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Fanourgakis G, Gaspa-Toneu L, Komarov PA, Papasaikas P, Ozonov EA, Smallwood SA, Peters AHFM. DNA methylation modulates nucleosome retention in sperm and H3K4 methylation deposition in early mouse embryos. Nat Commun 2025; 16:465. [PMID: 39774947 PMCID: PMC11706963 DOI: 10.1038/s41467-024-55441-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025] Open
Abstract
In the germ line and during early embryogenesis, DNA methylation (DNAme) undergoes global erasure and re-establishment to support germ cell and embryonic development. While DNAme acquisition during male germ cell development is essential for setting genomic DNA methylation imprints, other intergenerational roles for paternal DNAme in defining embryonic chromatin are unknown. Through conditional gene deletion of the de novo DNA methyltransferases Dnmt3a and/or Dnmt3b, we observe that DNMT3A primarily safeguards against DNA hypomethylation in undifferentiated spermatogonia, while DNMT3B catalyzes de novo DNAme during spermatogonial differentiation. Failing de novo DNAme in Dnmt3a/Dnmt3b double deficient spermatogonia is associated with increased nucleosome occupancy in mature sperm, preferentially at sites with higher CpG content, supporting the model that DNAme modulates nucleosome retention in sperm. To assess the impact of altered sperm chromatin in formatting embryonic chromatin, we measure H3K4me3 occupancy at paternal and maternal alleles in 2-cell embryos using a transposon-based tagging approach. Our data show that reduced DNAme in sperm renders paternal alleles permissive for H3K4me3 establishment in early embryos, independently of possible paternal inheritance of sperm born H3K4me3. Together, this study provides evidence that paternally inherited DNAme directs chromatin formation during early embryonic development.
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Affiliation(s)
- Grigorios Fanourgakis
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Laura Gaspa-Toneu
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland
| | - Pavel A Komarov
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland
| | - Panagiotis Papasaikas
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Evgeniy A Ozonov
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Sebastien A Smallwood
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland
| | - Antoine H F M Peters
- Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland.
- Faculty of Sciences, University of Basel, 4056, Basel, Switzerland.
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Viot G, Clement A, Clement P, Elder K, Menezo YJR. Treatment with 5-MTHF to support the one-carbon cycle can overcome the deleterious impact of a triple SNP mutation in the male partner's MTHFR gene for a couple with a history of repeated miscarriage. J Assist Reprod Genet 2025:10.1007/s10815-024-03371-8. [PMID: 39747776 DOI: 10.1007/s10815-024-03371-8] [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: 10/11/2024] [Accepted: 12/19/2024] [Indexed: 01/04/2025] Open
Abstract
A couple presenting with more than 3 years' history of infertility and three miscarriages was tested for serum homocysteine levels and for the two principal MTHFR SNPs: 677C < T and 1298A < C, as per our general policy for patients with infertility of long duration. The woman was found to be wild type for both MTHFR SNPs with a serum homocysteine 10.5 µM, slightly higher than our accepted normal value of 8.5 µM. The man was found to be a carrier of a triple mutation for 677C < T and 1298 A < C, with an elevated homocysteine level of 19 µM. Since high doses of folic acid (FA) exacerbate perturbations in the DNA methylome, the husband was treated with 5-methyl tetrahydrofolate together with nutritional support of the one-carbon cycle (OCC). After 3 months of treatment, the couple conceived, and the woman delivered a healthy female baby. Three years later, she again conceived and delivered a second healthy female baby. Our treatment can restore fertility in males affected by a triple SNP mutation in the MTHFR gene; this confirms that Hcy and MTHFR SNP testing should not be overlooked in patients affected by long duration of infertility/repeat miscarriages.
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Affiliation(s)
- Geraldine Viot
- Cabinet Medical, 40 Boulevard de Courcelles, 75017, Paris, France
| | - Arthur Clement
- Laboratoire Clément, Avenue d'Eylau, 75016, Paris, France
| | | | - Kay Elder
- Bourn Hall Clinic, Bourn, Cambridge, UK
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Cambiasso MY, Romanato M, Gotfryd L, Valzacchi GR, Calvo L, Calvo JC, Fontana VA. Sperm histone modifications may predict success in human assisted reproduction: a pilot study. J Assist Reprod Genet 2024; 41:3147-3159. [PMID: 39419944 PMCID: PMC11621280 DOI: 10.1007/s10815-024-03280-w] [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: 04/29/2024] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
PURPOSE Currently, assisted reproduction clinics employ various sperm selection techniques to identify the best sperm for fertilization. However, these techniques may not assess crucial sperm traits that can substantially impact embryonic quality. To address this, we propose analyzing diverse histone modifications as potential markers of sperm functionality and success in assisted reproduction techniques. METHODS Cross-sectional pilot study including infertile male patients attending an infertility clinic in CABA, Argentina between April and August 2019 was performed. We used immunofluorescence techniques to evaluate post-translational modifications of histones in sperm and established correlations with in vitro fertilization outcome and embryo quality. RESULTS Our findings indicate a negative correlation between H3K4me3 and H3K4me2 marks and fertilization rate and showed a positive correlation of this parameter with H3K9me mark. In addition, there was a positive correlation between H3K27me3 and good embryo quality. CONCLUSIONS This pilot study proposes a non-invasive strategy to predict embryo quality by analyzing spermatozoa prior to fertilization. The assessment of histone post-translational modifications in sperm samples could provide useful information for the recognition of epigenetic marks that could predict the health of the embryo of an assisted fertilization treatment.
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Affiliation(s)
- M Y Cambiasso
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
| | - M Romanato
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - L Gotfryd
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | | | - L Calvo
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - J C Calvo
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina
| | - V A Fontana
- CONICET, Instituto de Biología y Medicina Experimental (IBYME), Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina.
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4
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Geng Q, Gao R, Sun Y, Chen S, Sun L, Li W, Li Z, Zhao Y, Zhao F, Zhang Y, Li A, Liu H. Mitochondrial DNA content and methylation in sperm of patients with asthenozoospermia. J Assist Reprod Genet 2024; 41:2795-2805. [PMID: 39190228 PMCID: PMC11535106 DOI: 10.1007/s10815-024-03236-0] [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: 01/01/2024] [Accepted: 08/20/2024] [Indexed: 08/28/2024] Open
Abstract
PURPOSE The aim of the current study was to investigate the mtDNA methylation levels and mtDNA copy numbers in the sperm of patients with asthenozoospermia and compare them to those observed in controls with normozoospermia. METHODS Pyrosequencing analysis of the methylation levels of the mitochondrial D-loop and MT-CO1/chr1:631,907-632083/chrX:26,471,887-126,472,063 (hereinafter referred to as "MT-CO1-AVG") region and quantitative PCR analysis of the mtDNA copy number were performed on sperm from 30 patients with asthenozoospermia and 30 controls with normozoospermia. RESULTS Compared with those of controls with normozoospermia, the methylation levels of D-loop and MT-CO1-AVG regions and mtDNA copy number were significantly higher in patients with asthenozoospermia. The methylation level of the D-loop region in patients with asthenozoospermia and controls with normozoospermia and that of MT-CO1-AVG region in patients with asthenozoospermia showed a decreasing tendency with increasing total sperm motility. A significant inverse correlation between the mtDNA copy number and total sperm motility was observed in patients with asthenozoospermia but not in controls with normozoospermia. In patients with asthenozoospermia, but not in controls with normozoospermia, we observed a significant inverse correlation between D-loop methylation levels and mtDNA copy number, while no significant correlation was observed between MT-CO1-AVG methylation levels and mtDNA copy number. CONCLUSION These results reveal the occurrence of mtDNA methylation in human sperm and altered D-loop and MT-CO1-AVG methylation levels in patients with asthenozoospermia. Additional research is needed to determine the function of these features in the etiology and course of asthenozoospermia.
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Affiliation(s)
- Qiang Geng
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Ruifang Gao
- Department of Reproductive Medicine, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Tianjin, China.
| | - Yuan Sun
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Shaofeng Chen
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Lili Sun
- Department of Reproductive Medicine, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Tianjin, China
| | - Wei Li
- Department of Reproductive Medicine, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Tianjin, China
| | - Zhong Li
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yu Zhao
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Feng Zhao
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Ying Zhang
- Department of Reproductive Medicine, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Tianjin, China
| | - Anwen Li
- Department of Andrology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hongbin Liu
- Department of Reproductive Medicine, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Tianjin, China.
- Health Commission of Heping District, Tianjin, China.
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5
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Crafa A, Cannarella R, Calogero AE, Gunes S, Agarwal A. Behind the Genetics: The Role of Epigenetics in Infertility-Related Testicular Dysfunction. Life (Basel) 2024; 14:803. [PMID: 39063558 PMCID: PMC11277947 DOI: 10.3390/life14070803] [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: 05/27/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/28/2024] Open
Abstract
In recent decades, we have witnessed a progressive decline in male fertility. This is partly related to the increased prevalence of chronic diseases (e.g., obesity and diabetes mellitus) and risky lifestyle behaviors. These conditions alter male fertility through various non-genetic mechanisms. However, there is increasing evidence that they are also capable of causing sperm epigenetic alterations, which, in turn, can cause infertility. Furthermore, these modifications could be transmitted to offspring, altering their general and reproductive health. Therefore, these epigenetic modifications could represent one of the causes of the progressive decline in sperm count recorded in recent decades. This review focuses on highlighting epigenetic modifications at the sperm level induced by non-genetic causes of infertility. In detail, the effects on DNA methylation, histone modifications, and the expression profiles of non-coding RNAs are evaluated. Finally, a focus on the risk of transgenerational inheritance is presented. Our narrative review aims to demonstrate how certain conditions can alter gene expression, potentially leading to the transmission of anomalies to future generations. It emphasizes the importance of the early detection and treatment of reversible conditions (such as obesity and varicocele) and the modification of risky lifestyle behaviors. Addressing these issues is crucial for individual health, in preserving fertility, and in ensuring the well-being of future generations.
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Affiliation(s)
- Andrea Crafa
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (A.C.); (R.C.); (A.E.C.)
- Global Andrology Forum, Moreland Hills, OH 44022, USA
| | - Rossella Cannarella
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (A.C.); (R.C.); (A.E.C.)
- Global Andrology Forum, Moreland Hills, OH 44022, USA
- Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44106, USA
| | - Aldo E. Calogero
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy; (A.C.); (R.C.); (A.E.C.)
- Global Andrology Forum, Moreland Hills, OH 44022, USA
| | - Sezgin Gunes
- Global Andrology Forum, Moreland Hills, OH 44022, USA
- Department of Medical Biology, Faculty of Medicine, Ondokuz Mayis University, 55280 Samsun, Türkiye
| | - Ashok Agarwal
- Global Andrology Forum, Moreland Hills, OH 44022, USA
- Cleveland Clinic Foundation, Cleveland, OH 44195, USA
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6
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Wu D, Zhang K, Guan K, Khan FA, Pandupuspitasari NS, Negara W, Sun F, Huang C. Future in the past: paternal reprogramming of offspring phenotype and the epigenetic mechanisms. Arch Toxicol 2024; 98:1685-1703. [PMID: 38460001 DOI: 10.1007/s00204-024-03713-6] [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: 01/10/2024] [Accepted: 02/20/2024] [Indexed: 03/11/2024]
Abstract
That certain preconceptual paternal exposures reprogram the developmental phenotypic plasticity in future generation(s) has conceptualized the "paternal programming of offspring health" hypothesis. This transgenerational effect is transmitted primarily through sperm epigenetic mechanisms-DNA methylation, non-coding RNAs (ncRNAs) and associated RNA modifications, and histone modifications-and potentially through non-sperm-specific mechanisms-seminal plasma and circulating factors-that create 'imprinted' memory of ancestral information. The epigenetic landscape in sperm is highly responsive to environmental cues, due to, in part, the soma-to-germline communication mediated by epididymosomes. While human epidemiological studies and experimental animal studies have provided solid evidences in support of transgenerational epigenetic inheritance, how ancestral information is memorized as epigenetic codes for germline transmission is poorly understood. Particular elusive is what the downstream effector pathways that decode those epigenetic codes into persistent phenotypes. In this review, we discuss the paternal reprogramming of offspring phenotype and the possible underlying epigenetic mechanisms. Cracking these epigenetic mechanisms will lead to a better appreciation of "Paternal Origins of Health and Disease" and guide innovation of intervention algorithms to achieve 'healthier' outcomes in future generations. All this will revolutionize our understanding of human disease etiology.
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Affiliation(s)
- Di Wu
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China
| | - Kejia Zhang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China
| | - Kaifeng Guan
- School of Advanced Agricultural Sciences, Peking University, Beijing, 100871, China
| | - Faheem Ahmed Khan
- Research Center for Animal Husbandry, National Research and Innovation Agency, Jakarta Pusat, 10340, Indonesia
| | | | - Windu Negara
- Research Center for Animal Husbandry, National Research and Innovation Agency, Jakarta Pusat, 10340, Indonesia
| | - Fei Sun
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China.
| | - Chunjie Huang
- Institute of Reproductive Medicine, School of Medicine, Nantong University, Nantong, 226001, China.
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7
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De Jonge CJ, Barratt CLR, Aitken RJ, Anderson RA, Baker P, Chan DYL, Connolly MP, Eisenberg ML, Garrido N, Jørgensen N, Kimmins S, Krausz C, McLachlan RI, Niederberger C, O’Bryan MK, Pacey A, Priskorn L, Rautakallio-Hokkanen S, Serour G, Veltman JA, Vogel DL, Vazquez-Levin MH. Current global status of male reproductive health. Hum Reprod Open 2024; 2024:hoae017. [PMID: 38699533 PMCID: PMC11065475 DOI: 10.1093/hropen/hoae017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 02/22/2024] [Indexed: 05/05/2024] Open
Abstract
BACKGROUND The widespread interest in male reproductive health (MRH), fueled by emerging evidence, such as the global decline in sperm counts, has intensified concerns about the status of MRH. Consequently, there is a pressing requirement for a strategic, systematic approach to identifying critical questions, collecting pertinent information, and utilizing these data to develop evidence-based strategies. The methods for addressing these questions and the pathways toward their answers will inevitably vary based on the variations in cultural, geopolitical, and health-related contexts. To address these issues, a conjoint ESHRE and Male Reproductive Health Initiative (MRHI) Campus workshop was convened. OBJECTIVE AND RATIONALE The three objectives were: first, to assess the current state of MRH around the world; second, to identify some of the key gaps in knowledge; and, third, to examine how MRH stakeholders can collaboratively generate intelligent and effective paths forward. SEARCH METHODS Each expert reviewed and summarized the current literature that was subsequently used to provide a comprehensive overview of challenges related to MRH. OUTCOMES This narrative report is an overview of the data, opinions, and arguments presented during the workshop. A number of outcomes are presented and can be summarized by the following overarching themes: MRH is a serious global issue and there is a plethora of gaps in our understanding; there is a need for widespread international collaborative networks to undertake multidisciplinary research into fundamental issues, such as lifestyle/environmental exposure studies, and high-quality clinical trials; and there is an urgent requirement for effective strategies to educate young people and the general public to safeguard and improve MRH across diverse population demographics and resources. LIMITATIONS REASONS FOR CAUTION This was a workshop where worldwide leading experts from a wide range of disciplines presented and discussed the evidence regarding challenges related to MRH. While each expert summarized the current literature and placed it in context, the data in a number of areas are limited and/or sparse. Equally, important areas for consideration may have been missed. Moreover, there are clear gaps in our knowledge base, which makes some conclusions necessarily speculative and warranting of further study. WIDER IMPLICATIONS Poor MRH is a global issue that suffers from low awareness among the public, patients, and heathcare professionals. Addressing this will require a coordinated multidisciplinary approach. Addressing the significant number of knowledge gaps will require policy makers prioritizing MRH and its funding. STUDY FUNDING/COMPETING INTERESTS The authors would like to extend their gratitude to ESHRE for providing financial support for the Budapest Campus Workshop, as well as to Microptic S.L. (Barcelona) for kindly sponsoring the workshop. P.B. is the Director of the not-for-profit organization Global Action on Men's Health and receives fees and expenses for his work, (which includes the preparation of this manuscript). Conflicts of interest: C.J.D.J., C.L.R.B., R.A.A., P.B., M.P.C., M.L.E., N.G., N.J., C.K., AAP, M.K.O., S.R.-H., M.H.V.-L.: ESHRE Campus Workshop 2022 (Travel support-personal). C.J.D.J.: Cambridge University Press (book royalties-personal). ESHRE Annual Meeting 2022 and Yale University Panel Meeting 2023 (Travel support-personal). C.L.R.B.: Ferring and IBSA (Lecture), RBMO editor (Honorarium to support travel, etc.), ExSeed and ExScentia (University of Dundee), Bill & Melinda Gates Foundation (for research on contraception). M.P.C.: Previously received funding from pharmaceutical companies for health economic research. The funding was not in relation to this work and had no bearing on the contents of this work. No funding from other sources has been provided in relation to this work (funding was provided to his company Global Market Access Solutions). M.L.E.: Advisor to Ro, Doveras, Next, Hannah, Sandstone. C.K.: European Academy of Andrology (Past president UNPAID), S.K.: CEO of His Turn, a male fertility Diagnostic and Therapeutic company (No payments or profits to date). R.I.M.: www.healthymale.org.au (Australian Government funded not for profit in men's health sector (Employed as Medical Director 0.2 FET), Monash IVF Pty Ltd (Equity holder)). N.J.: Merck (consulting fees), Gedeon Richter (honoraria). S.R.-H.: ESHRE (Travel reimbursements). C.N.: LLC (Nursing educator); COMMIT (Core Outcomes Measures for Infertility Trials) Advisor, meeting attendee, and co-author; COMMA (Core Outcomes in Menopause) Meeting attendee, and co-author; International Federation of Gynecology and Obstetrics (FIGO) Delegate Letters and Sciences; ReproNovo, Advisory board; American Board of Urology Examiner; American Urological Association Journal subsection editor, committee member, guidelines co-author Ferring Scientific trial NexHand Chief Technology Officer, stock ownership Posterity Health Board member, stock ownership. A.P.: Economic and Social Research Council (A collaborator on research grant number ES/W001381/1). Member of an advisory committee for Merck Serono (November 2022), Member of an advisory board for Exceed Health, Speaker fees for educational events organized by Mealis Group; Chairman of the Cryos External Scientific Advisory Committee: All fees associated with this are paid to his former employer The University of Sheffield. Trustee of the Progress Educational Trust (Unpaid). M.K.O.: National Health and Medical Research Council and Australian Research Council (Funding for research of the topic of male fertility), Bill and Melinda Gates Foundation (Funding aimed at the development of male gamete-based contraception), Medical Research Future Fund (Funding aimed at defining the long-term consequences of male infertility). M.H.V.-L.: Department of Sexual and Reproductive Health and Research (SRH)/Human Reproduction Programme (HRP) Research Project Panel RP2/WHO Review Member; MRHI (Core Group Member), COMMIT (member), EGOI (Member); Human Reproduction (Associate Editor), Fertility and Sterility (Editor), AndroLATAM (Founder and Coordinator).
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Affiliation(s)
- Christopher J De Jonge
- Department of Urology, University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, USA
| | - Christopher L R Barratt
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - R John Aitken
- Discipline of Biological Sciences, School of Environment and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Newcastle, Australia
| | - Richard A Anderson
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | | | - David Y L Chan
- Assisted Reproductive Technology Unit, Department of Obstetrics and Gynaecology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, China
| | - Mark P Connolly
- Health Economics, Global Market Access Solutions LLC, Mooresville, NC, USA
- University Medical Center Groningen, Groningen, The Netherlands
| | - Michael L Eisenberg
- Department of Urology and Obstetrics & Gynecology, Stanford University, Stanford, CA, USA
| | - Nicolas Garrido
- IVIRMA Global Research Alliance, IVI Foundation, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Niels Jørgensen
- Department of Growth and Reproduction and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Montréal, QC, Canada
- Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, QC, Canada
| | - Csilla Krausz
- Department of Experimental and Clinical Biomedical Sciences, ‘Mario Serio’, University of Florence, University Hospital of Careggi (AOUC), Florence, Italy
| | - Robert I McLachlan
- Hudson Institute of Medical Research, Monash University, Melbourne, Australia
- Monash IVF Group, Cremorne, Australia
| | - Craig Niederberger
- Clarence C. Department of Urology, University of Illinois Chicago (UIC), College of Medicine, Department of Bioengineering, UIC College of Engineering, Chicago, IL,USA
| | - Moira K O’Bryan
- School of BioSciences and Bio21 Institute, The University of Melbourne, Parkville, Australia
| | - Allan Pacey
- Faculty of Biology, Medicine and Health, Core Technology Facility, University of Manchester, Manchester, UK
| | - Lærke Priskorn
- Department of Growth and Reproduction and International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | - Gamal Serour
- The International Islamic Center for Population Studies and Research, Al-Azhar University, Maadi, Cairo, Egypt
- Egyptian IVF Center, Maadi, Cairo, Egypt
| | - Joris A Veltman
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Donna L Vogel
- School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Mónica H Vazquez-Levin
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina—Fundación IBYME, Buenos Aires, Argentina
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8
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Barbonetti A, Tienforti D, Castellini C, Giulio FD, Muselli M, Pizzocaro A, Vena W, Baroni MG, Pivonello R, Isidori AM, Maggi M, Corona G. Effect of antioxidants on semen parameters in men with oligo-astheno-teratozoospermia: a network meta-analysis. Andrology 2024; 12:538-552. [PMID: 37495550 DOI: 10.1111/andr.13498] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/09/2023] [Accepted: 07/15/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND Although antioxidants are largely used in subfertile men with oligo-astheno-teratozoospermia (OAT), the choice among different molecules is challenged by the lack of comparative head-to-head studies. The network meta-analysis (NMA) can overcome limitations of pairwise meta-analyses, since it incorporates direct and indirect evidence into a single model generating an effectiveness hierarchy. OBJECTIVE To assess with a NMA the effects of antioxidants in improving seminal parameters in idiopathic OAT. MATERIALS AND METHODS PubMed, Scopus, Cinahl, and Cochrane Library databases were searched for randomized controlled trials (RCTs) comparing any antioxidant treatment to each other or placebo in men with at least one idiopathic seminal abnormality. Data were included in a random-effects NMA, where efficacy of treatments was ranked by surface under the cumulative ranking curve (SUCRA). RESULTS 29 RCTs provided information on 2045 men (mean age: 33.5 years) with idiopathic OAT and 19 antioxidant preparations. Compared to placebo, l-carnitine, especially in combination with l-acetyl-carnitine (LAC), had the highest SUCRA for sperm concentration, progressive motility, and morphology. Folate was the only other compound effective on sperm concentration. Vitamin E+selenium or zinc had the highest SUCRA for total motility. A contribution on progressive motility was revealed for pentoxifylline and vitamin E+CoQ10.
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Affiliation(s)
- Arcangelo Barbonetti
- Andrology Unit, Department of Clinical Medicine, Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Daniele Tienforti
- Andrology Unit, Department of Clinical Medicine, Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Chiara Castellini
- Andrology Unit, Department of Clinical Medicine, Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Francesca Di Giulio
- Andrology Unit, Department of Clinical Medicine, Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Mario Muselli
- Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Alessandro Pizzocaro
- Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Walter Vena
- Endocrinology, Diabetology and Andrology Unit, Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy
| | - Marco Giorgio Baroni
- Andrology Unit, Department of Clinical Medicine, Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Rosario Pivonello
- Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia, Andrologia e Nutrizione, Unità di Andrologia e Medicina della Riproduzione Sessuale Maschile e Femminile, Università Federico II di Napoli, Naples, Italy
- UNESCO Chair for Health Education and Sustainable Development, Università Federico II di Napoli, Naples, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Policlinico Umberto I Hospital, Rome, Italy
| | - Mario Maggi
- Andrology, Women's Endocrinology and Gender Incongruence Unit, - Careggi Teaching Hospital, Mario Serio Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
- Istituto Nazionale Biostrutture e Biosistemi, Rome, Italy
- Endocrinology Unit, Careggi Teaching Hospital, Mario Serio Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
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9
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Ren Y, Zeng Y, Wu Y, Zhang Q, Xiao X. Maternal methyl donor supplementation: A potential therapy for metabolic disorder in offspring. J Nutr Biochem 2024; 124:109533. [PMID: 37977406 DOI: 10.1016/j.jnutbio.2023.109533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 11/07/2023] [Accepted: 11/11/2023] [Indexed: 11/19/2023]
Abstract
The prevalences of diabetes mellitus and obesity are increasing yearly and has become a serious social burden. In addition to genetic factors, environmental factors in early life development are critical in influencing the prevalence of metabolic disorders in offspring. A growing body of evidence suggests the critical role of early methyl donor intervention in offspring health. Emerging studies have shown that methyl donors can influence offspring metabolism through epigenetic modifications and changing metabolism-related genes. In this review, we focus on the role of folic acid, betaine, vitamin B12, methionine, and choline in protecting against metabolic disorders in offspring. To address the current evidence on the potential role of maternal methyl donors, we summarize clinical studies as well as experimental animal models that support the impact of maternal methyl donors on offspring metabolism and discuss the mechanisms of action that may bring about these positive effects. Given the worldwide prevalence of metabolic disorders, these findings could be utilized in clinical practice, in which methyl donor supplementation in the early life years may reverse metabolic disorders in offspring and block the harmful intergenerational effect.
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Affiliation(s)
- Yaolin Ren
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yuan Zeng
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yifan Wu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
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10
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Kimmins S, Anderson RA, Barratt CLR, Behre HM, Catford SR, De Jonge CJ, Delbes G, Eisenberg ML, Garrido N, Houston BJ, Jørgensen N, Krausz C, Lismer A, McLachlan RI, Minhas S, Moss T, Pacey A, Priskorn L, Schlatt S, Trasler J, Trasande L, Tüttelmann F, Vazquez-Levin MH, Veltman JA, Zhang F, O'Bryan MK. Frequency, morbidity and equity - the case for increased research on male fertility. Nat Rev Urol 2024; 21:102-124. [PMID: 37828407 DOI: 10.1038/s41585-023-00820-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2023] [Indexed: 10/14/2023]
Abstract
Currently, most men with infertility cannot be given an aetiology, which reflects a lack of knowledge around gamete production and how it is affected by genetics and the environment. A failure to recognize the burden of male infertility and its potential as a biomarker for systemic illness exists. The absence of such knowledge results in patients generally being treated as a uniform group, for whom the strategy is to bypass the causality using medically assisted reproduction (MAR) techniques. In doing so, opportunities to prevent co-morbidity are missed and the burden of MAR is shifted to the woman. To advance understanding of men's reproductive health, longitudinal and multi-national centres for data and sample collection are essential. Such programmes must enable an integrated view of the consequences of genetics, epigenetics and environmental factors on fertility and offspring health. Definition and possible amelioration of the consequences of MAR for conceived children are needed. Inherent in this statement is the necessity to promote fertility restoration and/or use the least invasive MAR strategy available. To achieve this aim, protocols must be rigorously tested and the move towards personalized medicine encouraged. Equally, education of the public, governments and clinicians on the frequency and consequences of infertility is needed. Health options, including male contraceptives, must be expanded, and the opportunities encompassed in such investment understood. The pressing questions related to male reproductive health, spanning the spectrum of andrology are identified in the Expert Recommendation.
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Affiliation(s)
- Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
- The Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
- The Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, Quebec, Canada
| | - Richard A Anderson
- MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | - Christopher L R Barratt
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - Hermann M Behre
- Center for Reproductive Medicine and Andrology, University Hospital, Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Sarah R Catford
- Hudson Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Obstetrics and Gynaecology, The Royal Women's Hospital, Melbourne, Victoria, Australia
| | | | - Geraldine Delbes
- Institut National de la Recherche Scientifique, Centre Armand-Frappier Sante Biotechnologie, Laval, Quebec, Canada
| | - Michael L Eisenberg
- Department of Urology and Obstetrics and Gynecology, Stanford University, Stanford, CA, USA
| | - Nicolas Garrido
- IVI Foundation, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Brendan J Houston
- School of BioSciences and Bio21 Institute, The University of Melbourne, Parkville, Melbourne, Australia
| | - Niels Jørgensen
- Department of Growth and Reproduction, International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Csilla Krausz
- Department of Experimental and Clinical Biomedical Sciences, 'Mario Serio', University of Florence, University Hospital of Careggi Florence, Florence, Italy
| | - Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Robert I McLachlan
- Hudson Institute of Medical Research and the Department of Obstetrics and Gynaecology, Monash University, Melbourne, Australia
- Monash IVF Group, Richmond, Victoria, Australia
| | - Suks Minhas
- Department of Surgery and Cancer Imperial, London, UK
| | - Tim Moss
- Healthy Male and the Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia
| | - Allan Pacey
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Lærke Priskorn
- Department of Growth and Reproduction, International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Stefan Schlatt
- Centre for Reproductive Medicine and Andrology, University of Münster, Münster, Germany
| | - Jacquetta Trasler
- Departments of Paediatrics, Human Genetics and Pharmacology & Therapeutics, McGill University and Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Leonardo Trasande
- Center for the Investigation of Environmental Hazards, Department of Paediatrics, NYU Grossman School of Medicine, New York, NY, USA
| | - Frank Tüttelmann
- Institute of Reproductive Genetics, University of Münster, Münster, Germany
| | - Mónica Hebe Vazquez-Levin
- Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas de Argentina, Fundación IBYME, Buenos Aires, Argentina
| | - Joris A Veltman
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, Institute of Reproduction and Development, Fudan University, Shanghai, China
| | - Moira K O'Bryan
- School of BioSciences and Bio21 Institute, The University of Melbourne, Parkville, Melbourne, Australia.
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11
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Lismer A, Shao X, Dumargne MC, Lafleur C, Lambrot R, Chan D, Toft G, Bonde JP, MacFarlane AJ, Bornman R, Aneck-Hahn N, Patrick S, Bailey JM, de Jager C, Dumeaux V, Trasler JM, Kimmins S. The Association between Long-Term DDT or DDE Exposures and an Altered Sperm Epigenome-a Cross-Sectional Study of Greenlandic Inuit and South African VhaVenda Men. ENVIRONMENTAL HEALTH PERSPECTIVES 2024; 132:17008. [PMID: 38294233 PMCID: PMC10829569 DOI: 10.1289/ehp12013] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/26/2023] [Accepted: 12/20/2023] [Indexed: 02/01/2024]
Abstract
BACKGROUND The organochlorine dichlorodiphenyltrichloroethane (DDT) is banned worldwide owing to its negative health effects. It is exceptionally used as an insecticide for malaria control. Exposure occurs in regions where DDT is applied, as well as in the Arctic, where its endocrine disrupting metabolite, p , p ' -dichlorodiphenyldichloroethylene (p , p ' -DDE) accumulates in marine mammals and fish. DDT and p , p ' -DDE exposures are linked to birth defects, infertility, cancer, and neurodevelopmental delays. Of particular concern is the potential of DDT use to impact the health of generations to come via the heritable sperm epigenome. OBJECTIVES The objective of this study was to assess the sperm epigenome in relation to p , p ' -DDE serum levels between geographically diverse populations. METHODS In the Limpopo Province of South Africa, we recruited 247 VhaVenda South African men and selected 50 paired blood serum and semen samples, and 47 Greenlandic Inuit blood and semen paired samples were selected from a total of 193 samples from the biobank of the INUENDO cohort, an EU Fifth Framework Programme Research and Development project. Sample selection was based on obtaining a range of p , p ' -DDE serum levels (mean = 870.734 ± 134.030 ng / mL ). We assessed the sperm epigenome in relation to serum p , p ' -DDE levels using MethylC-Capture-sequencing (MCC-seq) and chromatin immunoprecipitation followed by sequencing (ChIP-seq). We identified genomic regions with altered DNA methylation (DNAme) and differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3) in sperm. RESULTS Differences in DNAme and H3K4me3 enrichment were identified at transposable elements and regulatory regions involved in fertility, disease, development, and neurofunction. A subset of regions with sperm DNAme and H3K4me3 that differed between exposure groups was predicted to persist in the preimplantation embryo and to be associated with embryonic gene expression. DISCUSSION These findings suggest that DDT and p , p ' -DDE exposure impacts the sperm epigenome in a dose-response-like manner and may negatively impact the health of future generations through epigenetic mechanisms. Confounding factors, such as other environmental exposures, genetic diversity, and selection bias, cannot be ruled out. https://doi.org/10.1289/EHP12013.
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Affiliation(s)
- Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Xiaojian Shao
- Digital Technologies Research Centre, National Research Council Canada, Ottawa, Ontario, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | - Marie-Charlotte Dumargne
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada
| | - Christine Lafleur
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
| | - Romain Lambrot
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
| | - Donovan Chan
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Gunnar Toft
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | - Jens Peter Bonde
- Department of Occupational and Environmental Medicine, Bispebjerg University Hospital, Copenhagen, Denmark
- Institute of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Amanda J. MacFarlane
- Agriculture Food and Nutrition Evidence Center, Texas A&M University, Fort Worth, Texas, USA
| | - Riana Bornman
- Environmental Chemical Pollution and Health Research Unit, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- University of Pretoria Institute for Sustainable Malaria Control, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Natalie Aneck-Hahn
- University of Pretoria Institute for Sustainable Malaria Control, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Sean Patrick
- University of Pretoria Institute for Sustainable Malaria Control, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Janice M. Bailey
- Research Centre on Reproduction and Intergenerational Health, Department of Animal Sciences, Université Laval, Quebec, Quebec, Canada
| | - Christiaan de Jager
- Environmental Chemical Pollution and Health Research Unit, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
- University of Pretoria Institute for Sustainable Malaria Control, School of Health Systems and Public Health, Faculty of Health Sciences, University of Pretoria, South Africa
| | - Vanessa Dumeaux
- Department of Anatomy and Cell Biology, Western University, London, Ontario, Canada
- Department of Oncology, Western University, London, Ontario, Canada
| | - Jacquetta M. Trasler
- Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
- Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
- Department of Pediatrics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
- University of Montreal Hospital Research Centre, Montreal, Quebec, Canada
- Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal, Quebec, Canada
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12
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Yoshikawa M, Suemaru K. Prenatal folate deficiency impairs sociability and memory/recognition in mice offspring. Brain Res 2024; 1822:148639. [PMID: 37858854 DOI: 10.1016/j.brainres.2023.148639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/30/2023] [Accepted: 10/16/2023] [Indexed: 10/21/2023]
Abstract
Folate is essential for the normal growth and development of the fetus. Folic acid supplementation during the fetal period affects postnatal brain development and reduces the incidence of mental disorders in animal and human studies. However, the association between folate deficiency (FD) during pregnancy and developmental disorders in children remains poorly understood. In this study, we investigated whether prenatal FD is associated with neurodevelopmental disorders in offspring. ICR mice were fed a control diet (2 mg folic acid/kg diet) or a folate-deficient diet (0.3 mg folic acid/kg diet) from embryonic day 1 until parturition. We evaluated locomotor activity, anxiety, grooming, sociability and learning memory in male offspring at 7-10 weeks of age. No differences were found in locomotor activity or anxiety in the open field test, nor in grooming time in the self-grooming test. However, sociability, spatial memory, and novel object recognition were impaired in the FD mice compared with control offspring. Furthermore, we measured protein expression levels of the NMDA and AMPA receptors, as well as PSD-95 and the GABA-synthesizing enzymes GAD65/67 in the frontal cortex and hippocampus. In FD mice, expression levels of AMPA receptor 1 and PSD-95 in both regions were reduced compared with control mice. Moreover, NMDA receptor subunit 2B and GAD65/67 were significantly downregulated in the frontal cortex of prenatal FD mice compared with the controls. Collectively, these findings suggest that prenatal FD causes behavioral deficits together with a reduction in synaptic protein levels in the frontal cortex and hippocampus.
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Affiliation(s)
- Misato Yoshikawa
- School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
| | - Katsuya Suemaru
- School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
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13
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Golding MC. Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter. Birth Defects Res 2023; 115:1825-1834. [PMID: 37424262 PMCID: PMC10774456 DOI: 10.1002/bdr2.2215] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 06/16/2023] [Accepted: 06/23/2023] [Indexed: 07/11/2023]
Abstract
Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non-genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally-induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.
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Affiliation(s)
- Michael C. Golding
- Department of Veterinary Physiology & Pharmacology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas, USA, 77843
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14
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Fardous AM, Heydari AR. Uncovering the Hidden Dangers and Molecular Mechanisms of Excess Folate: A Narrative Review. Nutrients 2023; 15:4699. [PMID: 37960352 PMCID: PMC10648405 DOI: 10.3390/nu15214699] [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: 09/29/2023] [Revised: 10/26/2023] [Accepted: 11/03/2023] [Indexed: 11/15/2023] Open
Abstract
This review delves into the intricate relationship between excess folate (vitamin B9) intake, especially its synthetic form, namely, folic acid, and its implications on health and disease. While folate plays a pivotal role in the one-carbon cycle, which is essential for DNA synthesis, repair, and methylation, concerns arise about its excessive intake. The literature underscores potential deleterious effects, such as an increased risk of carcinogenesis; disruption in DNA methylation; and impacts on embryogenesis, pregnancy outcomes, neurodevelopment, and disease risk. Notably, these consequences stretch beyond the immediate effects, potentially influencing future generations through epigenetic reprogramming. The molecular mechanisms underlying these effects were examined, including altered one-carbon metabolism, the accumulation of unmetabolized folic acid, vitamin-B12-dependent mechanisms, altered methylation patterns, and interactions with critical receptors and signaling pathways. Furthermore, differences in the effects and mechanisms mediated by folic acid compared with natural folate are highlighted. Given the widespread folic acid supplementation, it is imperative to further research its optimal intake levels and the molecular pathways impacted by its excessive intake, ensuring the health and well-being of the global population.
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Affiliation(s)
- Ali M. Fardous
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
| | - Ahmad R. Heydari
- Department of Nutrition and Food Science, Wayne State University, Detroit, MI 48202, USA;
- Barbara Ann Karmanos Cancer Institute, Wayne State University, Detroit, MI 48202, USA
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15
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Zhu L, Tillquist N, Scatolin G, Gately R, Kawaida M, Reiter A, Reed S, Zinn S, Govoni K, Jiang Z. Maternal restricted- and over- feeding during gestation perturb offspring sperm epigenome in sheep. Reproduction 2023; 166:311-322. [PMID: 37647207 PMCID: PMC10962644 DOI: 10.1530/rep-23-0074] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 08/30/2023] [Indexed: 09/01/2023]
Abstract
In brief Inadequate maternal nutrition during gestation can have immediate and lifelong effects on offspring. This study shows that maternal restricted - and over- nutrition during gestation do not affect semen characteristics in F1 male offspring but alters offspring sperm sncRNA profiles and DNA methylome in sheep. Abstract There is a growing body of evidence that inadequate maternal nutrition during gestation can have immediate and lifelong effects on offspring. However, little is known about the effects of maternal nutrition during gestation on male offspring reproduction. Here, using a sheep model of maternal restricted - and over - nutrition (60 or 140% of the National Research Council requirements) during gestation, we found that maternal restricted - and over - nutrition do not affect semen characteristics (i.e. volume, sperm concentration, pH, sperm motility, sperm morphology) or scrotal circumference in male F1 offspring. However, using small RNA sequencing analysis, we demonstrated that both restricted - and over - nutrition during gestation induced marked changes in composition and expression of sperm small noncoding RNAs (sncRNAs) subpopulations including in male F1 offspring. Whole-genome bisulfite sequencing analysis further identified specific genomic loci where poor maternal nutrition resulted in alterations in DNA methylation. These findings indicate that maternal restricted - and over - nutrition during gestation induce epigenetic modifications in sperm of F1 offspring sperm in sheep, which may contribute to environmentally influenced phenotypes in ruminants.
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Affiliation(s)
- Linkai Zhu
- Department of Animal Sciences, Genetics Institute, University of Florida, FL 32610, USA
| | - Nicole Tillquist
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Giovanna Scatolin
- Department of Animal Sciences, Genetics Institute, University of Florida, FL 32610, USA
| | - Rachael Gately
- Department of Ambulatory Medicine and Theriogenology, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA 01536
| | - Mia Kawaida
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Amanda Reiter
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Sarah Reed
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Steven Zinn
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Kristen Govoni
- Department of Animal Science, University of Connecticut, CT, 06269, USA
| | - Zongliang Jiang
- Department of Animal Sciences, Genetics Institute, University of Florida, FL 32610, USA
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16
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Ren H, Wang K, Liu Z, Zhong X, Liang M, Liao Y. Effect of Low Dietary Folate on Mouse Spermatogenesis and Spindle Assembly Checkpoint Dysfunction May Contribute to Folate Deficiency-Induced Chromosomal Instability in Cultured Mouse Spermatogonia. DNA Cell Biol 2023; 42:515-525. [PMID: 37289823 DOI: 10.1089/dna.2023.0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023] Open
Abstract
Folate, as the initial substrate in one-carbon metabolism, is involved in the synthesis of important substances such as DNA, RNA, and protein. Folate deficiency (FD) is associated with male subfertility and impaired spermatogenesis, yet the underlying mechanisms are poorly understood. In the present study, we established an animal model of FD to investigate the effect of FD on spermatogenesis. GC-1 spermatogonia were used as a model to investigate the effect of FD on proliferation, viability, and chromosomal instability (CIN). Furthermore, we explored the expression of core genes and proteins of spindle assembly checkpoint (SAC), a signaling cascade ensuring accurate chromosome segregation and preventing CIN during mitosis. Cells were maintained in medium containing 0, 20, 200, or 2000 nM folate for 14 days. CIN was measured by using a cytokinesis-blocked micronucleus cytome assay. We found that sperm counts decreased significantly (p < 0.001) and the rate of sperm with defects in the head increased significantly (p < 0.05) in FD diet mice. We also found, relative to the folate-sufficient conditions (2000 nM), cells cultured with 0, 20, or 200 nM folate exhibited delayed growth and increased apoptosis in an inverse dose-dependent manner. FD (0, 20, or 200 nM) significantly induced CIN (p < 0.001, p < 0.001, and p < 0.05, respectively). Moreover, FD significantly and inverse dose dependently increased the mRNA and protein expression of several key SAC-related genes. The results indicate that FD impairs SAC activity, which contributes to mitotic aberrations and CIN. These findings establish a novel association between FD and SAC dysfunction. Thus, FD-impaired spermatogenesis may be partly due to genomic instability and proliferation inhibition of spermatogonia.
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Affiliation(s)
- Huanhuan Ren
- School of Life Science, Bengbu Medical College, Bengbu, China
- Department of Clinical Laboratory, Fuyang Fifth People's Hospital, Fuyang, China
| | - Kaixian Wang
- School of Life Science, Bengbu Medical College, Bengbu, China
| | - Zirui Liu
- School of Life Science, Bengbu Medical College, Bengbu, China
| | - Xuansheng Zhong
- School of Life Science, Bengbu Medical College, Bengbu, China
| | - Meng Liang
- School of Life Science, Bengbu Medical College, Bengbu, China
| | - Yaping Liao
- School of Life Science, Bengbu Medical College, Bengbu, China
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17
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Shi Q, Qi K. Developmental origins of health and disease: Impact of paternal nutrition and lifestyle. Pediatr Investig 2023; 7:111-131. [PMID: 37324600 PMCID: PMC10262906 DOI: 10.1002/ped4.12367] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 01/29/2023] [Indexed: 09/20/2023] Open
Abstract
Most epidemiological and experimental studies have focused on maternal influences on offspring's health. The impact of maternal undernutrition, overnutrition, hypoxia, and stress is linked to adverse offspring outcomes across a range of systems including cardiometabolic, respiratory, endocrine, and reproduction among others. During the past decade, it has become evident that paternal environmental factors are also linked to the development of diseases in offspring. In this article, we aim to outline the current understanding of the impact of male health and environmental exposure on offspring development, health, and disease and explore the mechanisms underlying the paternal programming of offspring health. The available evidence suggests that poor paternal pre-conceptional nutrition and lifestyle, and advanced age can increase the risk of negative outcomes in offspring, via both direct (genetic/epigenetic) and indirect (maternal uterine environment) effects. Beginning at preconception, and during utero and the early life after birth, cells acquire an epigenetic memory of the early exposure which can be influential across the entire lifespan and program a child's health. Potentially not only mothers but also fathers should be advised that maintaining a healthy diet and lifestyle is important to improve offspring health as well as the parental health status. However, the evidence is mostly based on animal studies, and well-designed human studies are urgently needed to verify findings from animal data.
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Affiliation(s)
- Qiaoyu Shi
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's HospitalCapital Medical University, National Center for Children's HealthBeijingChina
| | - Kemin Qi
- Laboratory of Nutrition and Development, Key Laboratory of Major Diseases in Children, Ministry of Education, Beijing Pediatric Research Institute, Beijing Children's HospitalCapital Medical University, National Center for Children's HealthBeijingChina
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18
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Lismer A, Kimmins S. Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development. Nat Commun 2023; 14:2142. [PMID: 37059740 PMCID: PMC10104880 DOI: 10.1038/s41467-023-37820-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 03/31/2023] [Indexed: 04/16/2023] Open
Abstract
Although more studies are demonstrating that a father's environment can influence child health and disease, the molecular mechanisms underlying non-genetic inheritance remain unclear. It was previously thought that sperm exclusively contributed its genome to the egg. More recently, association studies have shown that various environmental exposures including poor diet, toxicants, and stress, perturbed epigenetic marks in sperm at important reproductive and developmental loci that were associated with offspring phenotypes. The molecular and cellular routes that underlie how epigenetic marks are transmitted at fertilization, to resist epigenetic reprogramming in the embryo, and drive phenotypic changes are only now beginning to be unraveled. Here, we provide an overview of the state of the field of intergenerational paternal epigenetic inheritance in mammals and present new insights into the relationship between embryo development and the three pillars of epigenetic inheritance: chromatin, DNA methylation, and non-coding RNAs. We evaluate compelling evidence of sperm-mediated transmission and retention of paternal epigenetic marks in the embryo. Using landmark examples, we discuss how sperm-inherited regions may escape reprogramming to impact development via mechanisms that implicate transcription factors, chromatin organization, and transposable elements. Finally, we link paternally transmitted epigenetic marks to functional changes in the pre- and post-implantation embryo. Understanding how sperm-inherited epigenetic factors influence embryo development will permit a greater understanding related to the developmental origins of health and disease.
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Affiliation(s)
- Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, H3G 1Y6, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, H3G 1Y6, Canada.
- Department of Pathology and Cell Biology, Faculty of Medicine, University of Montreal Hospital Research Centre, Montreal, QC, H2X 0A9, Canada.
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19
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Breton-Larrivée M, Elder E, Legault LM, Langford-Avelar A, MacFarlane AJ, McGraw S. Mitigating the detrimental developmental impact of early fetal alcohol exposure using a maternal methyl donor-enriched diet. FASEB J 2023; 37:e22829. [PMID: 36856720 DOI: 10.1096/fj.202201564r] [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: 09/27/2022] [Revised: 01/23/2023] [Accepted: 02/03/2023] [Indexed: 03/02/2023]
Abstract
Fetal alcohol exposure at any stage of pregnancy can lead to fetal alcohol spectrum disorder (FASD), a group of life-long conditions characterized by congenital malformations, as well as cognitive, behavioral, and emotional impairments. The teratogenic effects of alcohol have long been publicized; yet fetal alcohol exposure is one of the most common preventable causes of birth defects. Currently, alcohol abstinence during pregnancy is the best and only way to prevent FASD. However, alcohol consumption remains astoundingly prevalent among pregnant women; therefore, additional measures need to be made available to help protect the developing embryo before irreparable damage is done. Maternal nutritional interventions using methyl donors have been investigated as potential preventative measures to mitigate the adverse effects of fetal alcohol exposure. Here, we show that a single acute preimplantation (E2.5; 8-cell stage) fetal alcohol exposure (2 × 2.5 g/kg ethanol with a 2h interval) in mice leads to long-term FASD-like morphological phenotypes (e.g. growth restriction, brain malformations, skeletal delays) in late-gestation embryos (E18.5) and demonstrate that supplementing the maternal diet with a combination of four methyl donor nutrients, folic acid, choline, betaine, and vitamin B12, prior to conception and throughout gestation effectively reduces the incidence and severity of alcohol-induced morphological defects without altering DNA methylation status of imprinting control regions and regulation of associated imprinted genes. This study clearly supports that preimplantation embryos are vulnerable to the teratogenic effects of alcohol, emphasizes the dangers of maternal alcohol consumption during early gestation, and provides a potential proactive maternal nutritional intervention to minimize FASD progression, reinforcing the importance of adequate preconception and prenatal nutrition.
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Affiliation(s)
- Mélanie Breton-Larrivée
- Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada
| | - Elizabeth Elder
- Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada
| | - Lisa-Marie Legault
- Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada
| | - Alexandra Langford-Avelar
- Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada
| | - Amanda J MacFarlane
- Agriculture, Food, and Nutrition Evidence Center, Texas A&M University, Texas, Fort Worth, USA.,Department of Nutrition, Texas A&M University, College Station, Texas, USA
| | - Serge McGraw
- Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal, Canada.,Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Canada.,Department of Obstetrics and Gynecology, Université de Montréal, Montreal, Canada
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20
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Alata Jimenez N, Castellano M, Santillan EM, Boulias K, Boan A, Arias Padilla LF, Fernandino JI, Greer EL, Tosar JP, Cochella L, Strobl-Mazzulla PH. Paternal methotrexate exposure affects sperm small RNA content and causes craniofacial defects in the offspring. Nat Commun 2023; 14:1617. [PMID: 36959185 PMCID: PMC10036556 DOI: 10.1038/s41467-023-37427-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 03/14/2023] [Indexed: 03/25/2023] Open
Abstract
Folate is an essential vitamin for vertebrate embryo development. Methotrexate (MTX) is a folate antagonist that is widely prescribed for autoimmune diseases, blood and solid organ malignancies, and dermatologic diseases. Although it is highly contraindicated for pregnant women, because it is associated with an increased risk of multiple birth defects, the effect of paternal MTX exposure on their offspring has been largely unexplored. Here, we found MTX treatment of adult medaka male fish (Oryzias latipes) causes cranial cartilage defects in their offspring. Small non-coding RNA (sncRNAs) sequencing in the sperm of MTX treated males identify differential expression of a subset of tRNAs, with higher abundance for specific 5' tRNA halves. Sperm RNA methylation analysis on MTX treated males shows that m5C is the most abundant and differential modification found in RNAs ranging in size from 50 to 90 nucleotides, predominantly tRNAs, and that it correlates with greater testicular Dnmt2 methyltransferase expression. Injection of sperm small RNA fractions from MTX-treated males into normal fertilized eggs generated cranial cartilage defects in the offspring. Overall, our data suggest that paternal MTX exposure alters sperm sncRNAs expression and modifications that may contribute to developmental defects in their offspring.
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Affiliation(s)
- Nagif Alata Jimenez
- Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina
- Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina
| | - Mauricio Castellano
- Functional Genomics Unit, Instituto Pasteur de Montevideo, Montevideo, Uruguay
- School of Science, Universidad de la República, Montevideo, Uruguay
| | - Emilio M Santillan
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Konstantinos Boulias
- Department of Pediatrics, HMS Initiative for RNA Medicine, Harvard Medical School, Boston, MA, USA
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Agustín Boan
- Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina
- Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina
| | - Luisa F Arias Padilla
- Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina
- Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina
| | - Juan I Fernandino
- Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina
- Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina
| | - Eric L Greer
- Department of Pediatrics, HMS Initiative for RNA Medicine, Harvard Medical School, Boston, MA, USA
- Division of Newborn Medicine, Boston Children's Hospital, Boston, MA, USA
| | - Juan P Tosar
- Functional Genomics Unit, Instituto Pasteur de Montevideo, Montevideo, Uruguay
- School of Science, Universidad de la República, Montevideo, Uruguay
| | - Luisa Cochella
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MA, USA
| | - Pablo H Strobl-Mazzulla
- Laboratory of Developmental Biology, Instituto de Investigaciones Biotecnológicas- Instituto Tecnológico de Chascomús (CONICET-UNSAM), Chascomús, Argentina.
- Escuela de Bio y Nanotecnologías (UNSAM), Chascomús, Argentina.
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21
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Sapehia D, Mahajan A, Srinivasan R, Kaur J. Pre-natal dietary imbalance of folic acid and vitamin B12 deficiency adversely impacts placental development and fetal growth. Placenta 2023; 132:44-54. [PMID: 36657272 DOI: 10.1016/j.placenta.2023.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 12/15/2022] [Accepted: 01/02/2023] [Indexed: 01/05/2023]
Abstract
INTRODUCTION The common practice of supplementing folic acid during pregnancy and the absence of such guidelines for vitamin B12 lead to an imbalance of these vitamins, especially in developing countries like India, where many women are vitamin B12 deficient. METHODS The present study was designed to explore the effect of low vitamin B12 in combination with different levels of folic acid in the parental diet on fetal growth parameters and maternal reproductive performance in a transgenerational manner. The reversibility of these effects was studied by shifting the mice to a regular diet in the F1 generation in the case of transient groups and continued on the same diet in the sustained groups after the dietary exposure in the F0 generation. RESULTS Vitamin B12 deficiency and different levels of folic acid resulted in the decreased placental and fetal weight of the F1 generation. Surprisingly, a decreased placental weight, low fetal weight, and reduced crown-rump length and head circumference were observed in F2 fetuses of vitamin B12 deficient with folate over-supplemented (BDFO) transient group, i.e. when F1 mice were shifted to normal diet conditions. Reduced follicles in ovaries and alteration in placental pathology in all the F0 groups and BDFO of the F1 transient group were also seen. DISCUSSION Overall, the study revealed that dietary imbalance of vitamin B12 and folic acid, particularly B12 deficiency with over-supplemented folic acid, negatively affects placental and fetal development and maternal reproductive performance. Such effects are passed on to the next generation too.
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Affiliation(s)
| | | | - Radhika Srinivasan
- Department Cytology & Gynaecological Pathology, PGIMER, Chandigarh, India.
| | - Jyotdeep Kaur
- Department of Biochemistry, PGIMER, Chandigarh, India.
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22
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Lipkin WI, Bresnahan M, Susser E. Cohort-guided insights into gene-environment interactions in autism spectrum disorders. Nat Rev Neurol 2023; 19:118-125. [PMID: 36646930 PMCID: PMC9841497 DOI: 10.1038/s41582-022-00764-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/09/2022] [Indexed: 01/18/2023]
Abstract
Prospective birth cohorts offer unprecedented opportunities to investigate the pathogenesis of complex disorders such as autism, in which gene-environment interactions must be appreciated in a temporal context. This Perspective article considers the history of autism research, including missteps that reflected an incomplete understanding of the epidemiology of autistic spectrum disorders, the effects of advocacy and philanthropy on the trajectory of scientific inquiry, and the current and future roles of prospective birth cohort research in illuminating the pathology of these and other complex disorders wherein exposures during gestation might not manifest until later in life.
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Affiliation(s)
- W Ian Lipkin
- Center for Infection and Immunity, Mailman School of Public Health, Columbia University, New York, NY, USA.
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Michaeline Bresnahan
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
| | - Ezra Susser
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
- New York State Psychiatric Institute, New York, NY, USA
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23
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Bhadsavle SS, Golding MC. Paternal epigenetic influences on placental health and their impacts on offspring development and disease. Front Genet 2022; 13:1068408. [PMID: 36468017 PMCID: PMC9716072 DOI: 10.3389/fgene.2022.1068408] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 11/04/2022] [Indexed: 07/25/2023] Open
Abstract
Our efforts to understand the developmental origins of birth defects and disease have primarily focused on maternal exposures and intrauterine stressors. Recently, research into non-genomic mechanisms of inheritance has led to the recognition that epigenetic factors carried in sperm also significantly impact the health of future generations. However, although researchers have described a range of potential epigenetic signals transmitted through sperm, we have yet to obtain a mechanistic understanding of how these paternally-inherited factors influence offspring development and modify life-long health. In this endeavor, the emerging influence of the paternal epigenetic program on placental development, patterning, and function may help explain how a diverse range of male exposures induce comparable intergenerational effects on offspring health. During pregnancy, the placenta serves as the dynamic interface between mother and fetus, regulating nutrient, oxygen, and waste exchange and coordinating fetal growth and maturation. Studies examining intrauterine maternal stressors routinely describe alterations in placental growth, histological organization, and glycogen content, which correlate with well-described influences on infant health and adult onset of disease. Significantly, the emergence of similar phenotypes in models examining preconception male exposures indicates that paternal stressors transmit an epigenetic memory to their offspring that also negatively impacts placental function. Like maternal models, paternally programmed placental dysfunction exerts life-long consequences on offspring health, particularly metabolic function. Here, focusing primarily on rodent models, we review the literature and discuss the influences of preconception male health and exposure history on placental growth and patterning. We emphasize the emergence of common placental phenotypes shared between models examining preconception male and intrauterine stressors but note that the direction of change frequently differs between maternal and paternal exposures. We posit that alterations in placental growth, histological organization, and glycogen content broadly serve as reliable markers of altered paternal developmental programming, predicting the emergence of structural and metabolic defects in the offspring. Finally, we suggest the existence of an unrecognized developmental axis between the male germline and the extraembryonic lineages that may have evolved to enhance fetal adaptation.
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Affiliation(s)
| | - Michael C. Golding
- Department of Veterinary Physiology and Pharmacology, School of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, United States
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24
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New evidence for deleterious effects of environmental contaminants on the male gamete. Anim Reprod Sci 2022; 246:106886. [PMID: 34774338 DOI: 10.1016/j.anireprosci.2021.106886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 12/14/2022]
Abstract
The decreasing trend in human and domestic animal fertility in recent decades has resulted in the question of whether reduced sperm quality is associated with changes in global climate and the environment. Proposed causes for reduced sperm quality include environmental contaminants, which enter into the body of animals through the food chain and are transported to the reproductive tract, where contaminating agents can have effects on fertilization capacities of gametes. In this review, there is a focus on various environmental contaminants and potential effects on male fertility. Human-derived contaminants, particularly endocrine-disrupting phthalates and the pesticide atrazine, are discussed. Naturally occurring toxins are also addressed, in particular mycotoxins such as aflatoxin which can be components in food consumed by humans and animals. Mechanisms by which environmental contaminants reduce male fertility are not clearly defined; however, are apparently multifactorial (i.e., direct and indirect effects) with there being diverse modes of action. Results from studies with humans, rodents and domestic animals indicate there are deleterious effects of contaminants on male gametes at various stages of spermatogenesis (i.e., in the testis) during passage through the epididymis, and in mature spermatozoa, after ejaculation and during capacitation. Considering there is never detection of a single contaminant, this review addresses synergistic or additive effects of combinations of contaminants. There is new evidence highlighted for the long-lasting effects of environmental contaminants on spermatozoa and developing embryos. Understanding the risk associated with environmental contaminants for animal reproduction may lead to new management strategies, thereby improving reproductive processes.
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25
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L. Charest P, Tessougue E, Lessard M, Herst PM, Navarro P, Kimmins S, Trasler JM, MacFarlane AJ, Benoit-Biancamano MO, Bailey JL, Dalvai M. Exposure to environmental contaminants and folic acid supplementation intergenerationally impact fetal skeleton development through the paternal lineage in a rat model. FRONTIERS IN TOXICOLOGY 2022; 4:881622. [PMID: 36238601 PMCID: PMC9552329 DOI: 10.3389/ftox.2022.881622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/26/2022] [Indexed: 11/13/2022] Open
Abstract
Persistent organic pollutants (POPs) are ubiquitous in the environment, which is of concern since they are broadly toxic for wildlife and human health. It is generally accepted that maternal prenatal folic acid supplementation (FA) may beneficially impact offspring development, but it has been recently shown that the father's exposures also influence the health of his offspring. Bone is an endocrine organ essential for whole-body homeostasis and is susceptible to toxicants. Herein, we tested the hypotheses that prenatal paternal exposure to POPs induces developmental bone disorders in fetuses across multiple generations and that FA supplementation attenuates these disorders. We used a four-generation rat model, in which F0 founder females were divided into four treatment groups. F0 females were gavaged with corn oil or an environmentally-relevant POPs mixture and fed either a control diet (2 mg FA/kg), or FA supplemented diet (6 mg FA/kg) before mating and until parturition (four treatments in total). After the birth of the F1 litters, all F0 females and subsequent generations received the FA control diet. Staining with alcian blue and alizarin red S of male and female fetal skeletons was performed at Gestational Day 19.5. Paternal direct and ancestral exposure to POPs delayed bone ossification and decreased the length of long limb bones in fetuses. Maternal FA supplementation did not counteract the POPs-associated delayed fetal ossification and reduced long bone length. In conclusion, prenatal paternal POPs exposure causes developmental bone abnormalities over multiple generations, which were not corrected by maternal FA supplementation.
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Affiliation(s)
- Phanie L. Charest
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
| | - Emmanuel Tessougue
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
| | - Maryse Lessard
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
| | - Pauline M. Herst
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
| | - Pauline Navarro
- Department of Nutrition, Faculty of Agricultural and Food Sciences, Institute of Nutrition and Functional Foods, Université Laval, Quebec City, QC, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC, Canada
| | - Jacquetta M. Trasler
- Departments of Pediatrics, Human Genetics and Pharmacology and Therapeutics, Research Institute-McGill University Health Center, McGill University, Montreal, QC, Canada
| | | | - Marie-Odile Benoit-Biancamano
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
- Groupe de Recherche En Pharmacologie Animale du Québec (GREPAQ), Department of Pathology and Microbiology, Faculty of Veterinary Medicine, Université de Montréal, Sainte Hyacinthe, QC, Canada
| | - Janice L. Bailey
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
- *Correspondence: Janice L. Bailey, ; Mathieu Dalvai,
| | - Mathieu Dalvai
- Department of Animal Sciences, Faculty of Agricultural and Food Sciences, Université Laval, Quebec City, QC, Canada
- Centre de Recherche en Reproduction Développement et Santé Intergénérationnelle (CRDSI), Université Laval, Quebec City, QC, Canada
- *Correspondence: Janice L. Bailey, ; Mathieu Dalvai,
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Canada's Colonial Genocide of Indigenous Peoples: A Review of the Psychosocial and Neurobiological Processes Linking Trauma and Intergenerational Outcomes. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19116455. [PMID: 35682038 PMCID: PMC9179992 DOI: 10.3390/ijerph19116455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/23/2022] [Accepted: 05/23/2022] [Indexed: 12/04/2022]
Abstract
The policies and actions that were enacted to colonize Indigenous Peoples in Canada have been described as constituting cultural genocide. When one considers the long-term consequences from the perspective of the social and environmental determinants of health framework, the impacts of such policies on the physical and mental health of Indigenous Peoples go well beyond cultural loss. This paper addresses the impacts of key historical and current Canadian federal policies in relation to the health and well-being of Indigenous Peoples. Far from constituting a mere lesson in history, the connections between colonialist policies and actions on present-day outcomes are evaluated in terms of transgenerational and intergenerational transmission processes, including psychosocial, developmental, environmental, and neurobiological mechanisms and trauma responses. In addition, while colonialist policies have created adverse living conditions for Indigenous Peoples, resilience and the perseverance of many aspects of culture may be maintained through intergenerational processes.
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27
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Olovnikov AM. Eco-crossover, or environmentally regulated crossing-over, and natural selection are two irreplaceable drivers of adaptive evolution: Eco-crossover hypothesis. Biosystems 2022; 218:104706. [DOI: 10.1016/j.biosystems.2022.104706] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 05/19/2022] [Accepted: 05/19/2022] [Indexed: 12/31/2022]
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28
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Menezo Y, Clement P, Elder K. Are UMFA (un-metabolized folic acid) and endocrine disruptor chemicals (EDCs) co-responsible for sperm degradation? An epigenetic/methylation perspective. Andrologia 2022; 54:e14400. [PMID: 35274767 PMCID: PMC9541233 DOI: 10.1111/and.14400] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/06/2022] [Accepted: 02/10/2022] [Indexed: 01/26/2023] Open
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29
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Parental folate deficiency induces birth defects in mice accompanied with increased de novo mutations. Cell Discov 2022; 8:18. [PMID: 35190523 PMCID: PMC8861018 DOI: 10.1038/s41421-021-00364-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/08/2021] [Indexed: 01/06/2023] Open
Abstract
Dietary folate deficiency (FD) is associated with the occurrence of birth defects. However, the mechanisms underlying this association remain elusive. In particular, how FD affects genome stability is unknown. To examine whether a folate-deficient diet can affect genome stability, C57BL/6 mice were maintained on a synthetic diet lacking of folic acid (FA) for two generations. F0 mice received the FD diet beginning at 3 weeks of age, and their offspring (F1) began the FD diet after weaning. Both male and female F1 mice fed the FD diet were intentionally crossed with F1 mice fed the normal diet to produce F2 mice. F2 embryos were dissected and collected at E14.5 and E18.5. The malformation ratio was significantly increased in F2 embryos fed the FD diet for two generations compared to those fed the normal diet. Whole-genome sequencing of multiple sibship with F1 males on the FD diet showed that the de novo mutation (DNM) rate in F2 embryos was three times of the reported spontaneous rate in mice. Furthermore, many DNMs observed in the F2 mice exhibited an allele ratio of 1:3 instead of 2:2, suggesting that these mutations are likely to accumulate in gamete cells as a form of mismatch in the DNA duplex. Our study indicated that FD for two generations significantly enhances DNM accumulation during meiosis, which might contribute to the increased negative birth outcomes among F2 mice. Not only maternal but also paternal FA supplementation is probably also necessary and beneficial to prevent birth defects.
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30
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Zhang H, Shan L, Aniagu S, Jiang Y, Chen T. Paternal acrylamide exposure induces transgenerational effects on sperm parameters and learning capability in mice. Food Chem Toxicol 2022; 161:112817. [PMID: 35032568 DOI: 10.1016/j.fct.2022.112817] [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: 10/12/2021] [Revised: 12/29/2021] [Accepted: 01/10/2022] [Indexed: 11/26/2022]
Abstract
Acrylamide (AA) has been shown to have neurological and reproductive toxicities, but little is known about transgenerational effects of AA. In this study, male C57BL/6 mice were exposed to AA (0.01, 1, 10 μg/mL) and its metabolite glycidamide (GA, 10 μg/mL) in drinking water, which were then mated with unexposed female mice to produce F1 and F2 generations. We found that both AA and GA at high concentrations decreased sperm motility in F0 mice and increased sperm malformation rates in mice from all the three generations. In addition, AA and GA increased sperm reactive oxygen species as well as decreased serum testosterone levels, and increased the escape latency time in exposed mice and their offspring. We further found that AA-induced mRNA expression changes in the hippocampus of F0 mice persist to the F2 generation. In the sperm of F0 mice, AA induced significant DNA methylation changes in genes involved in neural and reproduction; the mRNA expression levels of Dnmt3b, a DNA methyltransferase, were dramatically decreased in the testes of F0 and F1 mice. In conclusion, our study indicates that paternal AA exposure leads to DNA methylation-mediated transgenerational adverse effects on sperm parameters and leaning capability in mice.
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Affiliation(s)
- Hang Zhang
- Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
| | - Lidong Shan
- Medical College of Soochow University, Suzhou, China
| | - Stanley Aniagu
- Toxicology, Risk Assessment, and Research Division, Texas Commission on Environmental Quality, 12015, Park 35 Cir, Austin, TX, USA
| | - Yan Jiang
- Medical College of Soochow University, Suzhou, China.
| | - Tao Chen
- Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China.
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31
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Wang W, Peng M, Yuan H, Liu C, Zhang Y, Fang Y, Su Y, Zhang X, Zhang H, Tang Y, Zhao K. Studying the mechanism of sperm DNA damage caused by folate deficiency. J Cell Mol Med 2021; 26:776-788. [PMID: 34953021 PMCID: PMC8817123 DOI: 10.1111/jcmm.17119] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 10/25/2021] [Accepted: 11/08/2021] [Indexed: 12/27/2022] Open
Abstract
Sperm DNA injury is one of the common causes of male infertility. Folic acid deficiency would increase the methylation level of the important genes, including those involved in DNA double-strand break (DSB) repair pathway. In the early stages, we analysed the correlation between seminal plasma folic acid concentration and semen parameters in 157 infertility patients and 91 sperm donor volunteers, and found that there was a significant negative correlation between seminal folic acid concentration and sperm DNA Fragmentation Index (DFI; r = -0.495, p < 0.01). Then through reduced representation bisulphite sequencing, global DNA methylation of sperm of patients in the low folic acid group and the high folic acid group was analysed, it was found that the methylation level in Rad54 promoter region increased in the folic acid deficiency group compared with the normal folic acid group. Meanwhile, the results of animal model and spermatocyte line (GC-2) also found that folic acid deficiency can increase the methylation level in Rad54 promoter region, increased sperm DFI in mice, increased the expression of γ-H2AX, that is, DNA injury marker protein, and increased sensitivity of GC-2 to external damage and stimulation. The study indicates that the expression of Rad54 is downregulated by folic acid deficiency via DNA methylation. This may be one of the mechanisms of sperm DNA damage caused by folate deficiency.
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Affiliation(s)
- Wei Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meilin Peng
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongfang Yuan
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Liu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiwei Fang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufang Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xinzong Zhang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute(Guangdong Provincial Fertility Hospital), Guangdong, China
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yunge Tang
- NHC Key Laboratory of Male Reproduction and Genetics, Guangdong Provincial Reproductive Science Institute(Guangdong Provincial Fertility Hospital), Guangdong, China
| | - Kai Zhao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Abstract
The intestinal tract is the entry gate for nutrients and symbiotic organisms, being in constant contact with external environment. DNA methylation is one of the keys to how environmental conditions, diet and nutritional status included, shape functionality in the gut and systemically. This review aims to summarise findings on the importance of methylation to gut development, differentiation and function. Evidence to date on how external factors such as diet, dietary supplements, nutritional status and microbiota modifications modulate intestinal function through DNA methylation is also presented.
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Takemori K, Matsuo T, Watanabe T, Ebara S, Chikugo T, Kometani T. Effects of Inadequate Folate Intake on the Onset and Progression of Hypertensive Vascular Injury. J Nutr Sci Vitaminol (Tokyo) 2021; 67:310-316. [PMID: 34719616 DOI: 10.3177/jnsv.67.310] [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: 11/27/2022]
Abstract
We investigated the effects of inadequate folate intake on the onset and progression of hypertensive organ injury. In the present study, 5-wk-old male stroke-prone spontaneously hypertensive rats (SHRSP) were fed with a normal-folate (control; 160-170 μg of folate/100 g diet) or low-folate (8-10 μg of folate/100 g diet) diet until they reached 25 wk of age. After the animals reached 10 wk of age, the bodyweight of the rats in the low-folate group was lower than that of the rats in the control group. Regarding blood pressure, both groups had severe hypertension of ≥230 mmHg at 12 wk of age that was not significantly different between the groups. At 16 wk of age, the low-folate group had a low number of blood cell types. The folate levels in the serum, liver, and kidneys of these rats were significantly lower (p<0.01) and the serum homocysteine level in the low-folate group was significantly higher than in the controls. The low-folate group had a significantly lower testicular weight than the control group (p<0.05) and arterial hypertrophy, spermatogenesis arrest, and interstitial connective tissue hyperplasia were observed. However, there was no clear difference in lesions in other organs. These results indicated that under low folate status, SHRSP causes hematopoietic disorders and exacerbates hypertensive vascular injury at various degrees by organ type.
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Affiliation(s)
- Kumiko Takemori
- Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University
| | - Takuya Matsuo
- Department of Arts and Sciences, Faculty of Medicine, Kindai University
| | - Toshiaki Watanabe
- Department of Health and Nutrition, Faculty of Health Science, Osaka Aoyama University
| | - Shuhei Ebara
- Department of Health and Nutrition, Faculty of Health Science, Osaka Aoyama University
| | - Takaaki Chikugo
- Department of Pathology, Faculty of Medicine, Kindai University
| | - Takashi Kometani
- Department of Food Science and Nutrition, Faculty of Agriculture, Kindai University
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Lee SK. Sure, Fathers Give Birth, Too! Postnatal paternal folate deficiency increases congenital disabilities through H3K4me3 histone methylation changes in sperm and embryos. Mol Cells 2021; 44:696-698. [PMID: 34588323 PMCID: PMC8490204 DOI: 10.14348/molcells.2021.0202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022] Open
Affiliation(s)
- Sun-Kyung Lee
- Department of Life Sciences, Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Korea
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35
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Zhang Y, Yuan H, Peng M, Hu Z, Fan Z, Xu J, He L, Wang Y, Wang W, Su Y, Liu C, Zhang H, Zhao K. Folic acid deficiency damages male reproduction via endoplasmic reticulum stress-associated PERK pathway induced by Caveolin-1 in mice. Syst Biol Reprod Med 2021; 67:383-394. [PMID: 34474604 DOI: 10.1080/19396368.2021.1954724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Folic acid is critical to maintaining normal male reproductive function. Endoplasmic reticulum (ER) stress plays a crucial role in folic acid deficiency. Studies have shown that Caveolin-1 (Cav-1) is involved in ER stress, but the specific mechanism in male reproduction is still unclear. This study aimed to investigate the effects of folic acid deficiency on spermatogenesis and elucidate the underlying mechanisms. C57BL/6 mice fed with folic acid deficiency induced diet(0.3 mg/kg) were used. A significant decrease in the sperm concentration in the folic acid deficiency group was observed. Meanwhile, folic acid deficiency decreased Cav-1 expression in the testis tissue and increased endoplasmic reticulum stress-related PERK, eIF2α, ATF4, CHOP gene expression. Our results suggest that folic acid deficiency can affect male reproduction through the Cav-1-PERK-eIFα-ATF4-CHOP pathway.Abbreviations: ATF4: activating transcription factor 4; Ca2+: calcium ion; Cav-1: Caveolin-1; CCK-8: cell counting kit-8; CHOP: CCAAT-enhancer-binding protein homologous protein; DNA: Deoxyribonucleic acid; DSB: double strand breakage; eIF2α: eukaryotic Initiation Factor 2 alpha; ER: endoplasmic reticulum; FD: folic acid deficiency; FITC: fluorescein isothiocyanate; HE: hematoxylin and eosin; H3K4me3: histone H3 lysine 4 trimethylation; PERK: protein kinase RNA-like endoplasmic reticulum kinase; PI: propidium iodide; RT-qPCR: quantitative reverse transcription PCR; TUNEL: TdT mediated dUTP Nick End Labeling.
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Affiliation(s)
- Yuan Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongfang Yuan
- Department of Obstetrics And Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meilin Peng
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiyong Hu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zunpan Fan
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jia Xu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liting He
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongfeng Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wei Wang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yufang Su
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chunyan Liu
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiping Zhang
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Zhao
- Institute of Reproductive Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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36
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Consequences of Paternal Nutrition on Offspring Health and Disease. Nutrients 2021; 13:nu13082818. [PMID: 34444978 PMCID: PMC8400857 DOI: 10.3390/nu13082818] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/10/2021] [Accepted: 08/13/2021] [Indexed: 12/30/2022] Open
Abstract
It is well established that the maternal diet during the periconceptional period affects the progeny’s health. A growing body of evidence suggests that the paternal diet also influences disease onset in offspring. For many years, sperm was considered only to contribute half of the progeny’s genome. It now appears that it also plays a crucial role in health and disease in offspring’s adult life. The nutritional status and environmental exposure of fathers during their childhood and/or the periconceptional period have significant transgenerational consequences. This review aims to describe the effects of various human and rodent paternal feeding patterns on progeny’s metabolism and health, including fasting or intermittent fasting, low-protein and folic acid deficient food, and overnutrition in high-fat and high-sugar diets. The impact on pregnancy outcome, metabolic pathways, and chronic disease onset will be described. The biological and epigenetic mechanisms underlying the transmission from fathers to their progeny will be discussed. All these data provide evidence of the impact of paternal nutrition on progeny health which could lead to preventive diet recommendations for future fathers.
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Bodden C, Hannan AJ, Reichelt AC. Of 'junk food' and 'brain food': how parental diet influences offspring neurobiology and behaviour. Trends Endocrinol Metab 2021; 32:566-578. [PMID: 33941448 DOI: 10.1016/j.tem.2021.04.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/10/2021] [Accepted: 04/07/2021] [Indexed: 02/08/2023]
Abstract
Unhealthy lifestyles and mental health problems are increasingly prevalent globally. Not only are 'junk food'-induced overweight and obesity risk factors for the development of brain disorders but they are also associated intergenerationally with ill health. Here, we reflect on the current knowledge of how maternal and paternal diet influences offspring brain development and behaviour, potentially predisposing children to mental health problems. Mounting evidence indicates diet-induced maternal and paternal programming of infant metabolism and neurobehavioural function, with potential downstream effects on mental health and resilience. Beyond the central nervous system (CNS), the microbiota-gut-brain axis has emerged as an important mediator of host physiology. We discuss how intergenerational seeding of the gut microbiome via parental lineage can influence offspring gut health and neurobiology.
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Affiliation(s)
- Carina Bodden
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia.
| | - Anthony J Hannan
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Amy C Reichelt
- Department of Medical Sciences, Adelaide Medical School, The University of Adelaide, Adelaide, SA 5005, Australia.
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Lambrot R, Chan D, Shao X, Aarabi M, Kwan T, Bourque G, Moskovtsev S, Librach C, Trasler J, Dumeaux V, Kimmins S. Whole-genome sequencing of H3K4me3 and DNA methylation in human sperm reveals regions of overlap linked to fertility and development. Cell Rep 2021; 36:109418. [PMID: 34289352 DOI: 10.1016/j.celrep.2021.109418] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 02/12/2021] [Accepted: 06/28/2021] [Indexed: 12/19/2022] Open
Abstract
The paternal environment has been linked to infertility and negative outcomes. Such effects may be transmitted via sperm through histone modifications. To date, in-depth profiling of the sperm chromatin in men has been limited. Here, we use deep sequencing to characterize the sperm profiles of histone H3 lysine 4 tri-methylation (H3K4me3) and DNA methylation in a representative reference population of 37 men. Our analysis reveals that H3K4me3 is localized throughout the genome and at genes for fertility and development. Remarkably, enrichment is also found at regions that escape epigenetic reprogramming in primordial germ cells, embryonic enhancers, and short-interspersed nuclear elements (SINEs). There is significant overlap in H3K4me3 and DNA methylation throughout the genome, suggesting a potential interplay between these marks previously reported to be mutually exclusive in sperm. Comparisons made between H3K4me3 marked regions in sperm and the embryonic transcriptome suggest an influence of paternal chromatin on embryonic gene expression.
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Affiliation(s)
- Romain Lambrot
- Department of Animal Science, McGill University, Montreal, QC, Canada
| | - Donovan Chan
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada
| | - Xiaojian Shao
- Digital Technologies Research Centre, National Research Council, Ottawa, ON, Canada
| | - Mahmoud Aarabi
- Department of Laboratory Medicine and Pathobiology, North York General Hospital, University of Toronto, Toronto, ON, Canada; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Tony Kwan
- Human Genetics, McGill University, Montreal, QC, Canada
| | | | - Sergey Moskovtsev
- CReATe Fertility Centre, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada
| | - Clifford Librach
- CReATe Fertility Centre, Toronto, ON, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON, Canada
| | - Jacquetta Trasler
- Research Institute of the McGill University Health Centre, Montreal, QC, Canada; Human Genetics, McGill University, Montreal, QC, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada; Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - Vanessa Dumeaux
- PERFORM Center, Concordia University, Montreal, QC, Canada; Department of Biology, Concordia University, Montreal, QC, Canada.
| | - Sarah Kimmins
- Department of Animal Science, McGill University, Montreal, QC, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
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Mahajan A, Sapehia D, Bagga R, Kaur J. Different dietary combinations of folic acid and vitamin B12 in parental diet results in epigenetic reprogramming of IGF2R and KCNQ1OT1 in placenta and fetal tissues in mice. Mol Reprod Dev 2021; 88:437-458. [PMID: 34008284 DOI: 10.1002/mrd.23477] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 12/23/2022]
Abstract
Genomic imprinting is important for mammalian development and its dysregulation can cause various developmental defects and diseases. The study evaluated the effects of different dietary combinations of folic acid and B12 on epigenetic regulation of IGF2R and KCNQ1OT1 ncRNA in C57BL/6 mice model. Female mice were fed diets with nine combinations of folic acid and B12 for 4 weeks. They were mated and off-springs born (F1) were continued on the same diet for 6 weeks postweaning and were allowed to mate. The placenta and fetal (F2) tissues were collected at day 20 of gestation. Dietary deficiency of folate (BNFD and BOFD) and B12 (BDFN) with either state of other vitamin or combined deficiency of both vitamins (BDFD) in comparison to BNFN, were overall responsible for reduced expression of IGF2R in the placenta (F1) and the fetal liver (F2) whereas a combination of folate deficiency with different levels of B12 revealed sex-specific differences in kidney and brain. The alterations in the expression of IGF2R caused by folate-deficient conditions (BNFD and BOFD) and both deficient condition (BDFD) was found to be associated with an increase in suppressive histone modifications. Over-supplementation of either folate or B12 or both vitamins in comparison to BNFN, led to increase in expression of IGF2R and KCNQ1OT1 in the placenta and fetal tissues. The increase in the expression of IGF2R caused by folate over-supplementation (BNFO) was associated with decreased DNA methylation in fetal tissues. KCNQ1OT1 noncoding RNA (ncRNA), however, showed upregulation under deficient conditions of folate and B12 only in female fetal tissues which correlated well with hypomethylation observed under these conditions. An epigenetic reprograming of IGF2R and KCNQ1OT1 ncRNA in the offspring was evident upon different dietary combinations of folic acid and B12 in the mice.
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Affiliation(s)
- Aatish Mahajan
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Divika Sapehia
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rashmi Bagga
- Department of Obstetrics and Gynecology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jyotdeep Kaur
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Mathieu d’Argent E, Ravel C, Rousseau A, Morcel K, Massin N, Sussfeld J, Simon T, Antoine JM, Mandelbaume J, Daraï E, Kolanska K. High-Dose Supplementation of Folic Acid in Infertile Men Improves IVF-ICSI Outcomes: A Randomized Controlled Trial (FOLFIV Trial). J Clin Med 2021; 10:jcm10091876. [PMID: 33925981 PMCID: PMC8123699 DOI: 10.3390/jcm10091876] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/05/2023] Open
Abstract
Dietary supplementation is commonly used in men with male infertility but its exact role is poorly understood. The aim of this multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the impact of high-dose folic acid supplementation on IVF-ICSI outcomes. 162 couples with male infertility and an indication for IVF-ICSI were included for one IVF-ICSI cycle. Male partners of couples wishing to conceive, aged 18-60 years old, with at least one abnormal spermatic criterion were randomized in a 1:1 ratio to receive daily supplements containing 15 mg of folic acid or a placebo for 3 months from Day 0 until semen collection for IVF-ICSI. Sperm parameters and DNA fragmentation before and after the treatment and the biochemical and clinical pregnancy rates after the fresh embryo transfer were analyzed. We observed an increase in the biochemical pregnancy rate and a trend for a higher clinical pregnancy rate in the folic acid group compared to placebo (44.1% versus 22.4%, p = 0.01 and 35.6% versus 20.4%, p = 0.082, respectively). Even if no changes in sperm characteristics were observed, a decrease in DNA fragmentation in the folic acid group was noted (8.5 ± 4.5 vs. 6.4 ± 4.6, p < 0.0001). High-dose folic acid supplementation in men requiring IVF-ICSI for male infertility improves IVF-ICSI outcomes.
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Affiliation(s)
- Emmanuelle Mathieu d’Argent
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, AP-HP Sorbonne Université site Tenon, 4 rue de la Chine, 75020 Paris, France; (J.S.); (J.-M.A.); (E.D.); (K.K.)
- Correspondence:
| | - Celia Ravel
- CHU Rennes, Laboratoire de Biologie de la Reproduction-CECOS, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)-UMR_S 1085, Université de Rennes, 35000 Rennes, France;
| | - Alexandra Rousseau
- Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB), APHP Sorbonne Universite, Hôpital Saint Antoine, 75012 Paris, France; (A.R.); (T.S.)
| | - Karine Morcel
- Centre d’Assistance Médicale à la Procréation, Service de Gynécologie-Obstétrique, CHU de Brest, Hôpital Morvan, 29609 Brest, France;
| | - Nathalie Massin
- Centre Hospitalier Intercommunal de Créteil, Department of Gynecology, Obstetrics and Reproductive Medicine, Université Paris-Est Créteil, 94010 Créteil, France;
| | - Julie Sussfeld
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, AP-HP Sorbonne Université site Tenon, 4 rue de la Chine, 75020 Paris, France; (J.S.); (J.-M.A.); (E.D.); (K.K.)
| | - Tabassome Simon
- Department of Clinical Pharmacology and Clinical Research Platform of East of Paris (URCEST-CRC-CRB), APHP Sorbonne Universite, Hôpital Saint Antoine, 75012 Paris, France; (A.R.); (T.S.)
| | - Jean-Marie Antoine
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, AP-HP Sorbonne Université site Tenon, 4 rue de la Chine, 75020 Paris, France; (J.S.); (J.-M.A.); (E.D.); (K.K.)
| | - Jacqueline Mandelbaume
- Service de Biologie de la Reproduction, Centre d’Etudes et de Conservation des œufs et du Sperme Humains (CECOS), Hôpital Tenon, Assistance Publique-Hôpitaux de Paris (APHP), Université Paris 06, 75020 Paris, France;
| | - Emile Daraï
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, AP-HP Sorbonne Université site Tenon, 4 rue de la Chine, 75020 Paris, France; (J.S.); (J.-M.A.); (E.D.); (K.K.)
| | - Kamila Kolanska
- Service de Gynécologie Obstétrique et Médecine de la Reproduction, AP-HP Sorbonne Université site Tenon, 4 rue de la Chine, 75020 Paris, France; (J.S.); (J.-M.A.); (E.D.); (K.K.)
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Barratt CLR, De Jonge CJ, Anderson RA, Eisenberg ML, Garrido N, Rautakallio Hokkanen S, Krausz C, Kimmins S, O’Bryan MK, Pacey AA, Tüttelmann F, Veltman JA. A global approach to addressing the policy, research and social challenges of male reproductive health. Hum Reprod Open 2021; 2021:hoab009. [PMID: 33768166 PMCID: PMC7982782 DOI: 10.1093/hropen/hoab009] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 01/30/2021] [Indexed: 01/19/2023] Open
Abstract
Male infertility is a global health issue; yet to a large extent, our knowledge of its causes, impact and consequence is largely unknown. Recent data indicate that infertile men have an increased risk of somatic disorders such as cancer and die younger compared to fertile men. Moreover, several studies point to a significant adverse effect on the health of the offspring. From the startling lack of progress in male contraception combined with the paucity of improvements in the diagnosis of male infertility, we conclude there is a crisis in male reproductive health. The Male Reproductive Health Initiative has been organized to directly address these issues (www.eshre.eu/Specialty-groups/Special-Interest-Groups/Andrology/MRHI). The Working Group will formulate an evidence-based strategic road map outlining the ways forward. This is an open consortium desiring to engage with all stakeholders and governments.
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Affiliation(s)
- Christopher L R Barratt
- Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK,Correspondence address. Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD19SY, UK; E-mail: https://orcid.org/0000-0003-0062-9979; Department of Urology, University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, 55454, USA; E-mail: https://orcid.org/0000-0002-4083-5833
| | - Christopher J De Jonge
- Department of Urology, University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, USA,Correspondence address. Division of Systems Medicine, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD19SY, UK; E-mail: https://orcid.org/0000-0003-0062-9979; Department of Urology, University of Minnesota Medical Center, University of Minnesota, Minneapolis, MN, 55454, USA; E-mail: https://orcid.org/0000-0002-4083-5833
| | - Richard A Anderson
- Section of Obstetrics and Gynaecology, MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
| | - Michael L Eisenberg
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
| | - Nicolás Garrido
- IVI Foundation, Health Research Institute La Fe, Valencia, Spain
| | | | - Csilla Krausz
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Florence, Florence, Italy
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, and Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Canada
| | - Moira K O’Bryan
- Department of Anatomy and Developmental Biology, School of BioSciences, Faculty of Science, University of Melbourne, Parkville, Australia
| | - Allan A Pacey
- Department of Oncology & Metabolism, University of Sheffield, Sheffield, UK
| | - Frank Tüttelmann
- Institute of Reproductive Genetics, University of Münster, Münster, Germany
| | - Joris A Veltman
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
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Tariq H, Zahid N, Amir D, Ashraf M, Aftab MA, Yousaf S, Rehman R. Estimation of folic acid/micro nutrients levels; Does it reflect sperm parameters. Int J Clin Pract 2021; 75:e13790. [PMID: 33128252 DOI: 10.1111/ijcp.13790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/21/2020] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE To study the impact of vitamin B12, folic acid (FA) and methylmalonic acid (MMA) on sperm parameters; count, motility and morphology leading to male fertility. METHODS The cross-sectional study comprised of one hundred and eighty-six subjects with normal sperm parameters (fertile) and 88 subjects with abnormal sperm parameters labelled as "infertile" from a sample population of Karachi, Pakistan. Vitamin B12, FA and MMA levels in serum were analysed by enzyme linked immune sorbent assay. Unadjusted and adjusted prevalence ratio with their 95% CI were reported by using cox regression algorithm to assess the association of Vitamin B12, FA and MMA and other factors with male Infertility. Unadjusted and adjusted beta coefficients with 95% CI were reported by using linear regression analysis for assessing relationship of Vitamin B12, FA and MMA and other factors with semen parameters (count, motility and morphology); P value of <.05 was considered significant. RESULTS It was declared that with every 1 unit increase in vitamin B12, FA and MMA the prevalence of infertility was decreased by 1%, 17% and 74%, respectively. Multivariate analysis revealed that vitamin B12, FA and MMA had a significant association with total sperm count, motility and morphology. The sperm parameters were also affected by increase in; LH, BMI and body fat %. There was a significant positive correlation of; LH with Vitamin B12 and FA (0.423 < 0.001, 0.338 < 0.001) and testosterone with vitamin B12 and FA (0.326 < 0.001, 0.291 < 0.001), respectively. CONCLUSION All the studied micronutrients; Vitamin B12, FA and MMA had a positive effect on sperm parameters; count, motility and morphology and the associated reproductive hormones which explains their role on reproductive functions required to acquire fertility.
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Affiliation(s)
- Hemaila Tariq
- Medical College, Aga Khan University, Karachi, Pakistan
| | - Nida Zahid
- Epidemiology and Biostatistics, Senior Instructor Research, Aga Khan University, Karachi, Pakistan
| | - Daniyal Amir
- Medical College, Aga Khan University, Karachi, Pakistan
| | - Mussarat Ashraf
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
| | | | | | - Rehana Rehman
- Department of Biological and Biomedical Sciences, Aga Khan University, Karachi, Pakistan
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Komsky-Elbaz A, Kalo D, Roth Z. Carryover effect of atrazine and its metabolite-from treated bovine spermatozoa to the embryo's transcriptome†. Biol Reprod 2021; 104:1162-1180. [PMID: 33624745 DOI: 10.1093/biolre/ioab027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 01/14/2021] [Accepted: 02/15/2021] [Indexed: 01/20/2023] Open
Abstract
Atrazine (ATZ) is an extensively used herbicide and ubiquitous environmental contaminant. ATZ and its metabolite, diaminochlorotriazine (DACT), cause several cellular and functional alterations in spermatozoa. We aimed to examine the effect of ATZ/DACT on spermatozoon DNA integrity, fertilization competence, embryonic development, and transcriptome profile of in vitro-produced embryos derived from fertilization with pre-exposed sperm. Bovine spermatozoa exposed to ATZ (0.1 or 1 μM) or DACT (1 or 10 μM) during in vitro capacitation were used for in vitro fertilization of untreated oocytes. Cleavage and blastocyst-formation rates were evaluated 42 h and 7 days postfertilization, respectively. The association between DNA fragmentation and apoptosis (annexin V kit) was determined. Fertilization competence of annexin-positive (AV+) and annexin-negative (AV-) spermatozoa was examined. Microarray analysis was performed for 7-day blastocysts. Intracytoplasmic sperm injection was performed with control (AV+, AV-) and DACT (AV+, AV-) spermatozoa. Cleavage rates did not differ between groups and blastocyst formation tended to be higher for AV- vs. AV+ in both control and DACT groups, suggesting that acrosome reaction, rather than DNA fragmentation, underlies the reduced cleavage. Transcriptomic analysis revealed 139 and 230 differentially expressed genes in blastocysts derived from ATZ- and DACT-exposed spermatozoa, respectively, relative to controls. Proteomic analysis shown differential expression of proteins in ATZ- or DACT-treated spermatozoa, in particular proteins related to cellular processes and biological pathways. Therefore, we assume that factors delivered by the spermatozoa, regardless of DNA fragmentation, are also involved. Overall, the current study reveals a deleterious carryover effect of ATZ/DACT from the spermatozoa to the developing embryo.
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Affiliation(s)
- A Komsky-Elbaz
- Department of Animal Sciences, The Hebrew University, Rehovot, Israel.,Animal Sperm Research Center, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.,Center of Excellence in Agriculture and Environmental Health, Jerusalem, Israel
| | - D Kalo
- Department of Animal Sciences, The Hebrew University, Rehovot, Israel.,Animal Sperm Research Center, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.,Center of Excellence in Agriculture and Environmental Health, Jerusalem, Israel
| | - Z Roth
- Department of Animal Sciences, The Hebrew University, Rehovot, Israel.,Animal Sperm Research Center, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.,Center of Excellence in Agriculture and Environmental Health, Jerusalem, Israel
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44
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Lismer A, Dumeaux V, Lafleur C, Lambrot R, Brind'Amour J, Lorincz MC, Kimmins S. Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Dev Cell 2021; 56:671-686.e6. [PMID: 33596408 DOI: 10.1016/j.devcel.2021.01.014] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/01/2020] [Accepted: 01/20/2021] [Indexed: 12/12/2022]
Abstract
A father's lifestyle impacts offspring health; yet, the underlying molecular mechanisms remain elusive. We hypothesized that a diet that changes methyl donor availability will alter the sperm and embryo epigenomes to impact embryonic gene expression and development. Here, we demonstrate that a folate-deficient (FD) diet alters histone H3 lysine 4 trimethylation (H3K4me3) in sperm at developmental genes and putative enhancers. A subset of H3K4me3 alterations in sperm are retained in the pre-implantation embryo and associated with deregulated embryonic gene expression. Using a genetic mouse model in which sires have pre-existing altered H3K4me2/3 in sperm, we show that a FD diet exacerbates alterations in sperm H3K4me3 and embryonic gene expression, leading to an increase in developmental defect severity. These findings imply that paternal H3K4me3 is transmitted to the embryo and influences gene expression and development. It further suggests that epigenetic errors can accumulate in sperm to worsen offspring developmental outcomes.
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Affiliation(s)
- Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Vanessa Dumeaux
- PERFORM Center, Concordia University, Montreal, QC H4B 1R6, Canada
| | - Christine Lafleur
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC H9X 3V9, Canada
| | - Romain Lambrot
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC H9X 3V9, Canada
| | - Julie Brind'Amour
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Matthew C Lorincz
- Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, QC H3G 1Y6, Canada; Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, QC H9X 3V9, Canada.
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45
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Ozkocer SE, Konac E. The current perspective on genetic and epigenetic factors in sperm maturation in the epididymis. Andrologia 2021; 53:e13989. [PMID: 33491190 DOI: 10.1111/and.13989] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/07/2021] [Accepted: 01/08/2021] [Indexed: 12/11/2022] Open
Abstract
Male infertility affects approximately 30% of infertile couples. As spermatozoa mature in the epididymal lumen, their potential for mobility increases, and their protein, lipid and small RNA (sRNA) content changes, whereas capacitation and fertilisation take place in the female reproductive tract. Both of the latter processes are affected by maturation, because impaired maturation causes premature capacitation and fertilization. The epididymis produces a suitable environment for sperm maturation via ion transport, vesicle secretion and protein matrix formation. The microenvironment for sperm maturation varies in three broad segments: the caput, the corpus and the cauda epididymis. Epididymosomes transfer proteins, lipids and sRNAs from the epididymal epithelium to spermatozoa and genetic alterations of epididymal genes can lead to decreased sperm motility, morphological abnormalities of spermatozoa and subfertility. Genetic factors are involved in all aetiological categories in male infertility. However, studies conducted on the genes involved in epididymal functions are limited. The sRNA content of spermatozoa changes during epididymal migration, and these sRNAs play a role in embryo development and epigenetic inheritance. This review aims to clarify the role of the epididymal epithelium in the maturation of spermatozoa in light of the current molecular genomic knowledge.
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Affiliation(s)
- Suheyla Esra Ozkocer
- Faculty of Medicine, Department of Medical Biology and Genetics, Gazi University, Besevler, Ankara, Turkey.,Faculty of Medicine, Department of Histology and Embryology, Gazi University, Besevler, Ankara, Turkey
| | - Ece Konac
- Faculty of Medicine, Department of Medical Biology and Genetics, Gazi University, Besevler, Ankara, Turkey
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46
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Nilsson E, Ben Maamar M, Skinner MK. Environmental impacts on sperm and oocyte epigenetics affect embryo cell epigenetics and transcription to promote the epigenetic inheritance of pathology and phenotypic variation. Reprod Fertil Dev 2021; 33:102-107. [PMID: 38769672 DOI: 10.1071/rd20255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024] Open
Abstract
Previous studies have demonstrated that exposure to environmental factors can cause epigenetic modifications to germ cells, particularly sperm, to promote epigenetic and transcriptome changes in the embryo. These germ cell and embryo cell epigenetic alterations are associated with phenotypic changes in offspring. Epigenetic inheritance requires epigenetic changes (i.e. epimutations) in germ cells that promote epigenetic and gene expression changes in embryos. The objective of this perspective is to examine the evidence that germ cell epigenome modifications are associated with embryo cell epigenetic and transcriptome changes that affect the subsequent development of all developing somatic cells to promote phenotype change. Various epigenetic changes in sperm, including changes to histone methylation, histone retention, non-coding RNA expression and DNA methylation, have been associated with alterations in embryo cell epigenetics and gene expression. Few studies have investigated this link for oocytes. The studies reviewed herein support the idea that environmentally induced epigenetic changes in germ cells affect alterations in embryo cell epigenetics and transcriptomes that have an important role in the epigenetic inheritance of pathology and phenotypic change.
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Affiliation(s)
- Eric Nilsson
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA
| | - Millissia Ben Maamar
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA
| | - Michael K Skinner
- Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA; and Corresponding author
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47
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Morgan JE, Channon S, Penny H, Waters CS. Longitudinal studies examining the impact of prenatal and subsequent episodes of maternal depression on offspring antisocial behaviour. Eur Child Adolesc Psychiatry 2021; 30:5-40. [PMID: 31792693 PMCID: PMC7864821 DOI: 10.1007/s00787-019-01447-w] [Citation(s) in RCA: 8] [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: 10/21/2018] [Accepted: 11/20/2019] [Indexed: 12/16/2022]
Abstract
Maternal depression is associated with adverse child outcomes including antisocial behaviour (ASB). Prospective longitudinal studies have focused on the timing and cumulative exposure to maternal depression to further delineate the association and mechanisms of effect. The objective of this systematic review was to synthesise and evaluate the findings of longitudinal studies of maternal depression and offspring antisocial behaviour. Three databases were searched (Psychinfo, Web of Science, and Medline). Twenty of 5936 studies met inclusion criteria. Study quality was assessed using the Critical Appraisal Skills Programme criteria [Critical Appraisal Skills Programme (2017) CASP (cohort observation checklist). https://casp-uk.net/wpcontent/uploads/2018/01/CASP-Cohort-Study-Checklist.pdf ]. Results of individual studies were highly varied, using diverse analytical approaches and not all studies explored the independent effects of different episodes. Only three studies examined hypothesised mechanisms. Prenatal, postnatal, and later episodes of depression were all predictive of antisocial outcomes. One particular time period of depression exposure did not emerge as more predictive of offspring ASB than another. However, measures of maternal depression after the perinatal period were limited and typically included a one-off assessment of mothers' depressive symptoms that was concurrent to the assessment of offspring ASB. When cumulative exposure to maternal depression and specific timing effects were measured within the same study it was cumulative exposure that conferred the greatest risk for offspring ASB-particularly when this exposure began during the perinatal period. Findings are discussed in terms of limitations in the literature and highlight the need for future research to examine the biological and environmental mechanisms that underpin associations between maternal depression and offspring antisocial behaviour during different stages of development.
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Affiliation(s)
- Joanne E Morgan
- School of Psychology, Cardiff University, Cardiff, Wales, CF10 3AT, UK
| | - Sue Channon
- School of Psychology, Cardiff University, Cardiff, Wales, CF10 3AT, UK
| | - Helen Penny
- School of Psychology, Cardiff University, Cardiff, Wales, CF10 3AT, UK
| | - Cerith S Waters
- School of Psychology, Cardiff University, Cardiff, Wales, CF10 3AT, UK.
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48
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Le Blévec E, Muroňová J, Ray PF, Arnoult C. Paternal epigenetics: Mammalian sperm provide much more than DNA at fertilization. Mol Cell Endocrinol 2020; 518:110964. [PMID: 32738444 DOI: 10.1016/j.mce.2020.110964] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/22/2020] [Accepted: 07/22/2020] [Indexed: 12/16/2022]
Abstract
The spermatozoon is a highly differentiated cell with unique characteristics: it is mobile, thanks to its flagellum, and is very compact. The sperm cytoplasm is extremely reduced, containing no ribosomes, and therefore does not allow translation, and its nucleus contains very closed chromatin, preventing transcription. This DNA compaction is linked to the loss of nucleosomes and the replacement of histones by protamines. Based on these characteristics, sperm was considered to simply deliver paternal DNA to the oocyte. However, some parts of the sperm DNA remain organized in a nucleosomal format, and bear epigenetic information. In addition, the nucleus and the cytoplasm contain a multitude of RNAs of different types, including non-coding RNAs (ncRNAs) which also carry epigenetic information. For a long time, these RNAs were considered residues of spermatogenesis. After briefly describing the mechanisms of compaction of sperm DNA, we focus this review on the origin and function of the different ncRNAs. We present studies demonstrating the importance of these RNAs in embryonic development and transgenerational adaptation to stress. We also look at other epigenetic marks, such as DNA methylation or post-translational modifications of histones, and show that they are sensitive to environmental stress and transmissible to offspring. The post-fertilization role of certain sperm-borne proteins is also discussed.
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Affiliation(s)
- Emilie Le Blévec
- Université Grenoble Alpes, Grenoble, F-38000, France; Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, Grenoble, F-38000, France; IMV Technologies, ZI N° 1 Est, L'Aigle, F-61300, France
| | - Jana Muroňová
- Université Grenoble Alpes, Grenoble, F-38000, France; Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, Grenoble, F-38000, France
| | - Pierre F Ray
- Université Grenoble Alpes, Grenoble, F-38000, France; Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, Grenoble, F-38000, France; CHU de Grenoble, UM GI-DPI, Grenoble, F-38000, France
| | - Christophe Arnoult
- Université Grenoble Alpes, Grenoble, F-38000, France; Institute for Advanced Biosciences INSERM U1209, CNRS UMR5309, Grenoble, F-38000, France.
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49
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Rutkowska J, Lagisz M, Bonduriansky R, Nakagawa S. Mapping the past, present and future research landscape of paternal effects. BMC Biol 2020; 18:183. [PMID: 33246472 PMCID: PMC7694421 DOI: 10.1186/s12915-020-00892-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 10/08/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Although in all sexually reproducing organisms an individual has a mother and a father, non-genetic inheritance has been predominantly studied in mothers. Paternal effects have been far less frequently studied, until recently. In the last 5 years, research on environmentally induced paternal effects has grown rapidly in the number of publications and diversity of topics. Here, we provide an overview of this field using synthesis of evidence (systematic map) and influence (bibliometric analyses). RESULTS We find that motivations for studies into paternal effects are diverse. For example, from the ecological and evolutionary perspective, paternal effects are of interest as facilitators of response to environmental change and mediators of extended heredity. Medical researchers track how paternal pre-fertilization exposures to factors, such as diet or trauma, influence offspring health. Toxicologists look at the effects of toxins. We compare how these three research guilds design experiments in relation to objects of their studies: fathers, mothers and offspring. We highlight examples of research gaps, which, in turn, lead to future avenues of research. CONCLUSIONS The literature on paternal effects is large and disparate. Our study helps in fostering connections between areas of knowledge that develop in parallel, but which could benefit from the lateral transfer of concepts and methods.
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Affiliation(s)
- Joanna Rutkowska
- Institute of Environmental Sciences, Faculty of Biology, Jagiellonian University, Kraków, Poland
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Malgorzata Lagisz
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Russell Bonduriansky
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
| | - Shinichi Nakagawa
- Evolution & Ecology Research Centre, School of Biological, Earth and Environmental Sciences, BEES, The University of New South Wales, Sydney, Australia
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50
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Lismer A, Siklenka K, Lafleur C, Dumeaux V, Kimmins S. Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance. Nucleic Acids Res 2020; 48:11380-11393. [PMID: 33068438 PMCID: PMC7672453 DOI: 10.1093/nar/gkaa712] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 08/11/2020] [Accepted: 10/15/2020] [Indexed: 12/30/2022] Open
Abstract
Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.
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Affiliation(s)
- Ariane Lismer
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Canada
| | - Keith Siklenka
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Canada
| | - Christine Lafleur
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Canada
| | - Vanessa Dumeaux
- PERFORM Center and Department of Biology, Concordia University, Montreal, Canada
| | - Sarah Kimmins
- Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Canada
- Department of Animal Science, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Canada
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