[en] Metformin is a drug used for the treatment of type 2 diabetes and disorders associated with insulin resistance. Metformin is also used in the treatment of pregnancy disorders such as gestational diabetes. However, the consequences of foetal exposure to metformin on the fertility of exposed offspring remain poorly documented. In this study, we investigated the effect of in utero metformin exposure on the fertility of female and male offspring. We observed that metformin is detectable in the blood of the mother and in amniotic fluid and blood of the umbilical cord. Metformin was not measurable in any tissues of the embryo, including the gonads. The effect of metformin exposure on offspring was sex specific. The adult females that had been exposed to metformin in utero presented no clear reduction in fertility. However, the adult males that had been exposed to metformin during foetal life exhibited a 30% reduction in litter size compared with controls. The lower fertility was not due to a change in sperm production or the motility of sperm. Rather, the phenotype was due to lower sperm head quality - significantly increased spermatozoa head abnormality with greater DNA damage - and hypermethylation of the genomic DNA in the spermatozoa associated with lower expression of the ten-eleven translocation methylcytosine dioxygenase 1 (TET1) protein. In conclusion, while foetal metformin exposure did not dramatically alter gonad development, these results suggest that metabolic modification by metformin during the foetal period could change the expression of epigenetic regulators such as Tet1 and perturb the genomic DNA in germ cells, changes that might contribute to a reduced fertility.
Faure, Mélanie ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Neuroendocrinology ; l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France
Khoueiry, Rita; Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France
Quanico, Jusal; Université Lille 1, INSERM U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse (PRISM), Villeneuve d'Ascq, France
Acloque, Hervé; Université Paris-Saclay, INRAE, AgroParisTech, Génétique Animale et Biologie Intégrative (GABI), Jouy-en-Josas, France
Guerquin, Marie-Justine; UMR967 INSERM, Commissariat à l'Énergie Atomique (CEA)/Direction de la Recherche Fondamentale (DRF)/Institut de Radiobiologie Cellulaire et Moléculaire (iRCM)/Service Cellules Souches et Radiation (SCSR)/LDG, Université Paris Diderot, Sorbonne Paris Cité, Université Paris-Sud, Université Paris-Saclay, Laboratory of Development of the Gonads, Fontenay aux Roses, France
Bertoldo, Michael J; Fertility and Research Centre, School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia ; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
Chevaleyre, Claire; l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France
Ramé, Christelle; l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France
Fournier, Isabelle; Université Lille 1, INSERM U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse (PRISM), Villeneuve d'Ascq, France
Salzet, Michel; Université Lille 1, INSERM U1192 - Protéomique Réponse Inflammatoire Spectrométrie de Masse (PRISM), Villeneuve d'Ascq, France
Dupont, Joëlle; l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France
Froment, Pascal; l'Institut National de Recherche Pour l'Agriculture, l'Alimentation et l'Environnement (INRAE), UMR85 Physiologie de la Reproduction et des Comportements/Centre national de la Recherche Scientifique (CNRS), UMR7247/Université François Rabelais de Tours/Institut français du Cheval et de l'Équitation (IFCE), Nouzilly, France
Language :
English
Title :
In Utero Exposure to Metformin Reduces the Fertility of Male Offspring in Adulthood.
This work was supported by the national program « FERTiNERGY » funded by the French National Research Agency (ANR). MF was supported by the Region Centre and Institut National de la Recherche Agronomique.The authors would like to thank Deborah Crespin, Marine Cirot and Claude Cahier (EU0028, UEPAO, 1297) for animal care. We are grateful to Anne-Lyse Laine for the testosterone assays. We thank Xavier Druart and Guillaume Tsikis for permiting us to access CASA and for giving us the antibodies.
He L Wondisford FE. Metformin Action: Concentrations Matter. Cell Metab (2015) 21(2):159–62. doi: 10.1016/j.cmet.2015.01.003
El-Mir MY Nogueira V Fontaine E Avéret N Rigoulet M Leverve X. Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I. J Biol Chem (2000) 275(1):223–8. doi: 10.1074/jbc.275.1.223
Leverve XM Guigas B Detaille D Batandier C Koceir EA Chauvin C et al. Mitochondrial Metabolism and Type-2 Diabetes: A Specific Target of Metformin. Diabetes Metab (2003) 29(4 Pt 2):6S88–94. doi: 10.1016/S1262-3636(03)72792-X
Tang T Glanville J Orsi N Barth JH Balen AH. The Use of Metformin for Women With PCOS Undergoing IVF Treatment. Hum Reprod (2006) 21(6):1416–25. doi: 10.1093/humrep/del025
Renato P. Metformin in Women With PCOS, Pros. Endocrine (2015) 48(2):422–6. doi: 10.1007/s12020-014-0311-1
Foretz M Guigas B Bertrand L Pollak M Viollet B. Metformin: From Mechanisms of Action to Therapies. Cell Metab (2014) 20(6):953–66. doi: 10.1016/j.cmet.2014.09.018
Hanem LGE Salvesen Ø Juliusson PB Carlsen SM Nossum MCF Vaage MØ et al. Intrauterine Metformin Exposure and Offspring Cardiometabolic Risk Factors (PedMet Study): A 5–10 Year Follow-Up of the PregMet Randomised Controlled Trial. Lancet Child Adolesc Health (2019) 3(3):166–74. doi: 10.1016/S2352-4642(18)30385-7
Panchaud A Rousson V Vial T Bernard N Baud D Amar E et al. Pregnancy Outcomes in Women on Metformin for Diabetes or Other Indications Among Those Seeking Teratology Information Services. Br J Clin Pharmacol (2018) 84(3):568–78. doi: 10.1111/bcp.13481
Faure M Bertoldo MJ Khoueiry R Bongrani A Brion F Giulivi C et al. Metformin in Reproductive Biology. Front Endocrinol (2018) 9(November):1–12. doi: 10.3389/fendo.2018.00675
Bertoldo MJ Faure M Dupont J Froment P. Impact of Metformin on Reproductive Tissues: An Overview From Gametogenesis to Gestation. Ann Transl Med (2014) 2(6):55. doi: 10.3978/j.issn.2305-5839.2014.06.04
Ghazeeri GS Nassar AH Younes Z Awwad JT. Pregnancy Outcomes and the Effect of Metformin Treatment in Women With Polycystic Ovary Syndrome: An Overview. Acta Obstet Gynecol Scand (2012) 91(6):658–78. doi: 10.1111/j.1600-0412.2012.01385.x
Glueck CJ Goldenberg N Pranikoff J Loftspring M Sieve L Wang P. Height, Weight, and Motor-Social Development During the First 18 Months of Life in 126 Infants Born to 109 Mothers With Polycystic Ovary Syndrome Who Conceived on and Continued Metformin Through Pregnancy. Hum Reprod (Oxford England) (2004) 19(6):1323–30. doi: 10.1093/humrep/deh263
Glueck CJ Phillips H Cameron D Sieve-Smith L Wang P. Continuing Metformin Throughout Pregnancy in Women With Polycystic Ovary Syndrome Appears to Safely Reduce First-Trimester Spontaneous Abortion: A Pilot Study. Fertil Steril (2001) 75(1):46–52. doi: 10.1016/S0015-0282(00)01666-6
Kovo M Weissman A Gur D Levran D Rotmensch S Glezerman M. Neonatal Outcome in Polycystic Ovarian Syndrome Patients Treated With Metformin During Pregnancy. J Maternal-Fetal Neonatal Med: Off J Eur Assoc Perinatal Med Fed Asia Oceania Perinatal Soc Int Soc Perinatal Obstet (2006) 19(7):415–9. doi: 10.1080/14767050600682370
Salomäki H Vähätalo LH Laurila K Jäppinen NT Penttinen A-M Ailanen L et al. Prenatal Metformin Exposure in Mice Programs the Metabolic Phenotype of the Offspring During a High Fat Diet at Adulthood. PloS One (2013) 8(2):e56594. doi: 10.1371/annotation/abe54d92-1f87-4826-a0a5-ba55005f99b4
Vanky E Ødegård R. Metformin in Pregnancy – Safe or Sorry? Nat Rev Endocrinol (2018) 14(10):570–2. doi: 10.1038/s41574-018-0081-6
Álvarez D Ceballo K Olguín S Martinez-Pinto J Maliqueo M Fernandois D et al. Prenatal Metformin Treatment Improves Ovarian Function in Offspring of Obese Rats. J Endocrinol (2018) 239(3):325–38. doi: 10.1530/JOE-18-0352
Tertti K Laine K Ekblad U Rinne V Ronnemaa T. The Degree of Fetal Metformin Exposure Does Not Influence Fetal Outcome in Gestational Diabetes Mellitus. Acta Diabetol (2014) 51(5):731–8. doi: 10.1007/s00592-014-0570-6
Carlsen SM Vanky E. Metformin Influence on Hormone Levels at Birth, in PCOS Mothers and Their Newborns. Hum Reprod (2010) 25(3):786–90. doi: 10.1093/humrep/dep444
Rø TB Ludvigsen HV Carlsen SM Vanky E. Growth, Body Composition and Metabolic Profile of 8-Year-Old Children Exposed to Metformin In Utero. Scand J Clin Lab Invest (2012) 72(7):570–5.
Bertoldo MJ Guibert E Tartarin P Guillory V Froment P. Effect of Metformin on the Fertilizing Ability of Mouse Spermatozoa. Cryobiology (2014) 68(2):262–8. doi: 10.1016/j.cryobiol.2014.02.006
Faure M Guibert E Alves S Pain B Ramé C Dupont J et al. The Insulin Sensitiser Metformin Regulates Chicken Sertoli and Germ Cell Populations. Reproduction (2016) 151(5):527–38. doi: 10.1530/REP-15-0565
Casulari L Caldas A Domingues Casulari Motta L Lofrano-Porto A. Effects of Metformin and Short-Term Lifestyle Modification on the Improvement of Male Hypogonadism Associated With Metabolic Syndrome. Minerva Endocrinol (2010) 35(3):145–51.
Morgante G Tosti C Orvieto R Musacchio MC Piomboni P De Leo V. Metformin Improves Semen Characteristics of Oligo-Terato-Asthenozoospermic Men With Metabolic Syndrome. Fertil Steril (2010) 95(6):2150–2. doi: 10.1016/j.fertnstert.2010.12.009
Shpakov AO. Improvement Effect of Metformin on Female and Male Reproduction in Endocrine Pathologies and Its Mechanisms. Pharm (Basel) (2021) 14(1):42. doi: 10.3390/ph14010042
Svechnikov K Stukenborg J-B Savchuck I Söder O. Similar Causes of Various Reproductive Disorders in Early Life. Asian J Androl (2014) 16(1):50–9. doi: 10.4103/1008-682X.122199
O’Shaughnessy PJ Fowler PA. Endocrinology of the Mammalian Fetal Testis. Reproduction (2011) 141(1):37–46. doi: 10.1530/REP-10-0365
Tartarin P Moison D Guibert E Dupont J Habert R Rouiller-Fabre V et al. Metformin Exposure Affects Human and Mouse Fetal Testicular Cells. Hum Reprod (Oxford England) (2012) 27(11):3304–14. doi: 10.1093/humrep/des264
Tertti K Toppari J Virtanen HE Sadov S Rönnemaa T. Metformin Treatment Does Not Affect Testicular Size in Offspring Born to Mothers With Gestational Diabetes. Rev Diabetic Stud (2016) 13(1):59–65. doi: 10.1900/RDS.2016.13.59
Maple-Brown LJ Lindenmayer G Barzi F Whitbread C Connors C Moore E et al. Real-World Experience of Metformin Use in Pregnancy: Observational Data From the Northern Territory Diabetes in Pregnancy Clinical Register. J Diabetes (2019) 11(9):761–70. doi: 10.1111/1753-0407.12905
Løvvik TS Carlsen SM Salvesen Ø Steffensen B Bixo M Gómez-Real F et al. Use of Metformin to Treat Pregnant Women With Polycystic Ovary Syndrome (PregMet2): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet Diabetes Endocrinol (2019) 8587(19):1–11. doi: 10.1016/S2213-8587(19)30002-6
Nguyen L Chan SY Teo AKK. Metformin From Mother to Unborn Child – Are There Unwarranted Effects? EBioMedicine (2018) 35:394–404. doi: 10.1016/j.ebiom.2018.08.047
Tarry-Adkins JL Aiken CE Ozanne SE. Neonatal, Infant, and Childhood Growth Following Metformin Versus Insulin Treatment for Gestational Diabetes: A Systematic Review and Meta-Analysis. PloS Med (2019) 16(8):e1002848. doi: 10.1371/journal.pmed.1002848
Hanem LGE Stridsklev S Júlíusson PB Salvesen Ø Roelants M Carlsen SM et al. Metformin Use in PCOS Pregnancies Increases the Risk of Offspring Overweight at 4 Years of Age: Follow-Up of Two RCTs. J Clin Endocrinol Metab (2018) 103(4):1612–21. doi: 10.1210/jc.2017-02419
Hou M Venier N Sugar L Musquera M Pollak M Kiss A et al. Protective Effect of Metformin in CD1 Mice Placed on a High Carbohydrate-High Fat Diet. Biochem Biophys Res Commun (2010) 397(3):537–42. doi: 10.1016/j.bbrc.2010.05.152
Hou M Venier N Sugar L Musquera M Pollak M Kiss A et al. Biochemical and Biophysical Research Communications Protective Effect of Metformin in CD1 Mice Placed on a High Carbohydrate – High Fat Diet. Biochem Biophys Res Commun (2010) 397(3):537–42. doi: 10.1016/j.bbrc.2010.05.152
Foretz M Hébrard S Leclerc J Zarrinpashneh E Soty M Mithieux G et al. Metformin Inhibits Hepatic Gluconeogenesis in Mice Independently of the LKB1/AMPK Pathway via a Decrease in Hepatic Energy State. J Clin Invest (2010) 120(7):2355–69. doi: 10.1172/JCI40671
Froment P Staub C Hembert S Pisselet C Magistrini M Delaleu B et al. Reproductive Abnormalities in Human Insulin-Like Growth Factor-Binding Protein-1 Transgenic Male Mice. Endocrinology (2004) 145(4):2080–91. doi: 10.1210/en.2003-0956
Stübiger G Pittenauer E Allmaier G. MALDI Seamless Postsource Decay Fragment Ion Analysis of Sodiated and Lithiated Phospholipids. Anal Chem (2008) 80(5):1664–78. doi: 10.1021/ac7018766
Sørensen LK Hasselstrøm JB. A Hydrophilic Interaction Liquid Chromatography Electrospray Tandem Mass Spectrometry Method for the Simultaneous Determination of γ-Hydroxybutyrate and Its Precursors in Forensic Whole Blood. Forensic Sci Int (2012) 222(1–3):352–9. doi: 10.1016/j.forsciint.2012.07.017
Bertoldo MJ Guibert E Faure M Guillou F Ramé C Nadal-Desbarats L et al. Specific Deletion of AMP-Activated Protein Kinase (α1ampk) in Mouse Sertoli Cells Modifies Germ Cell Quality. Mol Cell Endocrinol (2016) 423:96–112. doi: 10.1016/j.mce.2016.01.001
Karimi M Johansson S Ekström TJ. Using LUMA: A Luminometric-Based Assay for Global DNA-Methylation. Epigenetics (2006) 1(1):45–8. doi: 10.4161/epi.1.1.2587
Champroux A Damon-Soubeyrand C Goubely C Bravard S Henry-Berger J Guiton R et al. Nuclear Integrity But Not Topology of Mouse Sperm Chromosome Is Affected by Oxidative DNA Damage. Genes (2018) 9(10):501. doi: 10.3390/genes9100501
Efimova OA Pendina AA Tikhonov AV Parfenyev SE Mekina ID Komarova EM et al. Genome-Wide 5-Hydroxymethylcytosine Patterns in Human Spermatogenesis are Associated With Semen Quality. Oncotarget (2017) 8(51):88294–307. doi: 10.18632/oncotarget.18331
Bridgeman SC Ellison GC Melton PE Newsholme P Mamotte CDS. Epigenetic Effects of Metformin: From Molecular Mechanisms to Clinical Implications. Diabetes Obes Metab (2018) 20(7):1553–62. doi: 10.1111/dom.13262
Wilcock C Bailey CJ. Sites of Metformin-Stimulated Glucose Metabolism. Biochem Pharmacol (1990) 39(11):1831–4. doi: 10.1016/0006-2952(90)90136-9
Gregg B Elghazi L Alejandro EU Smith MR Blandino-Rosano M El-Gabri D et al. Exposure of Mouse Embryonic Pancreas to Metformin Enhances the Number of Pancreatic Progenitors. Diabetologia (2014) 57(12):2566–75. doi: 10.1007/s00125-014-3379-5
Salomaki H Heinaniemi M Vahatalo LH Ailanen L Eerola K Ruohonen ST et al. Prenatal Metformin Exposure in a Maternal High Fat Diet Mouse Model Alters the Transcriptome and Modifies the Metabolic Responses of the Offspring. PloS One (2014) 9(12):1–22. doi: 10.1371/journal.pone.0115778
Léonhardt M Lesage J Croix D Dutriez-Casteloot I Beauvillain JC Dupouy JP. Effects of Perinatal Maternal Food Restriction on Pituitary-Gonadal Axis and Plasma Leptin Level in Rat Pup at Birth and Weaning and on Timing of Puberty. Biol Reprod (2003) 68(2):390–400. doi: 10.1095/biolreprod.102.003269
Painter RC Westendorp RGJ de Rooij SR Osmond C Barker DJP Roseboom TJ. Increased Reproductive Success of Women After Prenatal Undernutrition. Hum Reprod (2008) 23(11):2591–5. doi: 10.1093/humrep/den274
Kern PA Gregorio GB Di Lu T Rassouli N Ranganathan G. Adiponectin Expression From Human Adipose Tissue. Diabetes (2003) 52(17):1779–85. doi: 10.2337/diabetes.52.7.1779
Landrier JF Kasiri E Karkeni E Mihaly O Beke G Weiss K et al. Reduced Adiponectin Expression After High-Fat Diet Is Associated With Selective Up-Regulation of ALDH1A1 and Further Retinoic Acid Receptor Signaling in Adipose Tissue. FASEB J (2017) 31(1):203–11. doi: 10.1096/fj.201600263rr
Lu M Tang Q Olefsky JM Mellon PL Webster NJG. Adiponectin Activates Adenosine Monophosphate-Activated Protein Kinase and Decreases Luteinizing Hormone Secretion in LbetaT2 Gonadotropes. Mol Endocrinol (2008) 22(3):760–71. doi: 10.1210/me.2007-0330
Estienne A Bongrani A Reverchon M Ramé C Ducluzeau P-H Froment P et al. Involvement of Novel Adipokines, Chemerin, Visfatin, Resistin and Apelin in Reproductive Functions in Normal and Pathological Conditions in Humans and Animal Models. Int J Mol Sci (2019) 20(18):4431. doi: 10.3390/ijms20184431
Bongrani A Elfassy Y Brun JS Ramé C Mellouk N Fellahi S et al. Expression of Adipokines in Seminal Fluid of Men of Normal Weight. Asian J Androl (2019) 21(5):528–30. doi: 10.4103/aja.aja_25_19
Dobrzyn K Smolinska N Kiezun M Szeszko K Rytelewska E Kisielewska K et al. Adiponectin: A New Regulator of Female Reproductive System. Int J Endocrinol (2018) 2018:1–12. doi: 10.1155/2018/7965071
Elfassy Y Bastard JP McAvoy C Fellahi S Dupont J Levy R. Adipokines in Semen: Physiopathology and Effects on Spermatozoas. Int J Endocrinol (2018) 2018:3906490. doi: 10.1155/2018/3906490
Yang PK Hsu CY Chen MJ Lai MY Li ZR Chen CH et al. The Efficacy of 24-Month Metformin for Improving Menses, Hormones, and Metabolic Profiles in Polycystic Ovary Syndrome. J Clin Endocrinol Metab (2018) 103(3):890–9. doi: 10.1210/jc.2017-01739
Velazquez EM Sosa F Glueck CJ. Metformin Therapy in Polycystic Ovary Syndrome Reduces Hyperinsulinemia, Insulin Resistance, Hyperandrogenemia, and Systolic Blood Pressure, While Facilitating Normal Menses and Pregnancy. Metabolism (1994) 43(5):647–54. doi: 10.1016/0026-0495(94)90209-7
Smith LB Walker WH. Hormone Signaling in the Testis. 4th ed. In: Knobil and Neill's Physiology of Reproduction: Two-Volume Set. Vol. 1. Elsevier North-Holland, Inc.: Elsevier (2014). p. 637–90. doi: 10.1016/B978-0-12-397175-3.00016-8
Rouiller-Fabre V Muczynski V Lambrot R Lécureuil C Coffigny H Pairault C et al. Ontogenesis of Testicular Function in Humans. Folia Histochem Cytobiol Pol Acad Sci Pol Histochem Cytochem Soc (2009) 47(5):S19–24. doi: 10.2478/v10042-009-0065-4
Forcato S Montagnini BG de Góes MLM da Silva Novi DRB Inhasz Kiss AC Ceravolo GS et al. Reproductive Evaluations in Female Rat Offspring Exposed to Metformin During Intrauterine and Intrauterine/Lactational Periods. Reprod Toxicol (2019) 87:1–7. doi: 10.1016/j.reprotox.2019.04.009
Kong X-X Fu Y-C Xu J-J Zhuang X-L Chen Z-G Luo L-L. Resveratrol, an Effective Regulator of Ovarian Development and Oocyte Apoptosis. J Endocrinol Invest (2011) 34(11):e374–81. doi: 10.3275/7853.
Sabatini ME Guo L Lynch MP Doyle JO Lee H Rueda BR et al. Metformin Therapy in a Hyperandrogenic Anovulatory Mutant Murine Model With Polycystic Ovarian Syndrome Characteristics Improves Oocyte Maturity During Superovulation. J Ovarian Res (2011) 4(1):8. doi: 10.1186/1757-2215-4-8
Khorram O Keen-Rinehart E Chuang T-D Ross MG Desai M. Maternal Undernutrition Induces Premature Reproductive Senescence in Adult Female Rat Offspring. Fertil Steril (2015) 103(1):291–8.e2. doi: 10.1016/j.fertnstert.2014.09.026
Wang N Huang Y Wen J Su Q Huang Y Cai L et al. Early Life Exposure to Famine and Reproductive Aging Among Chinese Women. Menopause (2019) 26(5):463–8. doi: 10.1097/GME.0000000000001259
Carrell DT. Epigenetics of the Male Gamete. Fertil Steril (2012) 97(2):267–74. doi: 10.1016/j.fertnstert.2011.12.036
Stuppia L Franzago M Ballerini P Gatta V Antonucci I. Epigenetics and Male Reproduction: The Consequences of Paternal Lifestyle on Fertility, Embryo Development, and Children Lifetime Health. Clin Epigenet (2015) 7(1):1–15. doi: 10.1186/s13148-015-0155-4
Martínez D Pentinat T Ribó S Daviaud C Bloks VW Cebrià J et al. In Utero Undernutrition in Male Mice Programs Liver Lipid Metabolism in the Second-Generation Offspring Involving Altered Lxra DNA Methylation. Cell Metab (2014) 19(6):941–51. doi: 10.1016/j.cmet.2014.03.026
Bungard D Fuerth BJ Zeng P-Y Faubert B Maas NL Viollet B et al. ShelleyL.Berger. Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation. Science (2010) 329:1201–5. doi: 10.1126/science.1191241
Luense LJ Wang X Schon SB Weller AH Lin Shiao E Bryant JM et al. Comprehensive Analysis of Histone Post-Translational Modifications in Mouse and Human Male Germ Cells. Epigenet Chromatin (2016) 9(1):1–15. doi: 10.1186/s13072-016-0072-6
Shinagawa T Huynh LM Takagi T Tsukamoto D Tomaru C Kwak H-G et al. Disruption of Th2a and Th2b Genes Causes Defects in Spermatogenesis. Development (2015) 142(7):1287–92. doi: 10.1242/dev.121830
Hamad MF Shelko N Kartarius S Montenarh M Hammadeh ME. Impact of Cigarette Smoking on Histone (H2B) to Protamine Ratio in Human Spermatozoa and its Relation to Sperm Parameters. Andrology (2014) 2(5):666–77. doi: 10.1111/j.2047-2927.2014.00245.x
Barzideh J Scott RJ Aitken RJ. Analysis of the Global Methylation Status of Human Spermatozoa and its Association With the Tendency of These Cells to Enter Apoptosis. Andrologia (2012) 45(6):424–9. doi: 10.1111/and.12033
Urdinguio RG Bayón GF Dmitrijeva M Toraño EG Bravo C Fraga MF et al. Aberrant DNA Methylation Patterns of Spermatozoa in Men With Unexplained Infertility. Hum Reprod (2015) 30(5):1014–28. doi: 10.1093/humrep/dev053
Houshdaran S Cortessis VK Siegmund K Yang A Laird PW Sokol RZ. Widespread Epigenetic Abnormalities Suggest a Broad DNA Methylation Erasure Defect in Abnormal Human Sperm. PloS One (2007) 2(12):e1289. doi: 10.1371/journal.pone.0001289
Marques CJ Costa P Vaz B Carvalho F Fernandes S Barros A et al. Abnormal Methylation of Imprinted Genes in Human Sperm Is Associated With Oligozoospermia. Mol Hum Reprod (2008) 14(2):67–73. doi: 10.1093/molehr/gam093
Khazamipour N Noruzinia M Fatehmanesh P Keyhanee M Pujol P. MTHFR Promoter Hypermethylation in Testicular Biopsies of Patients With non-Obstructive Azoospermia: The Role of Epigenetics in Male Infertility. Hum Reprod (2009) 24(9):2361–4. doi: 10.1093/humrep/dep194
Hammoud AO Wilde N Gibson M Parks A Carrell DT Meikle AW. Male Obesity and Alteration in Sperm Parameters. Fertil Steril (2008) 90(6):2222–5. doi: 10.1016/j.fertnstert.2007.10.011
Minor A Chow V Ma S. Aberrant DNA Methylation at Imprinted Genes in Testicular Sperm Retrieved From Men With Obstructive Azoospermia and Undergoing Vasectomy Reversal. Reproduction (2011) 141(6):749–57. doi: 10.1530/REP-11-0008
Li L-H Donald JM Golub MS. Review on Testicular Development, Structure, Function, and Regulation in Common Marmoset. Birth Defects Res Part B Dev Reprod Toxicol (2005) 74(5):450–69. doi: 10.1002/bdrb.20057
Dhahbi JM Mote PL Fahy GM Spindler SR. Identification of Potential Caloric Restriction Mimetics by Microarray Profiling. Physiol Genomics (2005) 23(3):343–50. doi: 10.1152/physiolgenomics.00069.2005
Cuyàs E Fernández-Arroyo S Verdura S García RÁF Stursa J Werner L et al. Metformin Regulates Global DNA Methylation via Mitochondrial One-Carbon Metabolism. Oncogene (2017) 37(7):963–70. doi: 10.1038/onc.2017.367
Zhong T Men Y Lu L Geng T Zhou J Mitsuhashi A et al. Metformin Alters DNA Methylation Genome-Wide via the H19/SAHH Axis. Oncogene (2017) 36(17):2345–54. doi: 10.1038/onc.2016.391
Yang M Soga T Pollard PJ Yang M Soga T Pollard PJ. Oncometabolites: Linking Altered Metabolism With Cancer Find the Latest Version: Review Series Oncometabolites: Linking Altered Metabolism With Cancer. J Clin Investig (2013) 123(9):3652–8. doi: 10.1172/JCI67228
Ni K Dansranjavin T Rogenhofer N Oeztuerk N Deuker J Bergmann M et al. TET Enzymes are Successively Expressed During Human Spermatogenesis and Their Expression Level Is Pivotal for Male Fertility. Hum Reprod (2016) 31(7):1411–24. doi: 10.1093/humrep/dew096
Lee H-S. Impact of Maternal Diet on the Epigenome During In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood. Nutrients (2015) 7(11):9492–507. doi: 10.3390/nu7115467
Radford EJ Ito M Shi H Corish JA Yamazawa K Isganaitis E et al. In Utero Effects. In Utero Undernourishment Perturbs the Adult Sperm Methylome and Intergenerational Metabolism. Science (2014) 345(6198):1255903. doi: 10.1126/science.1255903
