors on pregnant women and offspring. RESULTS We recruited a group of 21 pregnant women with GDM and 20 controls without GDM. For each pregnant woman, reduced representation bisulfite sequencing and RNA-seq were performed using the placenta and paired neonatal umbilical cord blood specimens. Differentially methylated regions (DMRs) and differentially expressed genes (DEGs) were identified with body mass index as a covariate. Through the comparison of GDM and control samples, 2779 and 141 DMRs, 1442 and 488 DEGs were identified from placenta and umbilical cord blood, respectively. Functional enrichment analysis showed that the placenta methylation and expression profiles of GDM women mirrored the molecular characteristics of "type II diabetes" and "insulin resistance." Methylation-altered genes in umbilical cord blood were associated with pathways "type II diabetes" and "cholesterol metabolism." Remarkably, both DMRs and DEGs illustrated significant overlaps among placenta and umbilical cord blood samples. The overlapping DMRs were associated with "cholesterol metabolism." The top-ranking pathways enriched in the shared DEGs include "growth hormone synthesis, secretion and action" and "type II diabetes mellitus." CONCLUSIONS Our research demonstrated the epigenetic and transcriptomic alternations of GDM women and offspring. Our findings emphasized the importance of epigenetic modifications in the communication between pregnant women with GDM and offspring, and provided a reference for the prevention, control, treatment, and intervention of perinatal deleterious events of GDM and neonatal complications.
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Affiliation(s)
- Sha Lu
- Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang, People's Republic of China
- The Affiliated Hangzhou Women's Hospital of Hangzhou Normal University, Hangzhou, Zhejiang, People's Republic of China
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Jiahao Wang
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Nisile Kakongoma
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Wen Hua
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Jiahui Xu
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China
| | - Yunfei Wang
- Hangzhou ShengTing Biotech Co. Ltd, Hangzhou, Zhejiang, People's Republic of China
| | - Shutao He
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Hongcang Gu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, People's Republic of China
| | - Jiantao Shi
- State Key Laboratory of Molecular Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Wensheng Hu
- Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, Zhejiang, People's Republic of China.
- Zhejiang Chinese Medical University, Hangzhou, Zhejiang, People's Republic of China.
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Kallak TK, Fransson E, Bränn E, Berglund H, Lager S, Comasco E, Lyle R, Skalkidou A. Maternal prenatal depressive symptoms and toddler behavior: an umbilical cord blood epigenome-wide association study. Transl Psychiatry 2022; 12:186. [PMID: 35513368 PMCID: PMC9072531 DOI: 10.1038/s41398-022-01954-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 04/20/2022] [Accepted: 04/21/2022] [Indexed: 11/09/2022] Open
Abstract
Children of mothers with prenatal depressive symptoms (PND) have a higher risk of behavioral problems; fetal programming through DNA methylation is a possible underlying mechanism. This study investigated DNA methylation in cord blood to identify possible "at birth" signatures that may indicate susceptibility to behavioral problems at 18 months of age. Cord blood was collected from 256 children of mothers who had self-reported on symptoms of depression during pregnancy and the behavior of their child at 18 months of age. Whole genome DNA methylation was assessed using Illumina MethylationEPIC assay. The mother and child pairs were categorized into four groups, based on both self-reported depressive symptoms, PND or Healthy control (HC), and scores from the Child Behavior checklist (high or low for internalizing, externalizing, and total scores). Adjustments were made for batch effects, cell-type, and clinical covariates. Differentially methylated sites were identified using Kruskal-Wallis test, and Benjamini-Hochberg adjusted p values < 0.05 were considered significant. The analysis was also stratified by sex of the child. Among boys, we observed higher and correlated DNA methylation of one CpG-site in the promoter region of TPP1 in the HC group, with high externalizing scores compared to HC with low externalizing scores. Boys in the PND group showed lower DNA methylation in NUDT15 among those with high, compared to low, internalizing scores; the DNA methylation levels of CpGs in this gene were positively correlated with the CBCL scores. Hence, the differentially methylated CpG sites could be of interest for resilience, regardless of maternal mental health during pregnancy. The findings are in a relatively healthy study cohort, thus limiting the possibility of detecting strong effects associated with behavioral difficulties. This is the first investigation of cord blood DNA methylation signs of fetal programming of PND on child behavior at 18 months of age and thus calls for independent replications.
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Affiliation(s)
| | - Emma Fransson
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Emma Bränn
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Hanna Berglund
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Susanne Lager
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
| | - Erika Comasco
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Robert Lyle
- Department of Medical Genetics and Norwegian Sequencing Centre (NSC), Oslo University Hospital, Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Alkistis Skalkidou
- grid.8993.b0000 0004 1936 9457Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
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31
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Sasaki A, Murphy KE, Briollais L, McGowan PO, Matthews SG. DNA methylation profiles in the blood of newborn term infants born to mothers with obesity. PLoS One 2022; 17:e0267946. [PMID: 35500004 PMCID: PMC9060365 DOI: 10.1371/journal.pone.0267946] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/19/2022] [Indexed: 01/03/2023] Open
Abstract
Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5-24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context of childhood obesity. These preliminary findings are consistent with Developmental Origins of Health and Disease paradigm, which posits that adverse prenatal exposures set developmental health trajectories.
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Affiliation(s)
- Aya Sasaki
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Kellie E. Murphy
- Department of Obstetrics & Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Laurent Briollais
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Patrick O. McGowan
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
- Departments of Biological Sciences and Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Stephen G. Matthews
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Obstetrics & Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
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32
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Dessì A, Tognazzi C, Bosco A, Pintus R, Fanos V. Metabolomic profiles and microbiota of GDM offspring: The key for future perspective? Front Pediatr 2022; 10:941800. [PMID: 36275053 PMCID: PMC9579340 DOI: 10.3389/fped.2022.941800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Gestational diabetes mellitus (GDM), or any degree of glucose intolerance recognized for the first time during pregnancy, is one of the diseases that most frequently aggravates the course of gestation. Missed or late diagnosis and inadequate treatment are associated with high maternal and fetal morbidity, with possible short- and long-term repercussions. Estimates on the prevalence of GDM are alarming and increasing by about 30% in the last 10-20 years. In addition, there is the negative influence of the SARS-CoV-2 emergency on the glycemic control of pregnant women, making the matter increasingly topical. To date, knowledge on the metabolic maturation of newborns is still incomplete. However, in light of the considerable progress of the theory of "developmental origins of health and disease," the relevant role of the intrauterine environment cannot be overlooked. In fact, due to the high plasticity of the early stages of development, some detrimental metabolic alterations during fetal growth, including maternal hyperglycemia, are associated with a higher incidence of chronic diseases in adult life. In this context, metabolomic analysis which allows to obtain a detailed phenotypic portrait through the dynamic detection of all metabolites in cells, tissues and different biological fluids could be very useful for the early diagnosis and prevention of complications. Indeed, if the diagnostic timing is optimized through the identification of specific metabolites, the detailed understanding of the altered metabolic pathway could also allow better management and more careful monitoring, also from a nutritional profile, of the more fragile children. In this context, a further contribution derives from the analysis of the intestinal microbiota, the main responsible for the fecal metabolome, given its alteration in pregnancies complicated by GDM and the possibility of transmission to offspring. The purpose of this review is to analyze the available data regarding the alterations in the metabolomic profile and microbiota of the offspring of mothers with GDM in order to highlight future prospects for reducing GDM-related complications in children of mothers affected by this disorder.
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Affiliation(s)
- Angelica Dessì
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Chiara Tognazzi
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Alice Bosco
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Roberta Pintus
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
| | - Vassilios Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, Azienda Ospedaliera Universitaria (AOU) Cagliari, University of Cagliari, Cagliari, Italy
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33
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Shashikadze B, Flenkenthaler F, Stöckl JB, Valla L, Renner S, Kemter E, Wolf E, Fröhlich T. Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches. Genes (Basel) 2021; 12:1991. [PMID: 34946940 PMCID: PMC8701487 DOI: 10.3390/genes12121991] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 12/06/2021] [Accepted: 12/10/2021] [Indexed: 12/27/2022] Open
Abstract
Worldwide, gestational diabetes affects 2-25% of pregnancies. Due to related disturbances of the maternal metabolism during the periconceptional period and pregnancy, children bear an increased risk for future diseases. It is well known that an aberrant intrauterine environment caused by elevated maternal glucose levels is related to elevated risks for increased birth weights and metabolic disorders in later life, such as obesity or type 2 diabetes. The complexity of disturbances induced by maternal diabetes, with multiple underlying mechanisms, makes early diagnosis or prevention a challenging task. Omics technologies allowing holistic quantification of several classes of molecules from biological fluids, cells, or tissues are powerful tools to systematically investigate the effects of maternal diabetes on the offspring in an unbiased manner. Differentially abundant molecules or distinct molecular profiles may serve as diagnostic biomarkers, which may also support the development of preventive and therapeutic strategies. In this review, we summarize key findings from state-of-the-art Omics studies addressing the impact of maternal diabetes on offspring health.
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Affiliation(s)
- Bachuki Shashikadze
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Florian Flenkenthaler
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Jan B. Stöckl
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
| | - Libera Valla
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
| | - Simone Renner
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Elisabeth Kemter
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Eckhard Wolf
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
- Chair for Molecular Animal Breeding and Biotechnology, Gene Center and Department of Veterinary Sciences, LMU Munich, 81377 Munich, Germany; (L.V.); (S.R.); (E.K.)
- Center for Innovative Medical Models (CiMM), LMU Munich, 85764 Oberschleißheim, Germany
- German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany
| | - Thomas Fröhlich
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, LMU Munich, 81377 Munich, Germany; (B.S.); (F.F.); (J.B.S.)
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34
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Juvinao-Quintero DL, Cardenas A, Perron P, Bouchard L, Lutz SM, Hivert MF. Associations between an integrated component of maternal glycemic regulation in pregnancy and cord blood DNA methylation. Epigenomics 2021; 13:1459-1472. [PMID: 34596421 DOI: 10.2217/epi-2021-0220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background: Previous studies suggest that fetal programming to hyperglycemia in pregnancy is due to modulation of DNA methylation (DNAm), but they have been limited in their maternal glycemic characterization. Methods: In the Gen3G study, we used a principal component analysis to integrate multiple glucose and insulin values measured during the second trimester oral glucose tolerance test. We investigated associations between principal components and cord blood DNAm levels in an epigenome-wide analysis among 430 mother-child pairs. Results: The first principal component was robustly associated with lower DNAm at cg26974062 (TXNIP; p = 9.9 × 10-9) in cord blood. TXNIP is a well-known DNAm marker for type 2 diabetes in adults. Conclusion: We hypothesize that abnormal glucose metabolism in pregnancy may program dysregulation of TXNIP across the life course.
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Affiliation(s)
- Diana L Juvinao-Quintero
- Division of Chronic Disease Research Across the Life Course, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Andres Cardenas
- Division of Environmental Health Sciences, School of Public Health & Center for Computational Biology, University of California, Berkeley, CA 94720-7360, USA
| | - Patrice Perron
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.,Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada
| | - Luigi Bouchard
- Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.,Department of Medical Biology, Centre Intégré Universitaire en Santé et Services Sociaux Saguenay-Lac-Saint-Jean, Hôpital Universitaire de Chicoutimi, Saguenay, QC, G7H 5H6, Canada.,Department of Biochemistry & Functional Genomics, Université de Sherbrooke, Sherbrooke, QC, J1K 2R1, Canada
| | - Sharon M Lutz
- Division of Chronic Disease Research Across the Life Course, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA 02215, USA.,Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA 02215, USA
| | - Marie-France Hivert
- Division of Chronic Disease Research Across the Life Course, Department of Population Medicine, Harvard Pilgrim Health Care Institute, Harvard Medical School, Boston, MA 02215, USA.,Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.,Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA
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35
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Grilo LF, Tocantins C, Diniz MS, Gomes RM, Oliveira PJ, Matafome P, Pereira SP. Metabolic Disease Programming: From Mitochondria to Epigenetics, Glucocorticoid Signalling and Beyond. Eur J Clin Invest 2021; 51:e13625. [PMID: 34060076 DOI: 10.1111/eci.13625] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 12/11/2022]
Abstract
Embryonic and foetal development are critical periods of development in which several environmental cues determine health and disease in adulthood. Maternal conditions and an unfavourable intrauterine environment impact foetal development and may programme the offspring for increased predisposition to metabolic diseases and other chronic pathologic conditions throughout adult life. Previously, non-communicable chronic diseases were only associated with genetics and lifestyle. Now the origins of non-communicable chronic diseases are associated with early-life adaptations that produce long-term dysfunction. Early-life environment sets the long-term health and disease risk and can span through multiple generations. Recent research in developmental programming aims at identifying the molecular mechanisms responsible for developmental programming outcomes that impact cellular physiology and trigger adulthood disease. The identification of new therapeutic targets can improve offspring's health management and prevent or overcome adverse consequences of foetal programming. This review summarizes recent biomedical discoveries in the Developmental Origins of Health and Disease (DOHaD) hypothesis and highlight possible developmental programming mechanisms, including prenatal structural defects, metabolic (mitochondrial dysfunction, oxidative stress, protein modification), epigenetic and glucocorticoid signalling-related mechanisms suggesting molecular clues for the causes and consequences of programming of increased susceptibility of offspring to metabolic disease after birth. Identifying mechanisms involved in DOHaD can contribute to early interventions in pregnancy or early childhood, to re-set the metabolic homeostasis and break the chain of subsequent events that could lead to the development of disease.
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Affiliation(s)
- Luís F Grilo
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,PhD Programme in Experimental Biology and Biomedicine (PDBEB), Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Coimbra, Portugal
| | - Carolina Tocantins
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Mariana S Diniz
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Rodrigo Mello Gomes
- Department of Physiological Sciences, Biological Sciences Institute, Federal University of Goiás, Goiânia, Brazil
| | - Paulo J Oliveira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal
| | - Paulo Matafome
- Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.,Coimbra Institute for Clinical and Biomedical Research (iCBR) and Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.,Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.,Department of Complementary Sciences, Instituto Politécnico de Coimbra, Coimbra Health School (ESTeSC), Coimbra, Portugal
| | - Susana P Pereira
- CNC - Center for Neuroscience and Cell Biology, CIBB - Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal.,Laboratory of Metabolism and Exercise (LametEx), Research Centre in Physical Activity, Health and Leisure (CIAFEL), Laboratory for Integrative and Translational Research in Population Health (ITR), Faculty of Sport, University of Porto, Porto, Portugal
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36
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Popova PV, Pustozerov EA, Tkachuk AS, Grineva EN. Improving nutrition for the prevention of gestational diabetes: Current status and perspectives. World J Diabetes 2021; 12:1494-1506. [PMID: 34630902 PMCID: PMC8472503 DOI: 10.4239/wjd.v12.i9.1494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/20/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
Gestational diabetes mellitus (GDM) is a common complication of pregnancy and a serious public health problem. It carries significant risks of short-term and long-term adverse health effects for both mothers and their children. Risk factors, especially modifiable risk factors, must be considered to prevent GDM and its consequences. Observational studies have identified several nutritional and lifestyle factors associated with the risk of GDM. The results of intervention studies examining the effects of diet and lifestyle on the prevention of GDM are contradictory. Differences in the study populations, types and intensity of intervention, time frame of the intervention, and diagnostic criteria for GDM may explain the heterogeneity in the results of intervention studies. This review provides an overview of new diets and other factors that may help prevent GDM. The main results of epidemiological studies assessing the risk factors for GDM, as well as the results and methodological problems of intervention studies on the prevention of GDM and their meta-analyses, are discussed. In addition, the evidence that gene and lifestyle interactions influence the development of GDM, as well as prospects for increasing the effectiveness of interventions designed to prevent GDM, including new data on the possible uses of personalized diet therapy, are highlighted.
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Affiliation(s)
- Polina V Popova
- Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg 194156, Russia
- Department of Faculty Therapy, Saint Petersburg Pavlov State Medical University, Saint Petersburg 197022, Russia
| | - Evgenii A Pustozerov
- Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg 194156, Russia
- Department of Biomedical Engineering, Saint Petersburg State Electrotechnical University, Saint Petersburg 197341, Russia
| | - Aleksandra S Tkachuk
- Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg 194156, Russia
| | - Elena N Grineva
- Institute of Endocrinology, Almazov National Medical Research Centre, Saint Petersburg 194156, Russia
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37
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Copur S, Rossing P, Afsar B, Sag AA, Siriopol D, Kuwabara M, Ortiz A, Kanbay M. A primer on metabolic memory: why existing diabesity treatments fail. Clin Kidney J 2021; 14:756-767. [PMID: 34512957 PMCID: PMC8422888 DOI: 10.1093/ckj/sfaa143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Indexed: 11/28/2022] Open
Abstract
Despite massive government and private sector investments into prevention of cardiovascular disease, diabetes mellitus and obesity, efforts have largely failed, and the burden of cost remains in the treatment of downstream morbidity and mortality, with overall stagnating outcomes. A new paradigm shift in the approach to these patients may explain why existing treatment strategies fail, and offer new treatment targets. This review aims to provide a clinician-centred primer on metabolic memory, defined as the sum of irreversible genetic, epigenetic, cellular and tissue-level alterations that occur with long-time exposure to metabolic derangements.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Baris Afsar
- Department of Internal Medicine, Division of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alan A Sag
- Department of Radiology, Division of Vascular and Interventional Radiology, Duke University Medical Center, Durham, NC, USA
| | - Dimitrie Siriopol
- Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, 'Grigore T. Popa' University of Medicine, Iasi, Romania
| | | | - Alberto Ortiz
- School of Medicine, Dialysis Unit, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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38
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Canouil M, Khamis A, Keikkala E, Hummel S, Lobbens S, Bonnefond A, Delahaye F, Tzala E, Mustaniemi S, Vääräsmäki M, Jarvelin MR, Sebert S, Kajantie E, Froguel P, Andrew T. Epigenome-Wide Association Study Reveals Methylation Loci Associated With Offspring Gestational Diabetes Mellitus Exposure and Maternal Methylome. Diabetes Care 2021; 44:1992-1999. [PMID: 34116986 PMCID: PMC8740918 DOI: 10.2337/dc20-2960] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 04/26/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Gestational diabetes mellitus (GDM) is associated with an increased risk of obesity and insulin resistance in offspring later in life, which might be explained by epigenetic changes in response to maternal hyperglycemic exposure. RESEARCH DESIGN AND METHODS We explored the association between GDM exposure and maternal blood and newborn cord blood methylation in 536 mother-offspring pairs from the prospective FinnGeDi cohort using Illumina MethylationEPIC 850K BeadChip arrays. We assessed two hypotheses. First, we tested for shared maternal and offspring epigenetic effects resulting from GDM exposure. Second, we tested whether GDM exposure and maternal methylation had an epigenetic effect on the offspring. RESULTS We did not find any epigenetic marks (differentially methylated CpG probes) with shared and consistent effects between mothers and offspring. After including maternal methylation in the model, we identified a single significant (false discovery rate 1.38 × 10-2) CpG at the cg22790973 probe (TFCP2) associated with GDM. We identified seven additional FDR-significant interactions of maternal methylation and GDM status, with the strongest association at the same cg22790973 probe (TFCP2), as well as cg03456133, cg24440941 (H3C6), cg20002843 (LOC127841), cg19107264, and cg11493553 located within the UBE3C gene and cg17065901 in FAM13A, both susceptibility genes for type 2 diabetes and BMI, and cg23355087 within the DLGAP2 gene, known to be involved in insulin resistance during pregnancy. CONCLUSIONS Our study reveals the potential complexity of the epigenetic transmission between mothers with GDM and their offspring, likely determined by not only GDM exposure but also other factors indicated by maternal epigenetic status, such as maternal metabolic history.
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Affiliation(s)
- Mickaël Canouil
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
| | - Amna Khamis
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
| | - Elina Keikkala
- Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO), Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Sandra Hummel
- Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany
- Forschergruppe Diabetes, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
- Forschergruppe Diabetes e.V., Munich-Neuherberg, Germany
| | - Stephane Lobbens
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
| | - Amélie Bonnefond
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
| | - Fabien Delahaye
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
| | - Evangelia Tzala
- Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, U.K
| | - Sanna Mustaniemi
- Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO), Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Marja Vääräsmäki
- Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO), Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
| | - Marjo-Riitta Jarvelin
- Department of Epidemiology and Biostatistics, Medical Research Council-Public Health England Centre for Environment and Health, School of Public Health, Imperial College London, London, U.K
- Center for Lifecourse Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
- Unit of Primary Health Care, Oulu University Hospital, Oulu, Finland
- Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, U.K
| | - Sylvain Sebert
- Center for Lifecourse Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland
| | - Eero Kajantie
- Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology and Ophthalmology (PEDEGO), Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
- Population Health Unit, Finnish Institute for Health and Welfare, Helsinki, Finland
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Children's Hospital, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Philippe Froguel
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
| | - Toby Andrew
- Inserm U1283, CNRS UMR 8199, European Genomic Institute for Diabetes, Institut Pasteur de Lille, Lille, France
- Lille University Hospital, University of Lille, Lille, France
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K
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Joyce BT, Liu H, Wang L, Wang J, Zheng Y, Nannini D, Drong A, Shiau S, Li W, Leng J, Shen Y, Gao R, Baccarelli A, Hu G, Hou L. Novel epigenetic link between gestational diabetes mellitus and macrosomia. Epigenomics 2021; 13:1221-1230. [PMID: 34337972 DOI: 10.2217/epi-2021-0096] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Background & objectives: Examine maternal gestational diabetes mellitus (GDM), macrosomia and DNA methylation in candidate genes IGF1, IGF2, H19, ARHGRF11, MEST, NR3C1, ADIPOQ and RETN. Materials & methods: A total of 1145 children (572 GDM cases and 573 controls) from the Tianjin GDM study, including 177 with macrosomia, had blood DNA collection at median age 5.9 (range: 3.1-10.0). We used logistic regression to screen for associations with GDM and model macrosomia on 37 CpGs, and performed mediation analysis. Results: One CpG was associated with macrosomia at false discovery rate (FDR) <0.05 (cg14428359 in MEST); two (cg19466922 in MEST and cg26263166 in IGF2) were associated at p < 0.05 but mediated 26 and 13%, respectively. Conclusion: MEST and IGF2 were previously identified for potential involvement in fetal growth and development (Trial Registration number: NCT01554358 [ClinicalTrials.gov]).
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Affiliation(s)
- Brian T Joyce
- Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Huikun Liu
- Tianjin Women's & Children's Health Center, Tianjin, China
| | - Leishen Wang
- Tianjin Women's & Children's Health Center, Tianjin, China
| | - Jun Wang
- Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Yinan Zheng
- Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Drew Nannini
- Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Alex Drong
- Big Data Institute, University of Oxford, Oxford, UK.,Department of Environmental Health Science, Mailman School of Public Health, Columbia University, NY, 10032, USA
| | - Stephanie Shiau
- Department of Biostatistics & Epidemiology, Rutgers School of Public Health, Piscataway, NJ, 08854, USA
| | - Weiqin Li
- Tianjin Women's & Children's Health Center, Tianjin, China
| | - Junhong Leng
- Tianjin Women's & Children's Health Center, Tianjin, China
| | - Yun Shen
- Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA.,Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Six People's Hospital, Shanghai, China
| | - Ru Gao
- Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA
| | - Andrea Baccarelli
- Department of Environmental Health Science, Mailman School of Public Health, Columbia University, NY, 10032, USA
| | - Gang Hu
- Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA
| | - Lifang Hou
- Center for Global Oncology, Institute for Global Health, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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He J, Liu K, Hou X, Lu J. Comprehensive analysis of DNA methylation and gene expression profiles in gestational diabetes mellitus. Medicine (Baltimore) 2021; 100:e26497. [PMID: 34190178 PMCID: PMC8257864 DOI: 10.1097/md.0000000000026497] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/26/2021] [Accepted: 05/30/2021] [Indexed: 01/04/2023] Open
Abstract
ABSTRACT Gestational diabetes mellitus (GDM) has a high prevalence during pregnancy. This research aims to identify genes and their pathways related to GDM by combining bioinformatics analysis.The DNA methylation and gene expression profiles data set was obtained from Gene Expression Omnibus. Differentially expressed genes (DEG) and differentially methylated genes (DMG) were screened by R package limma. The methylation-regulated differentially expressed genes (MeDEGs) were obtained by overlapping the DEGs and DMGs. A protein-protein interaction network was constructed using the search tool for searching interacting genes. The results are visualized in Cytoscape. Disease-related miRNAs and pathways were retrieved from Human MicroRNA Disease Database and Comparative Toxic Genome Database. Real-time quantitative PCR further verified the expression changes of these genes in GDM tissues and normal tissues.After overlapping DEGs and DMGs, 138 MeDEGs were identified. These genes were mainly enriched in the biological processes of the "immune response," "defense response," and "response to wounding." Pathway enrichment shows that these genes are involved in "Antigen processing and presentation," "Graft-versus-host disease," "Type I diabetes mellitus," and "Allograft rejection." Six mRNAs (including superoxide dismutase 2 (SOD2), mitogen-activated protein kinase kinase kinase kinase 3 (MAP4K3), dual specificity phosphatase 5 (DUSP5), p21-activated kinases 2 (PAK2), serine protease inhibitor clade E member 1 (SERPINE1), and protein phosphatase 1 regulatory subunit 15B (PPP1R15B)) were identified as being related to GDM. The results obtained by real-time quantitative PCR are consistent with the results of the microarray analysis.This study identified new types of MeDEGs and discovered their related pathways and functions in GDM, which may be used as molecular targets and diagnostic biomarkers for the precise diagnosis and treatment of GDM.
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Affiliation(s)
- Jing He
- Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi
| | - Kang Liu
- Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Shanxi Medical University, Taiyuan, Shanxi
| | - Xiaohong Hou
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital of Wenzhou Medical University, Zhejiang, P. R. China
| | - Jieqiang Lu
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital of Wenzhou Medical University, Zhejiang, P. R. China
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41
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Retnakaran R. Diabetes in pregnancy 100 years after the discovery of insulin: Hot topics and open questions to be addressed in the coming years. Metabolism 2021; 119:154772. [PMID: 33838145 DOI: 10.1016/j.metabol.2021.154772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 03/26/2021] [Accepted: 04/04/2021] [Indexed: 12/15/2022]
Abstract
By making it possible for women with diabetes to achieve their family planning goals, the discovery of insulin ushered in the field of diabetes in pregnancy. The ensuing century has witnessed tremendous advances, with clinical focus on preconception planning and maternal glycemic control making successful pregnancy an achievable goal. Currently, the global epidemic of overweight/obesity has led to maternal hyperglycemia now affecting one in every six pregnancies worldwide, prompting intense research interest. Topics of particular interest include (i) the optimal approach to diagnosing gestational diabetes mellitus (GDM); (ii) the emergence of GDM as a chronic metabolic disorder identifying future risk of non-communicable disease; (iii) the transgenerational impact of maternal glycemia as per the Developmental Origins of Health and Disease; and (iv) the application of new technology for optimizing clinical management. These topics have raised exciting questions such as (i) whether the treatment of diabetes in pregnancy can impact growth/development in childhood, (ii) whether GDM can be prevented, and (iii) whether the diagnosis of GDM could facilitate the prevention of type 2 diabetes and cardiovascular disease. Indeed, this field may be on the precipice of a golden era of new concepts and evidence to optimize the health of mother and child.
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Affiliation(s)
- Ravi Retnakaran
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada; Division of Endocrinology, University of Toronto, Toronto, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
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Chen C, Jiang Y, Yan T, Chen Y, Yang M, Lv M, Xi F, Lu J, Zhao B, Luo Q. Placental maternally expressed gene 3 differentially methylated region methylation profile is associated with maternal glucose concentration and newborn birthweight. J Diabetes Investig 2021; 12:1074-1082. [PMID: 33090678 PMCID: PMC8169366 DOI: 10.1111/jdi.13432] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 09/14/2020] [Accepted: 10/05/2020] [Indexed: 12/17/2022] Open
Abstract
AIMS/INTRODUCTION Emerging evidence shows that epigenetic modifications occurring during fetal development in response to intrauterine exposures could be one of the mechanisms involved in the early determinants of adult metabolic disorders. This study aimed to investigate whether the placental maternally expressed gene 3 (MEG3) deoxyribonucleic acid (DNA) methylation profile is associated with maternal gestational diabetes mellitus status and newborn birthweight. MATERIALS AND METHODS Samples for measurement were collected from 23 women with gestational diabetes mellitus and 23 healthy controls. MEG3 gene expression and DNA methylation levels were assessed using quantitative real-time polymerase chain reaction and MethylTargetTM, respectively. Pearson correlation analyses were used to examine associations between placental DNA methylation levels and clinical variables of interest. The associated results were adjusted by multivariate linear regression for maternal age, body mass index, height, gestational age and newborn sex as confounders. RESULTS We found that the DNA methylation levels in the MEG3 differentially methylated region were significantly different between the gestational diabetes mellitus and control groups on the maternal side of the placenta (40.64 ± 2.15 vs 38.33 ± 2.92; P = 0.004). Furthermore, the mean MEG3 DNA methylation levels were correlated positively with maternal fasting glucose concentrations (R = 0.603, P < 0.001) and newborn birthweight (R = 0.568, P < 0.001). CONCLUSIONS The placental DNA methylation status in the MEG3 differentially methylated region was correlated with maternal glucose concentrations and newborn birthweight. These epigenetic adaptations might contribute to late-onset obesity, underlining the adverse intrauterine environment.
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Affiliation(s)
- Cheng Chen
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Ying Jiang
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Ting Yan
- Jinhua Municipal Central HospitalJinhuaChina
| | - Yuan Chen
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Mengmeng Yang
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Min Lv
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Fangfang Xi
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Juefei Lu
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Baihui Zhao
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
| | - Qiong Luo
- Department of ObstetricsWomen’s HospitalZhejiang University School of MedicineHangzhouChina
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43
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Lizárraga D, García-Gasca A. The Placenta as a Target of Epigenetic Alterations in Women with Gestational Diabetes Mellitus and Potential Implications for the Offspring. EPIGENOMES 2021; 5:epigenomes5020013. [PMID: 34968300 PMCID: PMC8594713 DOI: 10.3390/epigenomes5020013] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a pregnancy complication first detected in the second or third trimester in women that did not show evident glucose intolerance or diabetes before gestation. In 2019, the International Diabetes Federation reported that 15.8% of live births were affected by hyperglycemia during pregnancy, of which 83.6% were due to gestational diabetes mellitus, 8.5% were due to diabetes first detected in pregnancy, and 7.9% were due to diabetes detected before pregnancy. GDM increases the susceptibility to developing chronic diseases for both the mother and the baby later in life. Under GDM conditions, the intrauterine environment becomes hyperglycemic, while also showing high concentrations of fatty acids and proinflammatory cytokines, producing morphological, structural, and molecular modifications in the placenta, affecting its function; these alterations may predispose the baby to disease in adult life. Molecular alterations include epigenetic mechanisms such as DNA and RNA methylation, chromatin remodeling, histone modifications, and expression of noncoding RNAs (ncRNAs). The placenta is a unique organ that originates only in pregnancy, and its main function is communication between the mother and the fetus, ensuring healthy development. Thus, this review provides up-to-date information regarding two of the best-documented (epigenetic) mechanisms (DNA methylation and miRNA expression) altered in the human placenta under GDM conditions, as well as potential implications for the offspring.
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Effects of Environmental Conditions on Nephron Number: Modeling Maternal Disease and Epigenetic Regulation in Renal Development. Int J Mol Sci 2021; 22:ijms22084157. [PMID: 33923831 PMCID: PMC8073167 DOI: 10.3390/ijms22084157] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/08/2021] [Accepted: 04/15/2021] [Indexed: 12/14/2022] Open
Abstract
A growing body of evidence suggests that low nephron numbers at birth can increase the risk of chronic kidney disease or hypertension later in life. Environmental stressors, such as maternal malnutrition, medication and smoking, can influence renal size at birth. Using metanephric organ cultures to model single-variable environmental conditions, models of maternal disease were evaluated for patterns of developmental impairment. While hyperthermia had limited effects on renal development, fetal iron deficiency was associated with severe impairment of renal growth and nephrogenesis with an all-proximal phenotype. Culturing kidney explants under high glucose conditions led to cellular and transcriptomic changes resembling human diabetic nephropathy. Short-term high glucose culture conditions were sufficient for long-term alterations in DNA methylation-associated epigenetic memory. Finally, the role of epigenetic modifiers in renal development was tested using a small compound library. Among the selected epigenetic inhibitors, various compounds elicited an effect on renal growth, such as HDAC (entinostat, TH39), histone demethylase (deferasirox, deferoxamine) and histone methyltransferase (cyproheptadine) inhibitors. Thus, metanephric organ cultures provide a valuable system for studying metabolic conditions and a tool for screening for epigenetic modifiers in renal development.
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Baryla I, Pluciennik E, Kośla K, Wojcik M, Zieleniak A, Zurawska-Klis M, Cypryk K, Wozniak LA, Bednarek AK. Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM). PeerJ 2021; 9:e10604. [PMID: 33520443 PMCID: PMC7811782 DOI: 10.7717/peerj.10604] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 11/28/2020] [Indexed: 12/12/2022] Open
Abstract
Background Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients. Methods Leukocytes were obtained from 135 pregnant women with (n = 98) or without (n = 37) GDM and, in turn, 3 months (n = 8) and 1 year (n = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (SLC2A1, SLC2A4), glycolytic pathway (HK2, PKM2, PFK, LDHA), Wnt pathway (DVL2, CTNNB1), and inflammatory response (NFKB1). Results GDM patients displayed a significant downregulation of WWOX with simultaneous upregulation of HIF1A which resulted in approximately six times reduction in WWOX/HIF1A ratio. As a consequence, HIF1A induced genes (SLC2A1, HK2, PFK, PKM) were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with WWOX/HIF1A ratio. The postpartum WWOX expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy. Conclusions The obtained results suggest a significant contribution of the WWOX gene to glucose metabolism in patients with gestational diabetes. Decreased WWOX expression in GDM compared to normal pregnancy, and in particular reduction of WWOX/HIF1A ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.
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Affiliation(s)
- Izabela Baryla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Elzbieta Pluciennik
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Kośla
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
| | - Marzena Wojcik
- Department of Structural Biology, Medical University of Lodz, Lodz, Poland
| | - Andrzej Zieleniak
- Department of Structural Biology, Medical University of Lodz, Lodz, Poland
| | - Monika Zurawska-Klis
- Department of Internal Diseases and Diabetology, Medical University of Lodz, Lodz, Poland
| | - Katarzyna Cypryk
- Department of Internal Diseases and Diabetology, Medical University of Lodz, Lodz, Poland
| | | | - Andrzej K Bednarek
- Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland
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Yan P, Wang Y, Yu X, Liu Y, Zhang ZJ. Maternal diabetes and risk of childhood malignancies in the offspring: a systematic review and meta-analysis of observational studies. Acta Diabetol 2021; 58:153-168. [PMID: 32915298 DOI: 10.1007/s00592-020-01598-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 08/20/2020] [Indexed: 01/19/2023]
Abstract
AIMS Diabetes mellitus (DM) is widely recognized as a risk factor for diverse cancers in adults. However, the association between maternal diabetes and risk of childhood cancer in the offspring has so far not been well studied. We thus conducted a meta-analysis to evaluate the role of maternal diabetes on the risk of childhood cancer. METHODS We performed a comprehensive literature search to identify eligible studies published up to June 20, 2020, including the PubMed, Web of science and Embase databases. Summary odds ratios (OR) and 95% confidence intervals (CI) were computed using a random-effects model (I2 ≥ 25%) or a fixed-effect model (I2 < 25%). RESULTS Totally, sixteen case-control and six cohort studies on the risk of childhood cancer associated with maternal diabetes were included. Overall, children of diabetic women had a significantly increased risk in childhood malignancy (OR, 1.30; 95% CI, 1.10-1.53). Notably, a significantly elevated risk of childhood cancer in the offspring was found for women with pre-existing diabetes (OR, 1.41; 95% CI, 1.17-1.70), but not for women with gestational diabetes mellitus (GDM) (OR, 1.10; 95% CI, 0.94-1.28). For site-specific cancers, maternal diabetes was associated with a higher risk of leukemia in offspring (OR, 1.30; 95% CI, 1.15-1.48), especially for acute lymphoblastic leukemia (OR, 1.44; 95% CI, 1.27-1.64). However, no significant associations were observed between maternal diabetes and the risk of lymphomas and retinoblastoma. CONCLUSIONS Our meta-analysis indicates that maternal diabetes is associated with an increased risk of childhood cancer in the offspring, particularly for acute lymphoblastic leukemia. Future study should investigate the underlying biological mechanisms behind the association.
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Affiliation(s)
- Pengfei Yan
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, China
| | - Yongbo Wang
- Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China
| | - Xue Yu
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, China
| | - Yu Liu
- Department of Statistics and Management, School of Management, Wuhan Institute of Technology, Wuhan, 430205, China
| | - Zhi-Jiang Zhang
- Department of Preventive Medicine, School of Health Sciences, Wuhan University, Wuhan, 430071, China.
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Nakanishi M, Funahashi N, Fukuoka H, Nammo T, Sato Y, Yoshihara H, Oishi H, Tanaka M, Yano T, Minoura S, Kato N, Yasuda K. Effects of maternal and fetal choline concentrations on the fetal growth and placental DNA methylation of 12 target genes related to fetal growth, adipogenesis, and energy metabolism. J Obstet Gynaecol Res 2020; 47:734-744. [PMID: 33300271 DOI: 10.1111/jog.14599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 11/17/2020] [Accepted: 11/30/2020] [Indexed: 12/16/2022]
Abstract
AIM We performed a birth cohort study involving 124 mother-infant pairs to investigate whether placental DNA methylation is associated with maternal choline status and fetal development. METHODS Plasma choline concentration was assayed longitudinally in the 1st and 3rd trimesters and at term-pregnancy in mothers and cord blood. Placental DNA methylation was measured for 12 target candidate genes that are related to fetal growth, adipogenesis, lipid and energy metabolism, or long interspersed nuclear elements. RESULTS Higher maternal plasma and cord blood choline levels at term tended to associate with lower birthweight (r = -0.246, P < 0.013; r = -0.290, P < 0.002) and body mass index (BMI) at birth (r = 0.344, P < 1E-3; r = -0.360, P < 1E-3). The correlation between maternal plasma choline level and cord blood choline level was relatively modest (r = 0.049, P = 0.639). There was an inverse correlation between placental DNA methylation at the retinoid X receptor alpha (RXRA) gene and maternal plasma choline level (r = -0.188 to r = -0.452, P = 0.043 to P < 1E-3 at three points). RXRA methylation level was positively associated with birthweight and BMI at birth (r = 0.306, P = 0.001; r = 0.390, P < 1E-3). Further, RXRA methylation was inversely correlated with RXRA gene expression level (r = 0.333, P < 1E-3). CONCLUSION Our results suggest that the association between maternal choline status and placental RXRA methylation represents a potential fetal programing mechanism contributing to fetal growth.
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Affiliation(s)
- Misao Nakanishi
- Department of Obstetrics and Gynecology, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, Keio University Graduate School of Medicine, Tokyo, Japan
| | - Nobuaki Funahashi
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.,Division of Cancer Cell Research, Research Institute, Kanagawa Cancer Center, Kanagawa, Japan
| | - Hideoki Fukuoka
- Department of Innovation Research, Waseda University Comprehensive Research Organization, Tokyo, Japan.,Department of Progressive DOHaD Research, Fukushima Medical University, Fukushima, Japan
| | - Takao Nammo
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuichi Sato
- Department of Obstetrics and Gynecology, Obstetrics and Gynecology Tatedebari Sato Hospital, Gunma, Japan
| | - Hajime Yoshihara
- Japan Community Health Care Organization, Sagamino Hospital Center of Perinatal Medicine, Kanagawa, Japan
| | - Hajime Oishi
- Department of Obstetrics and Gynecology, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan
| | - Mamoru Tanaka
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Tetsu Yano
- Department of Obstetrics and Gynecology, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, Tokyo Yamate Medical Center, Tokyo, Japan
| | - Shigeki Minoura
- Department of Obstetrics and Gynecology, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Obstetrics and Gynecology, Shinjuku City Medical Association Residents' Health Center, Tokyo, Japan
| | - Norihiro Kato
- Department of Gene Diagnostics and Therapeutics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kazuki Yasuda
- Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
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Bosi E, Marselli L, De Luca C, Suleiman M, Tesi M, Ibberson M, Eizirik DL, Cnop M, Marchetti P. Integration of single-cell datasets reveals novel transcriptomic signatures of β-cells in human type 2 diabetes. NAR Genom Bioinform 2020; 2:lqaa097. [PMID: 33575641 PMCID: PMC7679065 DOI: 10.1093/nargab/lqaa097] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Revised: 07/26/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic islet β-cell failure is key to the onset and progression of type 2 diabetes (T2D). The advent of single-cell RNA sequencing (scRNA-seq) has opened the possibility to determine transcriptional signatures specifically relevant for T2D at the β-cell level. Yet, applications of this technique have been underwhelming, as three independent studies failed to show shared differentially expressed genes in T2D β-cells. We performed an integrative analysis of the available datasets from these studies to overcome confounding sources of variability and better highlight common T2D β-cell transcriptomic signatures. After removing low-quality transcriptomes, we retained 3046 single cells expressing 27 931 genes. Cells were integrated to attenuate dataset-specific biases, and clustered into cell type groups. In T2D β-cells (n = 801), we found 210 upregulated and 16 downregulated genes, identifying key pathways for T2D pathogenesis, including defective insulin secretion, SREBP signaling and oxidative stress. We also compared these results with previous data of human T2D β-cells from laser capture microdissection and diabetic rat islets, revealing shared β-cell genes. Overall, the present study encourages the pursuit of single β-cell RNA-seq analysis, preventing presently identified sources of variability, to identify transcriptomic changes associated with human T2D and underscores specific traits of dysfunctional β-cells across different models and techniques.
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Affiliation(s)
- Emanuele Bosi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Lorella Marselli
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Carmela De Luca
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mara Suleiman
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Marta Tesi
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
| | - Mark Ibberson
- Vital-IT Group, SIB Swiss Institute of Bioinformatics, University of Lausanne, Quartier Sorge, CH-1015 Lausanne, Switzerland
| | - Decio L Eizirik
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, B-1070, Belgium
| | - Piero Marchetti
- Department of Experimental and Clinical Medicine, Pancreatic Islets Laboratory, University of Pisa, Pisa, I-56124, Italy
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Antoun E, Kitaba NT, Titcombe P, Dalrymple KV, Garratt ES, Barton SJ, Murray R, Seed PT, Holbrook JD, Kobor MS, Lin DTS, MacIsaac JL, Burdge GC, White SL, Poston L, Godfrey KM, Lillycrop KA, UPBEAT Consortium. Maternal dysglycaemia, changes in the infant's epigenome modified with a diet and physical activity intervention in pregnancy: Secondary analysis of a randomised control trial. PLoS Med 2020; 17:e1003229. [PMID: 33151971 PMCID: PMC7643947 DOI: 10.1371/journal.pmed.1003229] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 10/06/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Higher maternal plasma glucose (PG) concentrations, even below gestational diabetes mellitus (GDM) thresholds, are associated with adverse offspring outcomes, with DNA methylation proposed as a mediating mechanism. Here, we examined the relationships between maternal dysglycaemia at 24 to 28 weeks' gestation and DNA methylation in neonates and whether a dietary and physical activity intervention in pregnant women with obesity modified the methylation signatures associated with maternal dysglycaemia. METHODS AND FINDINGS We investigated 557 women, recruited between 2009 and 2014 from the UK Pregnancies Better Eating and Activity Trial (UPBEAT), a randomised controlled trial (RCT), of a lifestyle intervention (low glycaemic index (GI) diet plus physical activity) in pregnant women with obesity (294 contol, 263 intervention). Between 27 and 28 weeks of pregnancy, participants had an oral glucose (75 g) tolerance test (OGTT), and GDM diagnosis was based on diagnostic criteria recommended by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), with 159 women having a diagnosis of GDM. Cord blood DNA samples from the infants were interrogated for genome-wide DNA methylation levels using the Infinium Human MethylationEPIC BeadChip array. Robust regression was carried out, adjusting for maternal age, smoking, parity, ethnicity, neonate sex, and predicted cell-type composition. Maternal GDM, fasting glucose, 1-h, and 2-h glucose concentrations following an OGTT were associated with 242, 1, 592, and 17 differentially methylated cytosine-phosphate-guanine (dmCpG) sites (false discovery rate (FDR) ≤ 0.05), respectively, in the infant's cord blood DNA. The most significantly GDM-associated CpG was cg03566881 located within the leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) (FDR = 0.0002). Moreover, we show that the GDM and 1-h glucose-associated methylation signatures in the cord blood of the infant appeared to be attenuated by the dietary and physical activity intervention during pregnancy; in the intervention arm, there were no GDM and two 1-h glucose-associated dmCpGs, whereas in the standard care arm, there were 41 GDM and 160 1-h glucose-associated dmCpGs. A total of 87% of the GDM and 77% of the 1-h glucose-associated dmCpGs had smaller effect sizes in the intervention compared to the standard care arm; the adjusted r2 for the association of LGR6 cg03566881 with GDM was 0.317 (95% confidence interval (CI) 0.012, 0.022) in the standard care and 0.240 (95% CI 0.001, 0.015) in the intervention arm. Limitations included measurement of DNA methylation in cord blood, where the functional significance of such changes are unclear, and because of the strong collinearity between treatment modality and severity of hyperglycaemia, we cannot exclude that treatment-related differences are potential confounders. CONCLUSIONS Maternal dysglycaemia was associated with significant changes in the epigenome of the infants. Moreover, we found that the epigenetic impact of a dysglycaemic prenatal maternal environment appeared to be modified by a lifestyle intervention in pregnancy. Further research will be needed to investigate possible medical implications of the findings. TRIAL REGISTRATION ISRCTN89971375.
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Affiliation(s)
- Elie Antoun
- Biological Sciences, Institute of Developmental Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - Negusse T. Kitaba
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Philip Titcombe
- MRC Lifecourse Epidemiology Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Kathryn V. Dalrymple
- Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, United Kingdom
| | - Emma S. Garratt
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Trust, Southampton, United Kingdom
| | - Sheila J. Barton
- MRC Lifecourse Epidemiology Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Robert Murray
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Paul T. Seed
- Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, United Kingdom
| | - Joanna D. Holbrook
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Michael S. Kobor
- BC Childrens Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
| | - David TS Lin
- BC Childrens Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Julia L. MacIsaac
- BC Childrens Hospital Research Institute, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, Canada
| | - Graham C. Burdge
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Sara L. White
- Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, United Kingdom
| | - Lucilla Poston
- Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, United Kingdom
| | - Keith M. Godfrey
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Trust, Southampton, United Kingdom
| | - Karen A. Lillycrop
- Biological Sciences, Institute of Developmental Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Trust, Southampton, United Kingdom
- * E-mail:
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50
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Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies. Genes (Basel) 2020; 11:genes11101146. [PMID: 33003346 PMCID: PMC7601230 DOI: 10.3390/genes11101146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 11/16/2022] Open
Abstract
Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.
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