|
1
|
Xue B, Johnson AK, Bassuk AG. Sex differences in the sensitization of prenatally programmed hypertension. Front Physiol 2025; 16:1589615. [PMID: 40356772 PMCID: PMC12066558 DOI: 10.3389/fphys.2025.1589615] [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: 03/07/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Studies have demonstrated that there are sex differences in the timing of onset and severity of prenatally programmed hypertension, with consistently milder phenotypes observed in females relative to male offspring. However, the root cause(s) for these sex-specific effects is unknown. Activation of the renin-angiotensin system (RAS), elevated oxidative stress and inflammation, and sympathetic hyperactivity in the cardiovascular organs and cardiovascular regulatory systems, are all involved in the pathogenesis of hypertension. Sex hormones interact with these prohypertensive systems to modulate blood pressure, and this interaction may lead to a sex-specific development of programmed hypertension. A more complete understanding of the functional capabilities of the sex hormones and their interactions with prohypertensive factors in offspring, from early life to aging, would likely lead to new insights into the basis of sex differences in programmed hypertension. Recently, we have discovered that sex differences also occur in the sensitization of offspring hypertension as programmed by maternal gestational hypertension and that this requires the brain RAS and proinflammatory factors. In this review, we will discuss the possible mechanisms underlying sex differences in sensitization to hypertension in the offspring of mothers exposed to various prenatal insults. These mechanisms operate at various levels from the periphery to the central nervous system (e.g., blood vessel, heart, kidney, and brain). Understanding the sex-specific mechanisms responsible for the sensitized state in offspring can help to develop therapeutic strategies for interrupting the vicious cycle of transgenerational hypertension and for treating hypertension in men and women differentially to maximize efficacy.
Collapse
Affiliation(s)
- Baojian Xue
- Stead Family Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
| | - Alan Kim Johnson
- Department of Psychological and Brain Sciences, College of Liberal Arts and Sciences, University of Iowa, Iowa, IA, United States
| | - Alexander G. Bassuk
- Stead Family Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
- The Iowa Neuroscience Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
- The Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa, IA, United States
| |
Collapse
|
|
2
|
Aguilera-Méndez A, Figueroa-Fierros I, Ruiz-Pérez X, Godínez-Hernández D, Saavedra-Molina A, Rios-Chavez P, Villafaña S, Boone-Villa D, Ortega-Cuellar D, Gauthereau-Torres MY, Nieto-Aguilar R, Palomera-Sanchez Z. The Beneficial Effects of Prenatal Biotin Supplementation in a Rat Model of Intrauterine Caloric Restriction to Prevent Cardiometabolic Risk in Adult Female Offspring. Int J Mol Sci 2024; 25:9052. [PMID: 39201737 PMCID: PMC11354830 DOI: 10.3390/ijms25169052] [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: 07/16/2024] [Revised: 08/10/2024] [Accepted: 08/15/2024] [Indexed: 09/03/2024] Open
Abstract
Numerous studies indicate that intrauterine growth restriction (IUGR) can predispose individuals to metabolic syndrome (MetS) in adulthood. Several reports have demonstrated that pharmacological concentrations of biotin have therapeutic effects on MetS. The present study investigated the beneficial effects of prenatal biotin supplementation in a rat model of intrauterine caloric restriction to prevent cardiometabolic risk in adult female offspring fed fructose after weaning. Female rats were exposed to a control (C) diet or global caloric restriction (20%) (GCR), with biotin (GCRB) supplementation (2 mg/kg) during pregnancy. Female offspring were exposed to 20% fructose (F) in drinking water for 16 weeks after weaning (C, C/F, GCR/F, and GCRB/F). The study assessed various metabolic parameters including Lee's index, body weight, feed conversion ratio, caloric intake, glucose tolerance, insulin resistance, lipid profile, hepatic triglycerides, blood pressure, and arterial vasoconstriction. Results showed that GCR and GCRB dams had reduced weights compared to C dams. Offspring of GCRB/F and GCR/F dams had lower body weight and Lee's index than C/F offspring. Maternal biotin supplementation in the GCRB/F group significantly mitigated the adverse effects of fructose intake, including hypertriglyceridemia, hypercholesterolemia, hepatic steatosis, glucose and insulin resistance, hypertension, and arterial hyperresponsiveness. This study concludes that prenatal biotin supplementation can protect against cardiometabolic risk in adult female offspring exposed to postnatal fructose, highlighting its potential therapeutic benefits.
Collapse
Affiliation(s)
- Asdrubal Aguilera-Méndez
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico; (I.F.-F.); (X.R.-P.); (D.G.-H.); (A.S.-M.)
| | - Ian Figueroa-Fierros
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico; (I.F.-F.); (X.R.-P.); (D.G.-H.); (A.S.-M.)
| | - Xóchilt Ruiz-Pérez
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico; (I.F.-F.); (X.R.-P.); (D.G.-H.); (A.S.-M.)
| | - Daniel Godínez-Hernández
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico; (I.F.-F.); (X.R.-P.); (D.G.-H.); (A.S.-M.)
| | - Alfredo Saavedra-Molina
- Instituto de Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico; (I.F.-F.); (X.R.-P.); (D.G.-H.); (A.S.-M.)
| | - Patricia Rios-Chavez
- Facultad de Biología, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58030, Mexico;
| | - Santiago Villafaña
- Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de Mexico 11340, Mexico;
| | - Daniel Boone-Villa
- Escuela de Medicina, Unidad Norte, Universidad Autónoma de Coahuila, Piedras Negras 26090, Mexico;
| | - Daniel Ortega-Cuellar
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Ciudad de Mexico 04530, Mexico;
| | | | - Renato Nieto-Aguilar
- Facultad de Odontología, Centro Universitario de Estudios de Postgrado e Investigación, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58330, Mexico;
| | - Zoraya Palomera-Sanchez
- Facultad de Medicina Veterinaria y Zootecnia, Universidad Michoacana de San Nicolás de Hidalgo, Morelia 58130, Mexico;
| |
Collapse
|
|
3
|
Souza ACD, Silva DGD, Jezuíno JDS, Ferreira ARO, Ribeiro MVG, Vidigal CB, Moura KF, Erthal RP, Mathias PCDF, Fernandes GSA, Palma-Rigo K, Ceravolo GS. Protein restriction during peripubertal period impairs endothelial aortic function in adult male Wistar rats. J Dev Orig Health Dis 2023; 14:451-458. [PMID: 37198976 DOI: 10.1017/s2040174423000119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Protein restriction during early phases of body development, such as intrauterine life can favor the development of vascular disorders. However, it is not known if peripubertal protein restriction can favor vascular dysfunction in adulthood. The present study aimed to evaluated whether a protein restriction diet during peripubertal period favors endothelial dysfunction in adulthood. Male Wistar rats from postnatal day (PND) 30 until 60 received a diet with either 23% protein (CTR group) or with 4% protein (LP group). At PND 120, the thoracic aorta reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was evaluated in the presence or absence of: endothelium, indomethacin, apocynin and tempol. The maximum response (Rmax) and pD2 (-log of the concentration of the drug that causes 50% of the Rmax) were calculated. The lipid peroxidation and catalase activity were also evaluated in the aorta. The data were analyzed by ANOVA (one or two-ways and Tukey's) or independent t-test; the results were expressed as mean ± S.E.M., p < 0.05. The Rmax to phenylephrine in aortic rings with endothelium were increased in LP rats when compared with the Rmax in CTR rats. Apocynin and tempol reduced Rmax to phenylephrine in LP aortic rings but not in CTR. The aortic response to the vasodilators was similar between the groups. Aortic catalase activity was lower and lipid peroxidation was greater in LP compared to CTR rats. Therefore, protein restriction during the peripubertal period causes endothelial dysfunction in adulthood through a mechanism related to oxidative stress.
Collapse
Affiliation(s)
- Amanda Cristina de Souza
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Deborah Gomes da Silva
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Juliana da Silva Jezuíno
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Anna Rebeka Oliveira Ferreira
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
| | - Maiara Vanusa Guedes Ribeiro
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
| | - Camila Borecki Vidigal
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Kawane Fabricio Moura
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| | - Rafaela Pires Erthal
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | | | - Glaura Scantamburlo Alves Fernandes
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
- Department of General Biology, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
| | - Kesia Palma-Rigo
- Department of Cell Biology and Genetics, Center of Biological Sciences, State University of Maringa, Maringa, Brazil
- Adventist College of Parana, Ivatuba, Brazil
| | - Graziela Scalianti Ceravolo
- Department of Physiological Sciences, Center of Biological Sciences, State University of Londrina, Londrina, Brazil
- Graduation Program of Physiological Sciences, Department of Physiological Sciences, State University of Londrina, Londrina, Brazil
| |
Collapse
|
|
4
|
Ricci TA, Boonpattrawong N, Laher I, Devlin AM. Maternal nutrition and effects on offspring vascular function. Pflugers Arch 2023:10.1007/s00424-023-02807-x. [PMID: 37041303 DOI: 10.1007/s00424-023-02807-x] [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: 02/14/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/13/2023]
Abstract
Maternal nutrition during pregnancy may have profound effects on the developing fetus and impact risk for cardiovascular disease later in life. Here, we provide a narrative review on the impact of maternal diet during pregnancy on offspring vascular function. We review studies reporting effects of maternal micronutrient (folic acid, iron) intakes, high-fat diets, dietary energy restriction, and low protein intake on offspring endothelial function. We discuss the differences in study design and outcomes and potential underlying mechanisms contributing to the vascular phenotypes observed in the offspring. We further highlight key gaps in the literature and identify targets for future investigations.
Collapse
Affiliation(s)
- Taylor A Ricci
- Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia, Canada
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
| | - Nicha Boonpattrawong
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada
- Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Ismail Laher
- Department of Anesthesiology, Pharmacology, and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Angela M Devlin
- Department of Pediatrics, The University of British Columbia, Vancouver, British Columbia, Canada.
- BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
| |
Collapse
|
|
5
|
The Impact of Nutrient Intake and Metabolic Wastes during Pregnancy on Offspring Hypertension: Challenges and Future Opportunities. Metabolites 2023; 13:metabo13030418. [PMID: 36984857 PMCID: PMC10052993 DOI: 10.3390/metabo13030418] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 03/09/2023] [Accepted: 03/10/2023] [Indexed: 03/14/2023] Open
Abstract
Hypertension can have its origin in early life. During pregnancy, many metabolic alterations occur in the mother that have a crucial role in fetal development. In response to maternal insults, fetal programming may occur after metabolic disturbance, resulting in programmed hypertension later in life. Maternal dietary nutrients act as metabolic substrates for various metabolic processes via nutrient-sensing signals. Different nutrient-sensing pathways that detect levels of sugars, amino acids, lipids and energy are integrated during pregnancy, while disturbed nutrient-sensing signals have a role in the developmental programming of hypertension. Metabolism-modulated metabolites and nutrient-sensing signals are promising targets for new drug discovery due to their pathogenic link to hypertension programming. Hence, in this review, we pay particular attention to the maternal nutritional insults and metabolic wastes affecting fetal programming. We then discuss the role of nutrient-sensing signals linking the disturbed metabolism to hypertension programming. This review also summarizes current evidence to give directions for future studies regarding how to prevent hypertension via reprogramming strategies, such as nutritional intervention, targeting nutrient-sensing signals, and reduction of metabolic wastes. Better prevention for hypertension may be possible with the help of novel early-life interventions that target altered metabolism.
Collapse
|
|
6
|
Ando C, Ma S, Miyoshi M, Furukawa K, Li X, Jia H, Kato H. Postnatal nutrition environment reprograms renal DNA methylation patterns in offspring of maternal protein-restricted stroke-prone spontaneously hypertensive rats. Front Nutr 2023; 10:1134955. [PMID: 37125041 PMCID: PMC10133489 DOI: 10.3389/fnut.2023.1134955] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 03/20/2023] [Indexed: 05/02/2023] Open
Abstract
Maternal malnutrition hampers the offspring health by manipulating the epigenome. Recent studies indicate that the changes in DNA methylation could be reversed by afterbirth nutrition supplementation. In this study, we used DNA methylation arrays to comprehensively investigate the DNA methylation status of the renal promoter regions and the effects of postnatal protein intake on DNA methylation. We fed stroke-prone spontaneously hypertensive (SHRSP) rat dams a normal diet or a low-protein diet during pregnancy, and their 4-week-old male offspring were fed a normal diet or a high-/low-protein diet for 2 weeks. We found that the methylation status of 2,395 differentially methylated DNA regions was reprogrammed, and 34 genes were reset by different levels of postnatal protein intake in the offspring. Among these genes, Adora2b, Trpc5, Ar, Xrcc2, and Atp1b1 are involved in renal disease and blood pressure regulation. Our findings indicate that postnatal nutritional interventions can potentially reprogram epigenetic changes, providing novel therapeutic and preventive epigenetic targets for salt-sensitive hypertension.
Collapse
Affiliation(s)
- Chika Ando
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Sihui Ma
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Faculty of Sport Sciences, Waseda University, Tokorozawa, Japan
| | - Moe Miyoshi
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kyohei Furukawa
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University, Sendai, Japan
| | - Xuguang Li
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Huijuan Jia
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- *Correspondence: Huijuan Jia,
| | - Hisanori Kato
- Health Nutrition, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
- Hisanori Kato,
| |
Collapse
|
|
7
|
Abdull Sukor AN, Ankasha SJ, Ugusman A, Aminuddin A, Mokhtar NM, Zainal Abidin S, Ahmad MF, Hamid A. Impact of offspring endothelial function from de novo hypertensive disorders during pregnancy: An evidence-based review. Front Surg 2022; 9:967785. [PMID: 36420416 PMCID: PMC9676434 DOI: 10.3389/fsurg.2022.967785] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 09/29/2022] [Indexed: 09/08/2024] Open
Abstract
De novo hypertensive disorders of pregnancy (HDP) which consist of gestational hypertension and preeclampsia affect maternal and offspring morbidity and mortality, and potentially increase the risk of cardiovascular disease in the offspring. It is well known that de novo HDP causes various maternal complications, including cardiovascular diseases, placental abruption and liver and kidney failure. However, there are studies suggesting that offspring of pregnancies complicated by de novo HDP have an increased risk of long-term cardiovascular disease. The endothelium is an important regulator of vascular function, and its dysfunction is highly associated with the development of cardiovascular diseases. Hence, this review aimed to systematically identify articles related to the effect of de novo HDP on the endothelial function of the offspring. A computerized database search was conducted on PubMed, Scopus, and Medline from 1976 until 2022. A total of 685 articles were obtained. We identified another three additional articles through review articles and Google Scholar. Altogether, we used 13 articles for data extraction. All studies reported that endothelial function was impaired in the offspring of de novo HDP. This is most likely attributed to impaired vasodilation, subclinical atherosclerosis formation, inflammation, and dysregulated epigenetic regulation of endothelial functions.
Collapse
Affiliation(s)
| | - Sheril June Ankasha
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Amilia Aminuddin
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Shahidee Zainal Abidin
- Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus, Malaysia
| | - Mohd Faizal Ahmad
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Adila A. Hamid
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| |
Collapse
|
|
8
|
Song R, Mishra JS, Dangudubiyyam SV, Antony KM, Baker TL, Watters JJ, Kumar S. Gestational Intermittent Hypoxia Induces Sex-Specific Impairment in Endothelial Mechanisms and Sex Steroid Hormone Levels in Male Rat Offspring. Reprod Sci 2022; 29:1531-1541. [PMID: 34550599 PMCID: PMC11157504 DOI: 10.1007/s43032-021-00739-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 09/07/2021] [Indexed: 10/20/2022]
Abstract
Obstructive sleep apnea (OSA) is highly prevalent during gestation and is linked with adverse fetal outcomes. We examined whether gestational intermittent hypoxia (GIH), the main feature of OSA, leads to sex-specific alterations in cardiovascular function and vascular mechanisms in the offspring. Pregnant rats exposed to intermittent hypoxia or ambient air from gestation days 10 to 21 and their offspring were used for the study. GIH exposure did not affect water and food intake in dams. Compared to controls, the male and female offspring born to GIH dams were smaller in weight by 14% and 12%, respectively, and exhibited catch-up growth. Cardiac function was not affected in either GIH males or females. At 12 weeks of age, blood pressure was increased in GIH males, but not GIH females, compared to their control counterparts. While mesenteric arterial contractile responses to phenylephrine and endothelin were unaffected in GIH males and females, relaxation response to acetylcholine was reduced in GIH males but not GIH females. Relaxation to sodium nitroprusside was unaffected in both GIH males and females. Total eNOS expression was not affected, but phospho(Ser1177)-eNOS levels were decreased in GIH males. eNOS expression and its phosphorylation status were unaffected in GIH females. Serum testosterone and estradiol levels were higher in GIH males but were unaltered in GIH females. Together, these findings suggest that GIH leads to a sex-specific increase in blood pressure in adult male offspring with blunted endothelium-mediated relaxation, decreased eNOS activity, and elevated sex steroid hormone levels.
Collapse
Affiliation(s)
- Ruolin Song
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA
| | - Jay S Mishra
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA
| | - Sri Vidya Dangudubiyyam
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA
| | - Kathleen M Antony
- Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53792, USA
| | - Tracy L Baker
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA
| | - Jyoti J Watters
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA
| | - Sathish Kumar
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden Drive, Madison, WI, 53706, USA.
- Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, 53792, USA.
| |
Collapse
|
|
9
|
Selivanova EK, Shvetsova AA, Shilova LD, Tarasova OS, Gaynullina DK. Intrauterine growth restriction weakens anticontractile influence of NO in coronary arteries of adult rats. Sci Rep 2021; 11:14475. [PMID: 34262070 PMCID: PMC8280217 DOI: 10.1038/s41598-021-93491-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 06/18/2021] [Indexed: 11/09/2022] Open
Abstract
Intrauterine growth restriction (IUGR) is one of the most common pathologies of pregnancy. The cardiovascular consequences of IUGR do not disappear in adulthood and can manifest themselves in pathological alterations of vasomotor control. The hypothesis was tested that IUGR weakens anticontractile influence of NO and augments procontractile influence of Rho-kinase in arteries of adult offspring. To model IUGR in the rat, dams were 50% food restricted starting from the gestational day 11 till delivery. Mesenteric and coronary arteries of male offspring were studied at the age of 3 months using wire myography, qPCR, and Western blotting. Contractile responses of mesenteric arteries to α1-adrenoceptor agonist methoxamine as well as influences of NO and Rho-kinase did not differ between control and IUGR rats. However, coronary arteries of IUGR rats demonstrated elevated contraction to thromboxane A2 receptor agonist U46619 due to weakened anticontractile influence of NO and enhanced role of Rho-kinase in the endothelium. This was accompanied by reduced abundance of SODI protein and elevated content of RhoA protein in coronary arteries of IUGR rats. IUGR considerably changes the regulation of coronary vascular tone in adulthood and, therefore, can serve as a risk factor for the development of cardiac disorders.
Collapse
Affiliation(s)
- Ekaterina K Selivanova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Moscow, Russia
| | - Anastasia A Shvetsova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Moscow, Russia
| | - Lyubov D Shilova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Moscow, Russia
| | - Olga S Tarasova
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Moscow, Russia
- Institute for Biomedical Problems, Russian Academy of Sciences, Moscow, Russia
| | - Dina K Gaynullina
- Department of Human and Animal Physiology, Lomonosov Moscow State University, Moscow, Russia.
- Russian National Research Medical University, Moscow, Russia.
| |
Collapse
|
|
10
|
Animal Models for DOHaD Research: Focus on Hypertension of Developmental Origins. Biomedicines 2021; 9:biomedicines9060623. [PMID: 34072634 PMCID: PMC8227380 DOI: 10.3390/biomedicines9060623] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/11/2022] Open
Abstract
Increasing evidence suggests that fetal programming through environmental exposure during a critical window of early life leads to long-term detrimental outcomes, by so-called developmental origins of health and disease (DOHaD). Hypertension can originate in early life. Animal models are essential for providing convincing evidence of a causal relationship between diverse early-life insults and the developmental programming of hypertension in later life. These insults include nutritional imbalances, maternal illnesses, exposure to environmental chemicals, and medication use. In addition to reviewing the various insults that contribute to hypertension of developmental origins, this review focuses on the benefits of animal models in addressing the underlying mechanisms by which early-life interventions can reprogram disease processes and prevent the development of hypertension. Our understanding of hypertension of developmental origins has been enhanced by each of these animal models, narrowing the knowledge gap between animal models and future clinical translation.
Collapse
|
|
11
|
Impact of the exposome on the development and function of pancreatic β-cells. Mol Aspects Med 2021; 87:100965. [PMID: 33965231 DOI: 10.1016/j.mam.2021.100965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 04/13/2021] [Accepted: 04/15/2021] [Indexed: 11/22/2022]
Abstract
The development and plasticity of the endocrine pancreas responds to both the intrauterine and postnatal exposome in a constant attempt to predict and respond to alterations in nutritional availability and metabolic requirements. Both under- and over-nutrition in utero, or exposure to adverse environmental pollutants or maternal behaviors, can each lead to altered β-cell or function at birth, and a subsequent mismatch in pancreatic hormonal demands and secretory capacity postnatally. This can be further exacerbated by metabolic stress postnatally such as from obesity or pregnancy, resulting in an increased risk of gestational diabetes, type 2 diabetes, and even type 1 diabetes. This review will discuss evidence identifying the cellular pathways in early life whereby the plasticity of the endocrine pancreatic can become pathologically limited. By necessity, much of this evidence has been gained from animal models, although extrapolation to human fetal development is possible from the fetal growth trajectory and study of the newborn. Cellular limitations to plasticity include the balance between β-cell proliferation and apoptosis, the appearance of β-cell oxidative stress, impaired glucose-stimulated insulin secretion, and sensitivity to circulating cytokines and responsiveness to programmed death receptor-1. Evidence suggests that many of the cellular pathways responsible for limiting β-cell plasticity are related to paracrine interactions within the islets of Langerhans.
Collapse
|
|
12
|
The Impact of Unbalanced Maternal Nutritional Intakes on Oocyte Mitochondrial Activity: Implications for Reproductive Function. Antioxidants (Basel) 2021; 10:antiox10010091. [PMID: 33440800 PMCID: PMC7826933 DOI: 10.3390/antiox10010091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/30/2020] [Accepted: 01/07/2021] [Indexed: 12/11/2022] Open
Abstract
Accumulating evidence on the effect of nutrition on reproduction is emerging from both animal and human studies. A healthy dietary pattern and nutrient supplementation, especially during the peri-conceptional period, might be helpful to achieve a live birth, although the mechanisms implicated are not fully understood. The endocrine system and the ooplasmic organelles apparatus, in particular the mitochondria, are clearly key elements during oogenesis and subsequent embryo development, and their proper functioning is associated with nutrition, even beyond maternal aging. Several studies in animal models have reported various adverse effects on mitochondria caused by unbalanced dietary intakes such as high fat diet, high fat high sugar diet, and low protein diet. The alterations produced might include mitochondrial intracellular distribution, content, structure, biogenesis, and functioning. This review summarizes the key role of mitochondria in female reproduction and the effects of different dietary macronutrient compositions on oocyte mitochondrial activity with their possible short-, medium-, and long-term effects.
Collapse
|
|
13
|
Christoforou ER, Sferruzzi-Perri AN. Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress. Cell Mol Life Sci 2020; 77:4861-4898. [PMID: 32494846 PMCID: PMC7658077 DOI: 10.1007/s00018-020-03566-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/23/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022]
Abstract
The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as 'developmental programming', whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins.
Collapse
Affiliation(s)
- Efthimia R Christoforou
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK.
| |
Collapse
|
|
14
|
Dangudubiyyam SV, Mishra JS, Zhao H, Kumar S. Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy increases blood pressure and impairs vascular relaxation mechanisms in the adult offspring. Reprod Toxicol 2020; 98:165-173. [PMID: 32980420 DOI: 10.1016/j.reprotox.2020.09.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/21/2022]
Abstract
Perfluorooctanesulfonate (PFOS) is a persistent environmental agent. We examined whether PFOS exposure during pregnancy alters blood pressure in male and female offspring, and if this is related to sex-specific changes in vascular mechanisms. PFOS was administered through drinking water (50 μg/mL) to pregnant Sprague-Dawley rats from gestational day 4 until delivery. PFOS-exposure decreased maternal weight gain but did not significantly alter feed and water intake in dams. The male and female pups born to PFOS mothers were smaller in weight by 29 % and 27 %, respectively. The male PFOS offspring remained smaller through adulthood, but the female PFOS offspring exhibited catch-up growth. The blood pressure at 12 and 16 weeks of age was elevated at similar magnitude in PFOS males and females than controls. Mesenteric arterial relaxation to acetylcholine was reduced in both PFOS males and females, but the extent of decrease was greater in females. Relaxation to sodium-nitroprusside was reduced in PFOS females but unaffected in PFOS males. Vascular eNOS expression was not changed, but phospho(Ser1177)-eNOS was decreased in PFOS males. In PFOS females, both total eNOS and phospho(Ser1177)-eNOS expression were reduced. In conclusion, PFOS exposure during prenatal life (1) caused low birth weight followed by catch-up growth only in females (2) lead to hypertension of similar magnitude in both males and females; (2) decreased endothelium-dependent vascular relaxation in males but suppressed both endothelium-dependent and -independent relaxation in females. The endothelial dysfunction is associated with reduced activity of eNOS in males and decreased expression and activity of eNOS in females.
Collapse
Affiliation(s)
- Sri Vidya Dangudubiyyam
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA; Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, WI 53715, USA.
| | - Jay S Mishra
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
| | - Hanjie Zhao
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA.
| | - Sathish Kumar
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA; Endocrinology-Reproductive Physiology Program, University of Wisconsin, Madison, WI 53715, USA; Department of Obstetrics and Gynecology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53792, USA.
| |
Collapse
|
|
15
|
Amino Acids and Developmental Origins of Hypertension. Nutrients 2020; 12:nu12061763. [PMID: 32545526 PMCID: PMC7353289 DOI: 10.3390/nu12061763] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 12/14/2022] Open
Abstract
During pregnancy, amino acids are important biomolecules that play essential roles in fetal growth and development. Imbalanced amino acid intake during gestation may produce long-term morphological or functional changes in offspring, for example, developmental programming that increases the risk of developing hypertension in later life. Conversely, supplementation with specific amino acids could reverse the programming processes in early life, which may counteract the rising epidemic of hypertension. This review provides an overview of the evidence supporting the importance of amino acids during pregnancy and fetal development, the impact of amino acids on blood pressure regulation, insight from animal models in which amino acids were used to prevent hypertension of developmental origin, and interactions between amino acids and the common mechanisms underlying development programming of hypertension. A better understanding of the pathophysiological roles of specific amino acids and their interactions in developmental programming of hypertension is essential so that pregnant mothers are able to benefit from accurate amino acid supplementation during pregnancy in order to prevent hypertension development in their children.
Collapse
|
|
16
|
Early-Life Programming and Reprogramming of Adult Kidney Disease and Hypertension: The Interplay between Maternal Nutrition and Oxidative Stress. Int J Mol Sci 2020; 21:ijms21103572. [PMID: 32443635 PMCID: PMC7278949 DOI: 10.3390/ijms21103572] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/12/2020] [Accepted: 05/18/2020] [Indexed: 02/06/2023] Open
Abstract
Kidney disease and hypertension both have attained the status of a global pandemic. Altered renal programming resulting in kidney disease and hypertension can begin in utero. Maternal suboptimal nutrition and oxidative stress have important implications in renal programming, while specific antioxidant nutrient supplementations may serve as reprogramming strategies to prevent kidney disease and hypertension of developmental origins. This review aims to summarize current knowledge on the interplay of maternal nutrition and oxidative stress in response to early-life insults and its impact on developmental programming of kidney disease and hypertension, covering two aspects. Firstly, we present the evidence from animal models supporting the implication of oxidative stress on adult kidney disease and hypertension programmed by suboptimal maternal nutrition. In the second part, we document data on specific antioxidant nutrients as reprogramming strategies to protect adult offspring against kidney disease and hypertension from developmental origins. Research into the prevention of kidney disease and hypertension that begin early in life will have profound implications for future health.
Collapse
|
|
17
|
Facchi JC, Lima TALD, Oliveira LRD, Costermani HDO, Miranda GDS, de Oliveira JC. Perinatal programming of metabolic diseases: The role of glucocorticoids. Metabolism 2020; 104:154047. [PMID: 31837301 DOI: 10.1016/j.metabol.2019.154047] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/23/2019] [Accepted: 12/09/2019] [Indexed: 12/20/2022]
Abstract
The worldwide increase in metabolic diseases has urged the scientific community to improve our understanding about the mechanisms underlying its cause and effects. A well supported area of studies had related maternal stress with early programming to the later metabolic diseases. Mechanisms upon origins of metabolic disturbances are not yet fully understood, even though stressful factors rising glucocorticoids have been put out as pivotal trigger by programming metabolic diseases as long-term consequence. Considering energy balance and glucose homeostasis, by producing and/or sensing regulator signals, hypothalamus-pituitary-adrenal axis and endocrine pancreas are directly affected by glucocorticoids excess. We focus on the evidences reporting the role of increased glucocorticoids due to perinatal insults on the physiological systems involved in the metabolic homeostasis and in the target organs such as endocrine pancreas, white adipose tissue and blood vessels. Besides, we review some mechanisms underlining the malprogramming of type 2 diabetes, obesity and hypertension. Studies on this field are currently ongoing and even there is a good understanding regarding the effects of glucocorticoids addressing metabolic diseases, few is known about the relationship between maternal insults rising glucocorticoids to pups' metabolic disturbances, a thorough understanding about that may provide pivotal clinical clues regarding those disorders.
Collapse
Affiliation(s)
- Júlia Cristina Facchi
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Thalyne Aparecida Leite de Lima
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Lucas Ryba de Oliveira
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Hercules de Oliveira Costermani
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Ginislene Dias Souza Miranda
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil
| | - Júlio Cezar de Oliveira
- Research Group on Perinatal Programming of Metabolic Diseases: DOHaD concept, Laboratory of Metabolic and Cardiovascular Diseases, Health Education and Research Center, NUPADS, Institute of Health Sciences, Federal University of Mato Grosso, University Campus of Sinop, Sinop, MT, Brazil.
| |
Collapse
|
|
18
|
Effects of intrauterine growth restriction on Ca 2+-activated force and contractile protein expression in the mesenteric artery of 1-year-old Wistar-Kyoto rats. J Physiol Biochem 2020; 76:111-121. [PMID: 31927696 DOI: 10.1007/s13105-020-00724-6] [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: 07/18/2019] [Accepted: 01/03/2020] [Indexed: 10/25/2022]
Abstract
Intrauterine growth restriction (IUGR) affects vascular reactivity in older rats, but at present the causative factors for this change are unknown. Therefore, we investigated downstream events associated with vascular reactivity, specifically, Ca2+-regulated force production and shifts in contractile protein content. The mesenteric artery from male and female 1-year-old Wistar-Kyoto rats was examined using two distinct experimental growth restriction models. Uterine ligation surgery restriction or a sham surgery was conducted at day 18 of pregnancy, whilst a food restriction diet (40% control diet) began on gestational day 15. Extracellular vascular reactivity was studied using intact mesenteric arteries, which were subsequently chemically permeabilized using 50 μM β-escin to examine Ca2+-activated force. Peak contractile responses to a K+-induced depolarization and phenylephrine were significantly elevated due to an increase in maximum Ca2+-activated force in the male surgery restricted group. No changes in contractile forces were reported between female experimental groups. Sections of mesenteric artery were examined using western blotting, revealing IUGR increased the relative abundance of the voltage-gated Ca2+ channel, inositol-1,4,5-trisphosphate receptor and myosin light chain kinase, in both male growth restricted groups, whereas no changes were seen in females. These findings demonstrate for the first time in 1-year-old rats that changes in vascular reactivity due to IUGR are caused by a change in Ca2+-activated force and shifts in important contractile protein content. These changes affect the Wistar-Kyoto rat in a sex-specific and maternal insult-dependent manner.
Collapse
|
|
19
|
Maternal nutritional restriction during gestation impacts differently on offspring muscular and elastic arteries and is associated with increased carotid resistance and ventricular afterload in maturity. J Dev Orig Health Dis 2019; 11:7-17. [PMID: 31138338 DOI: 10.1017/s2040174419000230] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND Intrauterine undernutrition could impact offspring left ventricle (LV) afterload and arterial function. The changes observed in adulthood could differ depending on the arterial type, pathway and properties studied. Aim: To analyze whether undernutrition during early and mid-gestation is associated with changes in cardiovascular properties in adulthood. METHODS Pregnant ewes were assigned to one of the two treatment groups: (1) standard nutritional offer (high pasture-allowance, HPA; n = 16) or (2) nutritional restriction (50-75% of control intake) from before conception until day 122 of gestation (≈85% term) (low pasture allowance, LPA; n = 17). When offspring reached adult life, cardiovascular parameters were assessed in conscious animals (applanation tonometry, vascular echography). MEASUREMENTS Peripheral and aortic pressure, carotid and femoral arteries diameters, intima-media thickness and stiffness, blood flow, local and regional resistances and LV afterload were measured. Blood samples were collected. Parameters were compared before and after adjustment for nutritional characteristics at birth and at the time of the cardiovascular evaluation. RESULTS Doppler-derived cerebral vascular resistances, mean pressure/flow ratio (carotid resistance) and afterload indexes were higher in descendants from LPA than in descendants from HPA ewes (p < 0.05). Descendants from LPA had lower femoral diameters (p < 0.05). Cardiovascular changes associated with nutritional restriction during pregnancy did not depend on the offsprings' nutritional conditions at birth and/or in adult life. CONCLUSION Pregnant ewes that experienced undernutrition gave birth to female offspring that exhibited increased carotid pathway resistances (cerebral microcirculatory resistances) and LV afterload when they reached the age of 2.5 years. There were differences in the impact of nutritional deficiency on elastic and muscular arteries.
Collapse
|
|
20
|
Hsu CN, Tain YL. The Good, the Bad, and the Ugly of Pregnancy Nutrients and Developmental Programming of Adult Disease. Nutrients 2019; 11:nu11040894. [PMID: 31010060 PMCID: PMC6520975 DOI: 10.3390/nu11040894] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 04/16/2019] [Accepted: 04/17/2019] [Indexed: 12/14/2022] Open
Abstract
Maternal nutrition plays a decisive role in developmental programming of many non-communicable diseases (NCDs). A variety of nutritional insults during gestation can cause programming and contribute to the development of adult-onset diseases. Nutritional interventions during pregnancy may serve as reprogramming strategies to reverse programming processes and prevent NCDs. In this review, firstly we summarize epidemiological evidence for nutritional programming of human disease. It will also discuss evidence from animal models, for the common mechanisms underlying nutritional programming, and potential nutritional interventions used as reprogramming strategies.
Collapse
Affiliation(s)
- Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| |
Collapse
|
|
21
|
Schutt AK, Blesson CS, Hsu JW, Valdes CT, Gibbons WE, Jahoor F, Yallampalli C. Preovulatory exposure to a protein-restricted diet disrupts amino acid kinetics and alters mitochondrial structure and function in the rat oocyte and is partially rescued by folic acid. Reprod Biol Endocrinol 2019; 17:12. [PMID: 30654812 PMCID: PMC6337842 DOI: 10.1186/s12958-019-0458-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 01/14/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Detrimental exposures during pregnancy have been implicated in programming offspring to develop permanent changes in physiology and metabolism, increasing the risk for developing diseases in adulthood such as hypertension, diabetes, heart disease and obesity. This study investigated the effects of protein restriction on the metabolism of amino acids within the oocyte, liver, and whole organism in a rat model as well as effects on mitochondrial ultrastructure and function in the cumulus oocyte complex. METHODS Wistar outbred female rats 8-11 weeks of age (n = 24) were assigned to three isocaloric dietary groups, including control (C), low protein (LP) and low protein supplemented with folate (LPF). Animals were superovulated and 48 h later underwent central catheterization. Isotopic tracers of 1-13C-5C2H3-methionine, 2H2-cysteine, U-13C3-cysteine and U-13C3-serine were administered by a 4 h prime-constant rate infusion. After sacrifice, oocytes were denuded of cumulus cells and liver specimens were obtained. RESULTS Oocytes demonstrated reduced serine flux in LP vs. LPF (p < 0.05), reduced cysteine flux in LP and LPF vs. C (p < 0.05), and a trend toward reduced transsulfuration in LP vs. C and LPF. Folic acid supplementation reversed observed effects on serine flux and transsulfuration. Preovulatory protein restriction increased whole-body methionine transmethylation, methionine transsulfuration and the flux of serine in LP and LPF vs. C (p = 0.003, p = 0.002, p = 0.005). The concentration of glutathione was increased in erythrocytes and liver in LP and LPF vs. C (p = 0.003 and p = 0.0003). Oocyte mitochondrial ultrastructure in LP and LPF had increased proportions of abnormal mitochondria vs. C (p < 0.01 and p < 0.05). Cumulus cell mitochondrial ultrastructure in LP and LPF groups had increased proportions of abnormal mitochondria vs. C (p < 0.001 and p < 0.05). Preovulatory protein restriction altered oocyte expression of Drp1, Opa-1, Mfn1/2, Parl and Ndufb6 (p < 0.05) and Hk2 (p < 0.01), which are genes involved in mitochondrial fission (division) and fusion, mitochondrial apoptotic mechanisms, respiratory electron transport and glucose metabolism. CONCLUSIONS Preovulatory protein restriction resulted in altered amino acid metabolism, abnormal cumulus oocyte complex mitochondrial ultrastructure and differential oocyte expression of genes related to mitochondrial biogenesis.
Collapse
Affiliation(s)
- Amy K. Schutt
- 0000 0001 2160 926Xgrid.39382.33Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX USA
- 0000 0001 2200 2638grid.416975.8Texas Children’s Hospital Pavilion for Women, 6651 Main St, Suite F1020, Houston, TX 77030 USA
| | - Chellakkan S. Blesson
- 0000 0001 2160 926Xgrid.39382.33Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX USA
| | - Jean W. Hsu
- 0000 0001 2160 926Xgrid.39382.33USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - Cecilia T. Valdes
- 0000 0001 2160 926Xgrid.39382.33Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX USA
| | - William E. Gibbons
- 0000 0001 2160 926Xgrid.39382.33Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX USA
| | - Farook Jahoor
- 0000 0001 2160 926Xgrid.39382.33USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX USA
| | - Chandra Yallampalli
- 0000 0001 2160 926Xgrid.39382.33Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX USA
| |
Collapse
|
|
22
|
Hsu CN, Tain YL. The Double-Edged Sword Effects of Maternal Nutrition in the Developmental Programming of Hypertension. Nutrients 2018; 10:nu10121917. [PMID: 30518129 PMCID: PMC6316180 DOI: 10.3390/nu10121917] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 11/22/2018] [Accepted: 11/30/2018] [Indexed: 02/06/2023] Open
Abstract
Hypertension is a growing global epidemic. Developmental programming resulting in hypertension can begin in early life. Maternal nutrition status has important implications as a double-edged sword in the developmental programming of hypertension. Imbalanced maternal nutrition causes offspring's hypertension, while specific nutritional interventions during pregnancy and lactation may serve as reprogramming strategies to reverse programming processes and prevent the development of hypertension. In this review, we first summarize the human and animal data supporting the link between maternal nutrition and developmental programming of hypertension. This review also presents common mechanisms underlying nutritional programming-induced hypertension. This will be followed by studies documenting nutritional interventions as reprogramming strategies to protect against hypertension from developmental origins. The identification of ideal nutritional interventions for the prevention of hypertension development that begins early in life will have a lifelong impact, with profound savings in the global burden of hypertension.
Collapse
Affiliation(s)
- Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - You-Lin Tain
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
- Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| |
Collapse
|
|
23
|
Brennan LJ, Goulopoulou S, Bourque SL. Prenatal therapeutics and programming of cardiovascular function. Pharmacol Res 2018; 139:261-272. [PMID: 30458216 DOI: 10.1016/j.phrs.2018.11.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/15/2018] [Accepted: 11/15/2018] [Indexed: 01/08/2023]
Abstract
Cardiovascular diseases (CVD) are a leading cause of mortality worldwide. Despite recognizing the importance of risk factors in dictating CVD susceptibility and onset, patient treatment remains a challenging endeavor. Increasingly, the benefits of prevention and mitigation of risk factors earlier in life are being acknowledged. The developmental origins of health and disease posits that insults during specific periods of development can influence long-term health outcomes; this occurs because the developing organism is highly plastic, and hence vulnerable to environmental perturbations. By extension, targeted therapeutics instituted during critical periods of development may confer long-term protection, and thus reduce the risk of CVD in later life. This review provides a brief overview of models of developmental programming, and then discusses the impact of perinatal therapeutic interventions on long-term cardiovascular function in the offspring. The discussion focuses on bioactive food components, as well as pharmacological agents currently approved for use in pregnancy; in short, those agents most likely to be used in pregnancy and early childhood.
Collapse
Affiliation(s)
- Lesley J Brennan
- Department of Anesthesiology & Pain Medicine, Pharmacology, and Pediatrics, Women and Children's Health Research Institute, University of Alberta, Canada.
| | - Styliani Goulopoulou
- Department of Physiology and Anatomy, University of North Texas Health Science Center, United States.
| | - Stephane L Bourque
- Department of Anesthesiology & Pain Medicine, Pharmacology, and Pediatrics, Women and Children's Health Research Institute, University of Alberta, Canada.
| |
Collapse
|
|
24
|
Camm EJ, Botting KJ, Sferruzzi-Perri AN. Near to One's Heart: The Intimate Relationship Between the Placenta and Fetal Heart. Front Physiol 2018; 9:629. [PMID: 29997513 PMCID: PMC6029139 DOI: 10.3389/fphys.2018.00629] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/09/2018] [Indexed: 01/19/2023] Open
Abstract
The development of the fetal heart is exquisitely controlled by a multitude of factors, ranging from humoral to mechanical forces. The gatekeeper regulating many of these factors is the placenta, an external fetal organ. As such, resistance within the placental vascular bed has a direct influence on the fetal circulation and therefore, the developing heart. In addition, the placenta serves as the interface between the mother and fetus, controlling substrate exchange and release of hormones into both circulations. The intricate relationship between the placenta and fetal heart is appreciated in instances of clinical placental pathology. Abnormal umbilical cord insertion is associated with congenital heart defects. Likewise, twin-to-twin transfusion syndrome, where monochorionic twins have unequal sharing of their placenta due to inter-twin vascular anastomoses, can result in cardiac remodeling and dysfunction in both fetuses. Moreover, epidemiological studies have suggested a link between placental phenotypic traits and increased risk of cardiovascular disease in adult life. To date, the mechanistic basis of the relationships between the placenta, fetal heart development and later risk of cardiac dysfunction have not been fully elucidated. However, studies using environmental exposures and gene manipulations in experimental animals are providing insights into the pathways involved. Likewise, surgical instrumentation of the maternal and fetal circulations in large animal species has enabled the manipulation of specific humoral and mechanical factors to investigate their roles in fetal cardiac development. This review will focus on such studies and what is known to date about the link between the placenta and heart development.
Collapse
Affiliation(s)
- Emily J Camm
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Kimberley J Botting
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience and Centre for Trophoblast Research, University of Cambridge, Cambridge, United Kingdom
| |
Collapse
|
|
25
|
Grandvuillemin I, Buffat C, Boubred F, Lamy E, Fromonot J, Charpiot P, Simoncini S, Sabatier F, Dignat-George F, Peyter AC, Simeoni U, Yzydorczyk C. Arginase upregulation and eNOS uncoupling contribute to impaired endothelium-dependent vasodilation in a rat model of intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 2018; 315:R509-R520. [PMID: 29741931 DOI: 10.1152/ajpregu.00354.2017] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Individuals born after intrauterine growth restriction (IUGR) are at increased risk of developing cardiovascular diseases in adulthood, notably hypertension (HTN). Alterations in the vascular system, particularly impaired endothelium-dependent vasodilation, may play an important role in long-term effects of IUGR. Whether such vascular dysfunction precedes HTN has not been fully established in individuals born after IUGR. Moreover, the intimate mechanisms of altered endothelium-dependent vasodilation remain incompletely elucidated. We therefore investigated, using a rat model of IUGR, whether impaired endothelium-dependent relaxation precedes the development of HTN and whether key components of the l-arginine-nitric oxide (NO) pathway are involved in its pathogenesis. Pregnant rats were fed with a control (CTRL, 23% casein) or low-protein diet (LPD, 9% casein) to induce IUGR. Systolic blood pressure (SBP) was measured by tail-cuff plethysmography in 5- and 8-wk-old male offspring. Aortic rings were isolated to investigate relaxation to acetylcholine, NO production, endothelial NO synthase (eNOS) protein content, arginase activity, and superoxide anion production. SBP was not different at 5 wk but significantly increased in 8-wk-old offspring of maternal LPD (LP) versus CTRL offspring. In 5-wk-old LP versus CTRL males, endothelium-dependent vasorelaxation was significantly impaired but restored by preincubation with l-arginine or the arginase inhibitor S-(2-boronoethyl)-l-cysteine; NO production was significantly reduced but restored by l-arginine pretreatment; total eNOS protein, dimer-to-monomer ratio, and arginase activity were significantly increased; superoxide anion production was significantly enhanced but normalized by pretreatment with the NO synthase inhibitor Nω-nitro-l-arginine. In this model, IUGR leads to early-impaired endothelium-dependent vasorelaxation, resulting from arginase upregulation and eNOS uncoupling, which precedes the development of HTN.
Collapse
Affiliation(s)
- Isabelle Grandvuillemin
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cardiovasculaire et Nutrition (C2VN), Aix Marseille University, Marseille, France.,Department of Neonatology, Assistance Publique Hôpitaux de Marseille (APHM), Centre Hospitalier Universitaire (CHU) La Conception, Marseille, France
| | - Christophe Buffat
- Unité de Recherche sur les Maladies Infectieuses Tropicales, Emergentes, Laboratory of Biochimical and Molecular Biology, Centre National de la Recherche Scientifique (CNRS), APHM, CHU la Conception, Aix Marseille University, Marseille, France
| | - Farid Boubred
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cardiovasculaire et Nutrition (C2VN), Aix Marseille University, Marseille, France.,Department of Neonatology, Assistance Publique Hôpitaux de Marseille (APHM), Centre Hospitalier Universitaire (CHU) La Conception, Marseille, France
| | - Edouard Lamy
- CNRS, Inst Movement Sci (ISM); Service Central de la Qualité et de l'Information Pharmaceutiques, APHM, Aix-Marseille University, Marseille, France
| | - Julien Fromonot
- UMR MD2 and Institute of Biological Research French Defense Ministry (IRBA), Aix-Marseille University, Marseille, France
| | - Philippe Charpiot
- CNRS, Inst Movement Sci (ISM); Service Central de la Qualité et de l'Information Pharmaceutiques, APHM, Aix-Marseille University, Marseille, France
| | - Stephanie Simoncini
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cardiovasculaire et Nutrition (C2VN), Aix Marseille University, Marseille, France
| | - Florence Sabatier
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cardiovasculaire et Nutrition (C2VN), Aix Marseille University, Marseille, France
| | - Françoise Dignat-George
- Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Cardiovasculaire et Nutrition (C2VN), Aix Marseille University, Marseille, France
| | - Anne-Christine Peyter
- Neonatal Research Laboratory, Clinic of Neonatology, Department Woman-Mother-Child, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne, Lausanne, Switzerland
| | - Umberto Simeoni
- Developmental Origins of Health and Disease (DOHaD) Laboratory, Division of Pediatrics, Department Woman-Mother-Child, CHUV, University of Lausanne, Lausanne, Switzerland
| | - Catherine Yzydorczyk
- Developmental Origins of Health and Disease (DOHaD) Laboratory, Division of Pediatrics, Department Woman-Mother-Child, CHUV, University of Lausanne, Lausanne, Switzerland
| |
Collapse
|
|
26
|
Folate treatment partially reverses gestational low-protein diet-induced glucose intolerance and the magnitude of reversal is age and sex dependent. Nutrition 2018; 49:81-89. [PMID: 29500969 DOI: 10.1016/j.nut.2017.10.014] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 09/18/2017] [Accepted: 10/16/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Gestational low-protein (LP) programming causes glucose intolerance (GI) and insulin resistance (IR) in adult offspring. Folate supplementation has been shown to rescue the offspring from various programming effects. The aim of this study was to investigate whether folate supplementation during pregnancy reverses LP-induced GI and IR. METHODS Pregnant rats were fed control (20% protein), isocaloric low-protein (LP, 6%) or LP with 5 mg/kg folate (LPF) diets from gestational day 4 to delivery. The control diet was given during lactation and to pups after weaning. Glucose tolerance test was done at 1, 2, and 3 mo of age followed by euglycemic-hyperinsulinemic clamp at 4 mo. Rats were sacrificed at 4 mo and their gonadal, renal, inguinal, brown fat, and pancreas were weighed and expressed relative to their body weight. RESULTS LP- and LPF-fed dams showed similar weight loss during late pregnancy after decreased feed intake. Both LP and LPF pups were smaller at birth but their weights caught up like that of controls by 3 mo. In males, folate supplementation reduced LP-induced GI at 2 mo (glucose area under the curve [AUC]: 1940 mmol/L × 180 min in LP, 1629 mmol/L × 180 min in LPF, and 1653 mmol/L × 180 min in controls; P <0.05, LP versus control and P <0.01, LP versus LPF) but the effect diminished at 3 mo. In females, folate reduced GI at 1 mo (glucose AUC: 1406 mmol/L × 180 min in LP, 1264 mmol/L × 180 min in LPF, and 1281 mmol/L × 180 min in controls; P <0.05, LP versus control and LP versus LPF) but had no effect at 2 and 3 mo. Interestingly, the LPF group had higher pancreatic weights than other groups, suggesting that folate helps in pancreatic development enabling the LPF rats to produce/secrete more insulin to maintain euglycemia. Euglycemic-hyperinsulinemic clamp shows both LP and LPF are insulin resistant compared with controls by 4 mo with LPF more severe than LP in males. Interestingly, females were more insulin resistant than males. CONCLUSIONS Folate treatment partially reverses LP-induced GI and the magnitude of reversal is age and sex dependent. Furthermore, folate treatment does not reverse IR in either sex but makes it worse in males at 4 mo. The present study demonstrated that folate treatment is not sufficient to rescue the LP programming effects.
Collapse
|
|
27
|
Dos Santos da Silva LLG, Saunders C, Campos ABF, Belfort GP, de Carvalho Padilha P, Pereira RA, Bornia RG. Hypertensive disorders of pregnancy in women with gestational diabetes mellitus from Rio de Janeiro, Brazil. Pregnancy Hypertens 2017; 10:196-201. [PMID: 29153679 DOI: 10.1016/j.preghy.2017.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 08/21/2017] [Accepted: 08/26/2017] [Indexed: 01/19/2023]
Abstract
Pregnant women with Gestational Diabetes Mellitus (GDM) have a greater chance of developing Hypertensive Disorders of Pregnancy (HDP) by the effect of insulin resistance in nitric oxide action.This study aims to describe factors associated with the development of HDP in pregnant women with GDM, assisted in a public maternity hospital in Rio de Janeiro, Brazil. This is a cross-sectional study including 292 pregnant adult women with GDM assisted at Maternidade Escola of the Universidade Federal do Rio de Janeiro. The women were examined during pregnancy and postpartum. Data were collected between 2011 and 2014 from medical records and through in-person interviews. The Student t-test and the chi-square test were applied; additionally, the magnitude of the association between independents variables and HDP was estimated by logistic regression models. The occurrence of HDP was observed in 19.5% (n=57) of the evaluated women: 9.2% had pregnancy hypertension and 10.3% had preeclampsia. The chance of HDP was higher among women with GDM in a previous pregnancy (Odds Ratio-OR=3.8; Confidence Interval of 95%-95% CI: 1.1; 12.8) and among those who were 35 years old or older (OR 3.3; 95% CI: 1.2; 8.7) after controlling the effects of pre-gestational weight and dietary ingestion of calcium, riboflavin, thiamine, vitamin A and protein. Women that had any alteration in blood pressure in a previous pregnancy and those over 35 years old were under higher risk of HDP. The findings may help in the design of interventions aiming to prevent HDP in adult women.
Collapse
Affiliation(s)
| | - Cláudia Saunders
- Professional Masters Program in Clinical Nutrition, Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Professional Masters Program in Perinatal Health of Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Aline Bull Ferreira Campos
- Graduate Program in Nutrition (PhD in Nutritional Sciences), Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Gabriella Pinto Belfort
- Graduate Program in Nutrition (PhD in Nutritional Sciences), Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Patricia de Carvalho Padilha
- Professional Masters Program in Clinical Nutrition, Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Professional Masters Program in Perinatal Health of Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Rosangela Alves Pereira
- Graduate Program in Nutrition (PhD in Nutritional Sciences), Instituto de Nutrição Josué de Castro da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| | - Rita Guérios Bornia
- Professional Masters Program in Perinatal Health of Maternidade Escola da Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
| |
Collapse
|
|
28
|
Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches. J Dev Orig Health Dis 2017; 8:448-464. [PMID: 28460648 DOI: 10.1017/s2040174417000265] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Individuals born after intrauterine growth restriction (IUGR) have an increased risk of perinatal morbidity/mortality, and those who survive face long-term consequences such as cardiovascular-related diseases, including systemic hypertension, atherosclerosis, coronary heart disease and chronic kidney disease. In addition to the demonstrated long-term effects of decreased nephron endowment and hyperactivity of the hypothalamic-pituitary-adrenal axis, individuals born after IUGR also exhibit early alterations in vascular structure and function, which have been identified as key factors of the development of cardiovascular-related diseases. The endothelium plays a major role in maintaining vascular function and homeostasis. Therefore, it is not surprising that impaired endothelial function can lead to the long-term development of vascular-related diseases. Endothelial dysfunction, particularly impaired endothelium-dependent vasodilation and vascular remodeling, involves decreased nitric oxide (NO) bioavailability, impaired endothelial NO synthase functionality, increased oxidative stress, endothelial progenitor cells dysfunction and accelerated vascular senescence. Preventive approaches such as breastfeeding, supplementation with folate, vitamins, antioxidants, L-citrulline, L-arginine and treatment with NO modulators represent promising strategies for improving endothelial function, mitigating long-term outcomes and possibly preventing IUGR of vascular origin. Moreover, the identification of early biomarkers of endothelial dysfunction, especially epigenetic biomarkers, could allow early screening and follow-up of individuals at risk of developing cardiovascular and renal diseases, thus contributing to the development of preventive and therapeutic strategies to avert the long-term effects of endothelial dysfunction in infants born after IUGR.
Collapse
|
|
29
|
Wang Y, Liu H, Sun Z. Lamarck rises from his grave: parental environment-induced epigenetic inheritance in model organisms and humans. Biol Rev Camb Philos Soc 2017; 92:2084-2111. [PMID: 28220606 DOI: 10.1111/brv.12322] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 01/12/2017] [Accepted: 01/18/2017] [Indexed: 12/12/2022]
Abstract
Organisms can change their physiological/behavioural traits to adapt and survive in changed environments. However, whether these acquired traits can be inherited across generations through non-genetic alterations has been a topic of debate for over a century. Emerging evidence indicates that both ancestral and parental experiences, including nutrition, environmental toxins, nurturing behaviour, and social stress, can have powerful effects on the physiological, metabolic and cellular functions in an organism. In certain circumstances, these effects can be transmitted across several generations through epigenetic (i.e. non-DNA sequence-based rather than mutational) modifications. In this review, we summarize recent evidence on epigenetic inheritance from parental environment-induced developmental and physiological alterations in nematodes, fruit flies, zebrafish, rodents, and humans. The epigenetic modifications demonstrated to be both susceptible to modulation by environmental cues and heritable, including DNA methylation, histone modification, and small non-coding RNAs, are also summarized. We particularly focus on evidence that parental environment-induced epigenetic alterations are transmitted through both the maternal and paternal germlines and exert sex-specific effects. The thought-provoking data presented here raise fundamental questions about the mechanisms responsible for these phenomena. In particular, the means that define the specificity of the response to parental experience in the gamete epigenome and that direct the establishment of the specific epigenetic change in the developing embryos, as well as in specific tissues in the descendants, remain obscure and require elucidation. More precise epigenetic assessment at both the genome-wide level and single-cell resolution as well as strategies for breeding at relatively sensitive periods of development and manipulation aimed at specific epigenetic modification are imperative for identifying parental environment-induced epigenetic marks across generations. Considering their diverse epigenetic architectures, the conservation and prevalence of the mechanisms underlying epigenetic inheritance in non-mammals require further investigation in mammals. Interpretation of the consequences arising from epigenetic inheritance on organisms and a better understanding of the underlying mechanisms will provide insight into how gene-environment interactions shape developmental processes and physiological functions, which in turn may have wide-ranging implications for human health, and understanding biological adaptation and evolution.
Collapse
Affiliation(s)
- Yan Wang
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China
| | - Huijie Liu
- Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| | - Zhongsheng Sun
- Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing 100101, China.,Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou 325000, China
| |
Collapse
|
|
30
|
Xie L, Zhang K, Rasmussen D, Wang J, Wu D, Roemmich JN, Bundy A, Johnson WT, Claycombe K. Effects of prenatal low protein and postnatal high fat diets on visceral adipose tissue macrophage phenotypes and IL-6 expression in Sprague Dawley rat offspring. PLoS One 2017; 12:e0169581. [PMID: 28141871 PMCID: PMC5283658 DOI: 10.1371/journal.pone.0169581] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Accepted: 12/19/2016] [Indexed: 01/05/2023] Open
Abstract
Adipose tissue macrophages (ATM) are implicated in adipose tissue inflammation and obesity-related insulin resistance. Maternal low protein models result in fetal programming of obesity. The study aims to answer whether maternal undernutrition by protein restriction affects the ATM M1 or M2 phenotype under postnatal high fat diet in F1 offspring. Using a rat model of prenatal low protein (LP, 8% protein) diet followed by a postnatal high fat energy diet (HE, 45% fat) or low fat normal energy diet (NE, 10% fat) for 12 weeks, we investigated the effects of these diets on adiposity, programming of the offspring ATM phenotype, and the associated inflammatory response in adipose tissue. Fat mass in newborn and 12-week old LP fed offspring was lower than that of normal protein (20%; NP) fed offspring; however, the adipose tissue growth rate was higher compared to the NP fed offspring. While LP did not affect the number of CD68+ or CD206+ cells in adipose tissue of NE offspring, it attenuated the number of these cells in offspring fed HE. In offspring fed HE, LP offspring had a lower percentage of CD11c+CD206+ ATMs, whose abundancy was correlated with the size of the adipocytes. Noteworthy, similar to HE treatment, LP increased gene expression of IL-6 within ATMs. Two-way ANOVA showed an interaction of prenatal LP and postnatal HE on IL-6 and IL-1β transcription. Overall, both LP and HE diets impact ATM phenotype by affecting the ratio of CD11c+CD206+ ATMs and the expression of IL-6.
Collapse
Affiliation(s)
- Linglin Xie
- Department of Nutrition and Food Sciences, Texas A&M University, College Station, Texas, United States of America
- Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
- * E-mail: (LX); (KJC)
| | - Ke Zhang
- Department of Pathology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
- ND INBRE Bioinformatics Core, University of North Dakota, Grand Forks, North Dakota, United States of America
| | - Dane Rasmussen
- Department of Basic Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America
| | - Junpeng Wang
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America
| | - Dayong Wu
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts, United States of America
| | - James N. Roemmich
- USDA Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, United States of America
| | - Amy Bundy
- USDA Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, United States of America
| | - W. Thomas Johnson
- USDA Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, United States of America
| | - Kate Claycombe
- USDA Agricultural Research Service, Grand Forks Human Nutrition Research Center, Grand Forks, North Dakota, United States of America
- * E-mail: (LX); (KJC)
| |
Collapse
|
|
31
|
Paulino-Silva KM, Costa-Silva JH. Hypertension in rat offspring subjected to perinatal protein malnutrition is not related to the baroreflex dysfunction. Clin Exp Pharmacol Physiol 2016; 43:1046-1053. [DOI: 10.1111/1440-1681.12628] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 07/18/2016] [Accepted: 07/23/2016] [Indexed: 11/30/2022]
Affiliation(s)
- K M Paulino-Silva
- Department of Physical Education and Sports Sciences; Academic Center of Vitória (CAV); Federal University of Pernambuco; Vitória de Santo Antão Brazil
| | - J H Costa-Silva
- Department of Physical Education and Sports Sciences; Academic Center of Vitória (CAV); Federal University of Pernambuco; Vitória de Santo Antão Brazil
| |
Collapse
|
|
32
|
More AS, Mishra JS, Hankins GD, Kumar S. Prenatal Testosterone Exposure Decreases Aldosterone Production but Maintains Normal Plasma Volume and Increases Blood Pressure in Adult Female Rats. Biol Reprod 2016; 95:42. [PMID: 27385784 PMCID: PMC5029475 DOI: 10.1095/biolreprod.116.141705] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 06/29/2016] [Indexed: 12/14/2022] Open
Abstract
Plasma testosterone levels are elevated in pregnant women with preeclampsia and polycystic ovaries; their offspring are at increased risk for hypertension during adult life. We tested the hypothesis that prenatal testosterone exposure induces dysregulation of the renin-angiotensin-aldosterone system, which is known to play an important role in water and electrolyte balance and blood pressure regulation. Female rats (6 mo old) prenatally exposed to testosterone were examined for adrenal expression of steroidogenic genes, telemetric blood pressure, blood volume and Na+ and K+ levels, plasma aldosterone, angiotensin II and vasopressin levels, and vascular responses to angiotensin II and arg8-vasopressin. The levels of Cyp11b2 (aldosterone synthase), but not the other adrenal steroidogenic genes, were decreased in testosterone females. Accordingly, plasma aldosterone levels were lower in testosterone females. Plasma volume and serum and urine Na+ and K+ levels were not significantly different between control and testosterone females; however, prenatal testosterone exposure significantly increased plasma vasopressin and angiotensin II levels and arterial pressure in adult females. In testosterone females, mesenteric artery contractile responses to angiotensin II were significantly greater, while contractile responses to vasopressin were unaffected. Angiotensin II type-1 receptor expression was increased, while angiotensin II type-2 receptor was decreased in testosterone arteries. These results suggest that prenatal testosterone exposure downregulates adrenal Cyp11b2 expression, leading to decreased plasma aldosterone levels. Elevated angiotensin II and vasopressin levels along with enhanced vascular responsiveness to angiotensin II may serve as an underlying mechanism to maintain plasma volume and Na+ and K+ levels and mediate hypertension in adult testosterone females.
Collapse
Affiliation(s)
- Amar S More
- Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas
| | - Jay S Mishra
- Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas
| | - Gary D Hankins
- Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas
| | - Sathish Kumar
- Division of Reproductive Endocrinology, Department of Obstetrics & Gynecology, The University of Texas Medical Branch at Galveston, Galveston, Texas
| |
Collapse
|
|
33
|
|
|
34
|
Sferruzzi-Perri AN, Camm EJ. The Programming Power of the Placenta. Front Physiol 2016; 7:33. [PMID: 27014074 PMCID: PMC4789467 DOI: 10.3389/fphys.2016.00033] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Accepted: 01/25/2016] [Indexed: 12/23/2022] Open
Abstract
Size at birth is a critical determinant of life expectancy, and is dependent primarily on the placental supply of nutrients. However, the placenta is not just a passive organ for the materno-fetal transfer of nutrients and oxygen. Studies show that the placenta can adapt morphologically and functionally to optimize substrate supply, and thus fetal growth, under adverse intrauterine conditions. These adaptations help meet the fetal drive for growth, and their effectiveness will determine the amount and relative proportions of specific metabolic substrates supplied to the fetus at different stages of development. This flow of nutrients will ultimately program physiological systems at the gene, cell, tissue, organ, and system levels, and inadequacies can cause permanent structural and functional changes that lead to overt disease, particularly with increasing age. This review examines the environmental regulation of the placental phenotype with particular emphasis on the impact of maternal nutritional challenges and oxygen scarcity in mice, rats and guinea pigs. It also focuses on the effects of such conditions on fetal growth and the developmental programming of disease postnatally. A challenge for future research is to link placental structure and function with clinical phenotypes in the offspring.
Collapse
Affiliation(s)
| | - Emily J Camm
- Department of Physiology, Development and Neuroscience, University of Cambridge Cambridge, UK
| |
Collapse
|
|
35
|
Lee JS, Fang SY, Roan JN, Jou IM, Lam CF. Spinal cord injury enhances arterial expression and reactivity of α1-adrenergic receptors-mechanistic investigation into autonomic dysreflexia. Spine J 2016; 16:65-71. [PMID: 26433037 DOI: 10.1016/j.spinee.2015.09.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 07/26/2015] [Accepted: 09/03/2015] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Autonomic dysreflexia (AD) usually presents with a significant increase in blood pressure, and uncontrollable autonomic response to stimuli below the level of spinal cord injury (SCI). PURPOSE This study analyzed the vasomotor function and molecular changes in the peripheral arteries below the lesion of SCI to characterize the mechanism of autonomic dysreflexia. STUDY DESIGN This was a randomized experimental study in rats. METHODS Contusive SCI was induced using a force-calibrated weight-drop device at the T10 level in anesthetized rats. Two weeks after severe SCI, blood flow in the femoral arteries was measured, and the vasomotor function and expression of α1-adrenergic receptors were analyzed. RESULTS Blood flow in the femoral artery was significantly reduced in rats with SCI (8.0±2 vs. 17.5±4 mL/min, SCI vs. control, respectively; p=.016). The contraction responses of femoral artery segments to cumulative addition of α1-adrenergic agonist phenylephrine were significantly enhanced in rats with SCI. Expression of α1-adrenergic receptor was upregulated in the medial layer of femoral artery vascular homogenates of these rats. CONCLUSION Our study provides evidence demonstrating that prolonged denervation below the lesion level following SCI results in a compensatory increased expression of α1-adrenergic receptors in the arterial smooth muscle layer, thereby enhancing the responsiveness to α1-adrenergic agonist and potentiating the development of AD.
Collapse
Affiliation(s)
- Jung-Shun Lee
- Divisions of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd, Tainan 704, Taiwan
| | - Shih-Yuan Fang
- Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd, Tainan 704, Taiwan
| | - Jun-Neng Roan
- Divisions of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd, Tainan 704, Taiwan
| | - I-Ming Jou
- Department of Orthopedics, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd, Tainan 704, Taiwan
| | - Chen-Fuh Lam
- Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Rd, Tainan 704, Taiwan; Department of Anesthesiology, Buddhist Tzu Chi General Hospital and Tzu Chi University School of Medicine, 707 Chung Yang Rd Section 3, Hualien 907, Taiwan.
| |
Collapse
|
|
36
|
You YA, Lee JH, Kwon EJ, Yoo JY, Kwon WS, Pang MG, Kim YJ. Proteomic Analysis of One-carbon Metabolism-related Marker in Liver of Rat Offspring. Mol Cell Proteomics 2015; 14:2901-9. [PMID: 26342040 PMCID: PMC4638034 DOI: 10.1074/mcp.m114.046888] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2014] [Indexed: 01/17/2023] Open
Abstract
Maternal food intake has a significant effect on the fetal environment, and an inadequate maternal diet may result in intrauterine growth restriction. Intrauterine growth restriction newborn rat pups nursed by normal diet-fed dams exhibited rapid catch-up growth, which plays a critical role in the risk for metabolic and cardiovascular disease in later life. Specifically, one-carbon metabolism in the liver plays a critical role in placental and fetal growth. Impaired functioning of one-carbon metabolism is associated with increased homocysteine levels. In this study, we applied a comprehensive proteomic approach to identify differential expression of proteins related to one-carbon metabolism in the livers of rat offspring as an effect of maternal food restriction during gestation. Data are available via ProteomeXchange with identifier PXD002578. We determined that betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial (ATP5B) expression levels were significantly reduced in the livers of rat offspring exposed to maternal food restriction during gestation compared with in the offspring of rats fed a normal diet (p < 0.05). Moreover, the expression levels of betaine-homocysteine S-methyltransferase 1, methylenetetrahydrofolate dehydrogenase 1, and ATP synthase subunit beta mitochondrial were negatively correlated with serum homocysteine concentration in male offspring exposed to maternal food restriction during gestation and normal diet during lactation. However, in female offspring only expression levels of methylenetetrahydrofolate dehydrogenase 1 were negatively correlated with homocysteine concentration. This study shows that maternal food restriction during late gestation and normal diet during lactation lead to increased homocysteine concentration through disturbance of one-carbon metabolism in the livers of male offspring. This suggests that male offspring have an increased gender-specific susceptibility to disease in later life through fetal programming.
Collapse
Affiliation(s)
- Young-Ah You
- From the ‡Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea
| | - Ji Hye Lee
- §Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, 158-710, Korea
| | - Eun Jin Kwon
- §Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, 158-710, Korea
| | - Jae Young Yoo
- From the ‡Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea
| | - Woo-Sung Kwon
- ¶Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do 456-756, Korea
| | - Myung-Geol Pang
- ¶Department of Animal Science and Technology, Chung-Ang University, Anseong, Gyeonggi-Do 456-756, Korea
| | - Young Ju Kim
- From the ‡Medical Research Institute, School of Medicine, Ewha Womans University, Seoul 158-710, Korea; §Department of Obstetrics and Gynecology, Ewha Womans University, Seoul, 158-710, Korea;
| |
Collapse
|
|
37
|
Long-term effects of maternal undernutrition on offspring carotid artery remodeling: role of miR-29c. J Dev Orig Health Dis 2015; 6:342-9. [PMID: 26008599 DOI: 10.1017/s2040174415001208] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The purpose of this study was to examine the hypothesis that excess maternal glucocorticoids in response to maternal undernutrition programs the expression of extracellular matrix (ECM) components potentially by miR-29c. We measured the expression of mRNA (qRT-PCR) and protein (Western blot) for collagen 3A1, collagen 4A5 and matrix metalloproteinase 2 (MMP2) in offspring carotid arteries from three groups of dams: 50% food-restricted in latter half of gestation [maternal undernutrition (MUN)], MUN dams who received metyrapone (MET) (500 mg/ml ) in drinking water from day 10 of gestation to term, and control dams fed an ad libitum diet. The expression of miR-29c was significantly decreased at 3 weeks, 3 months and 9 months in MUN carotid arteries, and these decreases in expression were partially blocked by treatment of dams with MET. The expression pattern of ECM genes that are targets of miR-29c correlated with miR-29c expression. Expression of mRNA was increased for elastin (ELN) and MMP2 mRNA in 3-week MUN carotids; in 9-month carotids there were also significant increases in expression of Col3A1 and Col4A5. These changes in mRNA expression of ECM genes at 3 weeks and 9 months were blocked by MET treatment. Similarly, the expression of ELN and MMP2 proteins at 3 weeks were increased in MUN carotids, and by 9 months there were also increases in expression of Col3A1 and Col4A5, which were blocked by MET in MUN carotids. Overall, the results demonstrate a close correlation between expression of miR-29c and the ECM proteins that are its targets thus supporting our central hypothesis.
Collapse
|
|
38
|
Maternal low-protein diet causes body weight loss in male, neonate Sprague-Dawley rats involving UCP-1-mediated thermogenesis. J Nutr Biochem 2015; 26:729-35. [PMID: 25858881 DOI: 10.1016/j.jnutbio.2015.01.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Revised: 01/09/2015] [Accepted: 01/23/2015] [Indexed: 12/24/2022]
Abstract
Brown adipose tissue (BAT) plays an important role in regulating body weight (BW) by modifying thermogenesis. Maternal low protein (LP) diets reduce offspring birth weight. Increased BAT thermogenesis in utero may be one mechanism for the lower BW. However, whether maternal LP nutrition alters BAT thermogenesis and BW of offspring in utero is not yet known. We fed obese-prone Sprague-Dawley dams 8% LP or 20% normal protein (NP) diets for 3 weeks prior to breeding and through pregnancy. BW and gene expression of interscapular BAT (iBAT) thermogenic markers were measured in male fetal (gestation day 18) and neonatal (day 0 or 1) offspring. BW of neonatal LP males was lower than NP males but no difference was observed in females. Gene and protein expression of UCP-1 and transcription factors PRDM16 and PPARα in iBAT were 2- to 6-fold greater in LP than in NP male neonatal offspring. FNDC5, a precursor of irisin and activator of thermogenesis, was expressed 2-fold greater in neonatal LP iBAT than NP males. However, fetal iBAT UCP-1, PRDM16, PPARα and irisin mRNA did not differ between LP and NP groups. Maternal LP diet had no effects on placental irisin and UCP-2 expression. These results suggest that prenatal protein restriction increases the risk for low BW through mechanisms affecting full-term offspring iBAT thermogenesis but not greatly altering fetal iBAT or placental thermogenesis.
Collapse
|
|
39
|
Sathishkumar K, Balakrishnan MP, Yallampalli C. Enhanced mesenteric arterial responsiveness to angiotensin II is androgen receptor-dependent in prenatally protein-restricted adult female rat offspring. Biol Reprod 2014; 92:55. [PMID: 25550341 DOI: 10.1095/biolreprod.114.126482] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022] Open
Abstract
Gestational protein restriction results in intrauterine growth restriction and hypertension in adult female growth-restricted rats. Enhanced vascular responsiveness to angiotensin II is observed, and blockade of the renin-angiotensin system abolishes hypertension in adult growth-restricted rats, suggesting that the renin-angiotensin system contributes to intrauterine growth restriction-induced hypertension. Moreover, growth-restricted adult rats have higher plasma testosterone levels, and antiandrogen treatment abolishes hypertension, indicating an important role for testosterone. We hypothesized that androgens may play a pivotal role in the enhanced responsiveness to Ang II and hypertension. Female offspring of pregnant rats fed 20% protein (control) or 6% protein diet (protein restricted), at 6 mo of age, were studied. Plasma testosterone and mean arterial pressure in protein-restricted offspring were significantly higher compared to controls. Flutamide treatment (10 mg/kg/day subcutaneously for 10 days) reduced mean arterial pressure in protein-restricted offspring but was without significant effect in controls. Vascular Agtr1/Agtr2 ratio was significantly higher in protein-restricted offspring, an effect that was reversed by flutamide. Flutamide treatment did not have any effect on Agtr1/Agtr2 ratio in controls. Enhanced contractile response to angiotensin II in mesenteric arteries was observed in protein-restricted offspring compared with control. Flutamide treatment reversed the enhanced contractile response to angiotensin II in protein-restricted offspring without significant effect in controls. Vascular reactivity to phenylephrine was similar between the control and protein-restricted offspring with and without flutamide treatment, suggesting that enhanced contractile response and flutamide's reversal effect is specific to angiotensin II. These results suggest that prenatally protein-restricted rats exhibit an enhanced responsiveness to angiotensin II that is testosterone-dependent.
Collapse
Affiliation(s)
- Kunju Sathishkumar
- Department of Obstetrics & Gynecology, The University of Texas Medical Branch, Galveston, Texas
| | - Meena P Balakrishnan
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas
| | | |
Collapse
|
|
40
|
Zohdi V, Lim K, Pearson JT, Black MJ. Developmental programming of cardiovascular disease following intrauterine growth restriction: findings utilising a rat model of maternal protein restriction. Nutrients 2014; 7:119-52. [PMID: 25551250 PMCID: PMC4303830 DOI: 10.3390/nu7010119] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 12/08/2014] [Indexed: 12/11/2022] Open
Abstract
Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of "programming". The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype.
Collapse
Affiliation(s)
- Vladislava Zohdi
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3800, Australia.
| | - Kyungjoon Lim
- Neuropharmacology Laboratory, Baker IDI Heart and Diabetes Institute, P.O. Box 6492 St Kilda Rd Central, Melbourne 8008, Australia.
| | - James T Pearson
- Department of Physiology, Monash University, Melbourne, VIC 3800, Australia.
| | - M Jane Black
- Department of Anatomy and Developmental Biology, Monash University, Melbourne, VIC 3800, Australia.
| |
Collapse
|
|
41
|
Blesson CS, Sathishkumar K, Chinnathambi V, Yallampalli C. Gestational protein restriction impairs insulin-regulated glucose transport mechanisms in gastrocnemius muscles of adult male offspring. Endocrinology 2014; 155:3036-46. [PMID: 24797633 PMCID: PMC4098002 DOI: 10.1210/en.2014-1094] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet-exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet-fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor substrate-1, and AS160 phosphorylation and impaired glucose transporter type 4 translocation.
Collapse
Affiliation(s)
- Chellakkan S Blesson
- Department of Obstetrics and Gynecology (C.S.B., C.Y.), Baylor College of Medicine, Houston, Texas 77030; and Division of Reproductive Endocrinology (K.S., V.C.), Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas 77555
| | | | | | | |
Collapse
|
|
42
|
Mezza T, Kulkarni RN. The regulation of pre- and post-maturational plasticity of mammalian islet cell mass. Diabetologia 2014; 57:1291-303. [PMID: 24824733 DOI: 10.1007/s00125-014-3251-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2013] [Accepted: 03/24/2014] [Indexed: 12/17/2022]
Abstract
Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and age-dependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.
Collapse
Affiliation(s)
- Teresa Mezza
- Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, 1 Joslin Place, Boston, MA, 02215, USA
| | | |
Collapse
|
|
43
|
de Bem GF, da Costa CA, de Oliveira PRB, Cordeiro VSC, Santos IB, de Carvalho LCRM, Souza MAV, Ognibene DT, Daleprane JB, Sousa PJC, Resende AC, de Moura RS. Protective effect of Euterpe oleracea Mart (açaí) extract on programmed changes in the adult rat offspring caused by maternal protein restriction during pregnancy. J Pharm Pharmacol 2014; 66:1328-38. [DOI: 10.1111/jphp.12258] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 03/02/2014] [Indexed: 11/29/2022]
Abstract
Abstract
Objectives
This study examined the effect of açaí (Euterpe oleracea Mart.) seed extract (ASE) on cardiovascular and renal alterations in adult offspring, whose mothers were fed a low-protein (LP) diet during pregnancy.
Methods
Four groups of rats were fed: control diet (20% protein); ASE (200 mg/kg per day); and LP (6% protein); LP + ASE (6% protein + ASE) during pregnancy. After weaning, all male offspring were fed a control diet and sacrificed at 4 months old. We evaluated the blood pressure, vascular function, serum and urinary parameters, plasma and kidney oxidative damage, and antioxidant activity and renal structural changes.
Key findings
Hypertension and the reduced acetylcholine-induced vasodilation in the LP group were prevented by ASE. Serum levels of urea, creatinine and fractional excretion of sodium were increased in LP and reduced in LP + ASE. ASE improved nitrite levels and the superoxide dismutase and glutathione peroxidase activity in LP, with a corresponding decrease of malondialdehyde and protein carbonyl levels. Kidney volume and glomeruli number were reduced and glomerular volume was increased in LP. These renal alterations were prevented by ASE.
Conclusions
Treatment of protein-restricted dams with ASE provides protection from later-life hypertension, oxidative stress, renal functional and structural changes, probably through a vasodilator and antioxidant activity.
Collapse
Affiliation(s)
- Graziele Freitas de Bem
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Cristiane Aguiar da Costa
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Izabelle Barcellos Santos
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Dayane Texeira Ognibene
- Department of Basic and Experimental Nutrition, Institute of Nutrition, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | | | | | - Angela Castro Resende
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| | - Roberto Soares de Moura
- Department of Pharmacology, Institute of Biology, Rio de Janeiro State University, Rio de Janeiro, Brazil
| |
Collapse
|
|
44
|
Durrant LM, Khorram O, Buchholz JN, Pearce WJ. Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone. Am J Physiol Regul Integr Comp Physiol 2014; 306:R401-10. [PMID: 24477541 DOI: 10.1152/ajpregu.00436.2013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Although the effects of prenatal undernutrition on adult cardiovascular health have been well studied, its effects on the cerebrovascular structure and function remain unknown. We used a pair-fed rat model of 50% caloric restriction from day 11 of gestation to term, with ad libitum feeding after birth. We validated that maternal food restriction (MFR) stress is mediated by glucocorticoids by administering metyrapone, a corticosterone synthesis inhibitor, to MFR mothers at day 11 of gestation. At age 8 mo, offspring from Control, MFR, and MFR + Metyrapone groups were killed, and middle cerebral artery (MCA) segments were studied using vessel-bath myography and confocal microscopy. Colocalization of smooth muscle α-actin (SMαA) with nonmuscle (NM), SM1 and SM2 myosin heavy-chain (MHC) isoforms was used to assess smooth muscle phenotype. Our results indicate that artery stiffness and wall thickness were increased, pressure-evoked myogenic reactivity was depressed, and myofilament Ca(2+) sensitivity was decreased in offspring of MFR compared with Control rats. MCA from MFR offspring exhibited a significantly greater SMαA/NM colocalization, suggesting that the smooth muscle cells had been altered toward a noncontractile phenotype. MET significantly reversed the effects of MFR on stiffness but not myogenic reactivity, lowered SMαA/NM colocalization, and increased SMαA/SM2 colocalization. Together, our data suggest that MFR alters cerebrovascular contractility via both glucocorticoid-dependent and glucocorticoid-independent mechanisms.
Collapse
Affiliation(s)
- Lara M Durrant
- Center for Perinatal Biology, Divisions of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, California; and
| | | | | | | |
Collapse
|
|
45
|
Abstract
Epigenetics, through control of gene expression circuitries, plays important roles in various physiological processes such as stem cell differentiation and self renewal. This occurs during embryonic development, in different tissues, and in response to environmental stimuli. The language of epigenetic program is based on specific covalent modifications of DNA and chromatin. Thus, in addition to the individual identity, encoded by sequence of the four bases of the DNA, there is a cell type identity characterized by its positioning in the epigenetic "landscape". Aberrant changes in epigenetic marks induced by environmental cues may contribute to the development of abnormal phenotypes associated with different human diseases such as cancer, neurological disorders and inflammation. Most of the epigenetic studies have focused on embryonic development and cancer biology, while little has been done to explore the role of epigenetic mechanisms in the pathogenesis of cardiovascular disease. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodeling and histone modifications play key roles in the pathogenesis of cardiovascular disease through (re)programming of cardiovascular (stem) cells commitment, identity and function.
Collapse
|
|
46
|
Bahls M, Sheldon RD, Taheripour P, Clifford KA, Foust KB, Breslin ED, Marchant-Forde JN, Cabot RA, Harold Laughlin M, Bidwell CA, Newcomer SC. Mother's exercise during pregnancy programmes vasomotor function in adult offspring. Exp Physiol 2013; 99:205-19. [PMID: 24163423 DOI: 10.1113/expphysiol.2013.075978] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The intrauterine environment is influenced by maternal behaviour and programmes atherosclerotic disease susceptibility in offspring. The aim of this investigation was to test the hypothesis that mothers' exercise during pregnancy improves endothelial function in 3-, 5- and 9-month-old porcine offspring. The pregnant sows in the exercise group ran for an average of 39.35 ± 0.75 min at 4.81 ± 0.35 km h(-1) each day for 5 days per week for all but the last week of gestation. This induced a significant reduction in resting heart rate (exercised group, 89.3 ± 3.5 beats min(-1); sedentary group, 102.1 ± 3.1 beats min(-1); P < 0.05) but no significant differences in gestational weight gain (65.8 ± 2.1 versus 63.3 ± 1.9%). No significant effect on bradykinin-induced vasorelaxation with and without l-NAME was observed. A significant main effect was identified on sodium nitroprusside-induced vasorelaxation (P = 0.01), manifested by a reduced response in femoral arteries of all age groups from exercised-trained swine. Nitric oxide signalling was not affected by maternal exercise. Protein expression of MYPT1 was reduced in femoral arteries from 3-month-old offspring of exercised animals. A significant interaction was observed for PPP1R14A (P < 0.05) transcript abundance and its protein product CPI-17. In conclusion, pregnant swine are able to complete an exercise-training protocol that matches the current recommendations for pregnant women. Gestational exercise is a potent stimulus for programming vascular smooth muscle relaxation in adult offspring. Specifically, exercise training for the finite duration of pregnancy decreases vascular smooth muscle responsiveness in adult offspring to an exogenous nitric oxide donor.
Collapse
Affiliation(s)
- Martin Bahls
- S. C. Newcomer: Department of Kinesiology, California State University San Marcos, 333 South Twin Oaks Valley Road, San Marcos, CA 92096, USA.
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Abstract
Pregnancy encompasses substantial changes in vascular function to accommodate dramatic increases in blood volume and uteroplacental blood flow to the growing fetus. Despite increased hemodynamics, decreased peripheral resistance results in a reduction in mean arterial blood pressure. Vascular tone, and hence peripheral resistance, is determined by a delicate balance of constrictor and dilator capacities. In the normal physiological response to pregnancy, endothelial-derived hyperpolarization (EDH) has been shown to be a major contributor; both EDH and nitric oxide (NO) are predominantly involved in providing an increased vascular capacity for vasodilation. The ability of EDH and NO to adequately accommodate increased blood volume is tested in pathological states such as placental insufficiency or diabetes and both EDH and NO-dependent mechanisms seem to be impacted in these situations. Pregnancy complications also have an impact on the cardiovascular health of the offspring. In adult offspring born from complicated pregnancies, the data suggest that EDH mechanisms are largely maintained, whereas NO is commonly reduced. A diversity of EDH mechanisms may be useful in providing many targets for potential therapeutic avenues for compromised pregnancies; however, further research delineating the mechanisms of EDH and the interactions of NO and EDH, in normal and pathological pregnancies is required.
Collapse
|
|
48
|
DelCurto H, Wu G, Satterfield MC. Nutrition and reproduction: links to epigenetics and metabolic syndrome in offspring. Curr Opin Clin Nutr Metab Care 2013; 16:385-91. [PMID: 23703295 DOI: 10.1097/mco.0b013e328361f96d] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
PURPOSE OF REVIEW Inappropriate exposure of gametes and/or products of conception to nutritional imbalance alters critical metabolic set points in the offspring and increases propensity to disease. This review will focus on recent findings highlighting clear links to epigenetic modifications in response to dietary manipulations as well as nutritional strategies with the potential to mitigate the effects of an otherwise poor nutritional environment. RECENT FINDINGS Maternal nutritional imbalance, either through global nutritional manipulation or deficiencies in select nutrients, predisposes the offspring to metabolic disease. Disease susceptibility is linked to global and/or specific modifications of the epigenome at key metabolic regulatory genes. Paternal nutritional imbalance also increases the likelihood of metabolic disease in offspring through similar epigenetic mechanisms. Finally, dietary intervention with select nutrients has been shown to ameliorate postnatal disease phenotypes in offspring, although the exact molecular mechanisms have not been elucidated. SUMMARY Select nutrients, such as amino acids and vitamins, not only serve as building blocks for growth but also mediate a myriad of physiological functions, including providing substrates for DNA synthesis. These nutrients hold great promise as intervention strategies to combat a suboptimal developmental environment.
Collapse
Affiliation(s)
- Hannah DelCurto
- Department of Animal Science, Texas A&M University, College Station, TX 77843–2471, USA
| | | | | |
Collapse
|
|
49
|
The fetal origins of hypertension: a systematic review and meta-analysis of the evidence from animal experiments of maternal undernutrition. J Hypertens 2013; 30:2255-67. [PMID: 22990358 DOI: 10.1097/hjh.0b013e3283588e0f] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Numerous experiments in animals have been performed to investigate the effect of prenatal undernutrition on the development of hypertension in later life, with inconclusive results. We systematically reviewed animal studies examining the effects of maternal undernutrition on SBP, DBP, and mean arterial blood pressure (BP) in offspring. METHODS A search was performed in Medline and Embase to identify articles that reported on maternal undernutrition and hypertension in experimental animal studies. Summary estimates of the effect of undernutrition on SBP, DBP, and mean arterial BP were obtained through meta-analysis. RESULTS Of the 6151 articles identified, 194 were considered eligible after screening titles and abstracts. After detailed evaluation, 101 met the inclusion criteria and were included in the review. Both maternal general and protein undernutrition increased SBP [general undernutrition: 14.5 mmHg, 95% confidence interval (CI) 10.8-18.3; protein undernutrition: 18.9 mmHg, 95% CI 16.1-21.8] and mean arterial BP (general undernutrition: 5.0 mmHg, 95% CI 1.4-8.6; protein undernutrition: 10.5 mmHg, 95% CI 6.7-14.2). There was substantial heterogeneity in the results. DBP was increased by protein undernutrition (9.5 mmHg, 95% CI 2.6-16.3), whereas general undernutrition had no significant effect. CONCLUSION The results of this meta-analysis generally support the view that in animals, maternal undernutrition--both general and protein--results in increased SBP and mean arterial BP. DBP was only increased after protein undernutrition. The results depended strongly on the applied measurement technique and animal model.
Collapse
|
|
50
|
Wang J, Wu Z, Li D, Li N, Dindot SV, Satterfield MC, Bazer FW, Wu G. Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal 2012; 17:282-301. [PMID: 22044276 PMCID: PMC3353821 DOI: 10.1089/ars.2011.4381] [Citation(s) in RCA: 189] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2011] [Accepted: 11/01/2011] [Indexed: 01/21/2023]
Abstract
SIGNIFICANCE Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults. Compelling experimental results also indicate that adverse effects of intrauterine growth restriction on offspring can be carried forward to subsequent generations through covalent modifications of DNA and core histones. RECENT ADVANCES DNA methylation is catalyzed by S-adenosylmethionine-dependent DNA methyltransferases. Methylation, demethylation, acetylation, and deacetylation of histone proteins are performed by histone methyltransferase, histone demethylase, histone acetyltransferase, and histone deacetyltransferase, respectively. Histone activities are also influenced by phosphorylation, ubiquitination, ADP-ribosylation, sumoylation, and glycosylation. Metabolism of amino acids (glycine, histidine, methionine, and serine) and vitamins (B6, B12, and folate) plays a key role in provision of methyl donors for DNA and protein methylation. CRITICAL ISSUES Disruption of epigenetic mechanisms can result in oxidative stress, obesity, insulin resistance, diabetes, and vascular dysfunction in animals and humans. Despite a recognized role for epigenetics in fetal programming of metabolic syndrome, research on therapies is still in its infancy. Possible interventions include: 1) inhibition of DNA methylation, histone deacetylation, and microRNA expression; 2) targeting epigenetically disturbed metabolic pathways; and 3) dietary supplementation with functional amino acids, vitamins, and phytochemicals. FUTURE DIRECTIONS Much work is needed with animal models to understand the basic mechanisms responsible for the roles of specific nutrients in fetal and neonatal programming. Such new knowledge is crucial to design effective therapeutic strategies for preventing and treating metabolic abnormalities in offspring born to mothers with a previous experience of malnutrition.
Collapse
Affiliation(s)
- Junjun Wang
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Zhenlong Wu
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Defa Li
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Ning Li
- State Key Laboratory of AgroBiotechnology, China Agricultural University, Beijing, China
| | - Scott V. Dindot
- Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, Texas
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas
- Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas
| | - M. Carey Satterfield
- Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, Texas
- Department of Animal Science, Texas A&M University, College Station, Texas
| | - Fuller W. Bazer
- Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, Texas
- Department of Animal Science, Texas A&M University, College Station, Texas
| | - Guoyao Wu
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
- Center for Animal Biotechnology and Genomics, Texas A&M University, College Station, Texas
- Department of Animal Science, Texas A&M University, College Station, Texas
| |
Collapse
|