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Inheritance of paternal lifestyles and exposures through sperm DNA methylation

Nature Reviews Urology volume 20, pages 356–370 (2023)Cite this article

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Abstract

Many different lifestyle factors and chemicals present in the environment are a threat to the reproductive tracts of humans. The potential for parental preconception exposure to alter gametes and for these alterations to be passed on to offspring and negatively affect embryo growth and development is of concern. The connection between maternal exposures and offspring health is a frequent focus in epidemiological studies, but paternal preconception exposures are much less frequently considered and are also very important determinants of offspring health. Several environmental and lifestyle factors in men have been found to alter sperm epigenetics, which can regulate gene expression during early embryonic development. Epigenetic information is thought to be a mechanism that evolved for organisms to pass on information about their lived experiences to offspring. DNA methylation is a well-studied epigenetic regulator that is sensitive to environmental exposures in somatic cells and sperm. The continuous production of sperm from spermatogonial stem cells throughout a man’s adult life and the presence of spermatogonial stem cells outside of the blood–testis barrier makes them susceptible to environmental insults. Furthermore, altered sperm DNA methylation patterns can be maintained throughout development and ultimately result in impairments, which could predispose offspring to disease. Innovations in human stem cell-based spermatogenic models can be used to elucidate the paternal origins of health and disease.

Key points

  • A number of lifestyle factors and environmental exposures can alter the epigenome in gametes, which can contribute to the development of disease in offspring.

  • Maternal exposures have been heavily investigated with respect to their influence on offspring, but paternal exposures have been largely overlooked.

  • Paternal exposures are important to explore as they often reflect maternal exposures and sperm are continuously produced throughout adult life from a stem cell pool located outside the blood–testis barrier.

  • Human stem cell-based methods might improve understanding of the influence of paternal exposures on offspring health and development without the challenges of species differences and confounding maternal exposures.

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Fig. 1: Epigenetic inheritance.
Fig. 2: Windows of susceptibility.
Fig. 3: Intergenerational transmission of environmental exposures and lifestyle factors.
Fig. 4: Overview of experimental designs for studying the transgenerational inheritance of paternal lifestyle and environmental exposures on the sperm epigenome.

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References

  1. Swan, S. & Colino, S. Count down: how our modern world is threatening sperm counts. Altering Male and Female Reproductive Development, and Imperiling the Future of the Human Race (CHE, 2021).

  2. Gore, A. C. et al. EDC-2: the Endocrine Society’s second scientific statement on endocrine-disrupting chemicals. Endocr. Rev. 36, E1–E150 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sharma, R., Biedenharn, K. R., Fedor, J. M. & Agarwal, A. Lifestyle factors and reproductive health: taking control of your fertility. Reprod. Biol. Endocrinol. 11, 66 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Skakkebaek, N. E. et al. Male reproductive disorders and fertility trends: influences of environment and genetic susceptibility. Physiol. Rev. 96, 55–97 (2015).

    Article  PubMed Central  Google Scholar 

  5. Zurlo, M. C., Cattaneo Della Volta, M. F. & Vallone, F. Predictors of quality of life and psychological health in infertile couples: the moderating role of duration of infertility. Qual. Life Res. 27, 945–954 (2018).

    Article  PubMed  Google Scholar 

  6. Donkin, I. & Barres, R. Sperm epigenetics and influence of environmental factors. Mol. Metab. https://doi.org/10.1016/j.molmet.2018.02.006 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Gluckman, P. D., Hanson, M. A., Cooper, C. & Thornburg, K. L. Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61–73 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jimenez-Chillaron, J. C. et al. Intergenerational transmission of glucose intolerance and obesity by in utero undernutrition in mice. Diabetes 58, 460–468 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Radford, E. J. et al. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Fleming, T. P. et al. Origins of lifetime health around the time of conception: causes and consequences. Lancet 391, 1842–1852 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Daly, M., Kipping, R. R., Tinner, L. E., Sanders, J. & White, J. W. Preconception exposures and adverse pregnancy, birth and postpartum outcomes: umbrella review of systematic reviews. Paediatr. Perinat. Epidemiol. 36, 288–299 (2022).

    Article  PubMed  Google Scholar 

  12. Hieronimus, B. & Ensenauer, R. Influence of maternal and paternal pre-conception overweight/obesity on offspring outcomes and strategies for prevention. Eur. J. Clin. Nutr. 75, 1735–1744 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Soubry, A. Epigenetics as a driver of developmental origins of health and disease: did we forget the fathers? BioEssays 40, 1700113 (2018).

    Article  Google Scholar 

  14. Soubry, A. POHaD: why we should study future fathers. Environ. Epigenetics 4, dvy007–dvy007 (2018).

    Article  Google Scholar 

  15. Schulze-Rath, R., Hammer, G. P. & Blettner, M. Are pre- or postnatal diagnostic X-rays a risk factor for childhood cancer? A systematic review. Radiat. Environ. Biophys. 47, 301 (2008).

    Article  PubMed  Google Scholar 

  16. Zhou, Q. et al. Association of preconception paternal alcohol consumption with increased fetal birth defect risk. JAMA Pediatrics 175, 742–743 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Svanes, C. et al. Father’s environment before conception and asthma risk in his children: a multi-generation analysis of the respiratory health in northern Europe study. Int. J. Epidemiol. 46, 235–245 (2017).

    PubMed  Google Scholar 

  18. Kaati, G., Bygren, L. O. & Edvinsson, S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur. J. Hum. Genet. 10, 682–688 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Pembrey, M. E. et al. Sex-specific, male-line transgenerational responses in humans. Eur. J. Hum. Genet. 14, 159–166 (2006).

    Article  PubMed  Google Scholar 

  20. Greeson, K. W. et al. Detrimental effects of flame retardant, PBB153, exposure on sperm and future generations. Sci. Rep. 10, 8567 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schrott, R. et al. Sperm DNA methylation altered by THC and nicotine: vulnerability of neurodevelopmental genes with bivalent chromatin. Sci. Rep. 10, 16022 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Moore, M. M., Myers, M. B. & Heflich, R. H. Mutagenesis and Genetic Toxicology (Wiley-Interscience, 2000).

  23. Hitchins, M. P. Constitutional epimutation as a mechanism for cancer causality and heritability? Nat. Rev. Cancer 15, 625–634 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Kanwal, R. & Gupta, S. Epigenetic modifications in cancer. Clin. Genet. 81, 303–311 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Sipahi, L. et al. Ancient evolutionary origins of epigenetic regulation associated with posttraumatic stress disorder. Front. Hum. Neurosci. 8, 284 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Xiao, S., Symosko, K. M. & Easley, C. A. in Principles of Toxicology: Environmental and Industrial Applications (eds Roberts, S. M., James, R. C., & Williams, P. L.) (Wiley, 2022).

  27. Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes Dev. 25, 1010–1022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Ying, H. & Huttley, G. Exploiting CpG hypermutability to identify phenotypically significant variation within human protein-coding genes. Genome Biol. Evol. 3, 938–949 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhou, Y. et al. The impact of DNA methylation dynamics on the mutation rate during human germline development. G3 10, 3337–3346 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Venkatesh, S. & Workman, J. L. Histone exchange, chromatin structure and the regulation of transcription. Nat. Rev. Mol. Cell Biol. 16, 178–189 (2015).

    Article  CAS  PubMed  Google Scholar 

  31. Inbar-Feigenberg, M., Choufani, S., Butcher, D. T., Roifman, M. & Weksberg, R. Basic concepts of epigenetics. Fertil. Steril. 99, 607–615 (2013).

    Article  CAS  PubMed  Google Scholar 

  32. Mattei, A. L., Bailly, N. & Meissner, A. DNA methylation: a historical perspective. Trends Genet. 38, 676–707 (2022).

    Article  CAS  PubMed  Google Scholar 

  33. Smith, Z. D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).

    Article  CAS  PubMed  Google Scholar 

  34. Jin, Z. & Liu, Y. DNA methylation in human diseases. Genes Dis. 5, 1–8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Liang, G. & Weisenberger, D. J. DNA methylation aberrancies as a guide for surveillance and treatment of human cancers. Epigenetics 12, 416–432 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Nabais, M. F. et al. Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders. Genome Biol. 22, 90 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martin, E. M. & Fry, R. C. Environmental influences on the epigenome: exposure-associated DNA methylation in human populations. Annu. Rev. Public Health 39, 309–333 (2018).

    Article  PubMed  Google Scholar 

  38. Åsenius, F. et al. The DNA methylome of human sperm is distinct from blood with little evidence for tissue-consistent obesity associations. PLoS Genet. 16, e1009035 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Guo, H. et al. The DNA methylation landscape of human early embryos. Nature 511, 606–610 (2014).

    Article  CAS  PubMed  Google Scholar 

  40. Suen, J.-L. et al. Environmental factor-mediated transgenerational inheritance of Igf2r hypomethylation and pulmonary allergic response via targeting dendritic cells. Front. Immunol., https://doi.org/10.3389/fimmu.2020.603831 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sen, A. et al. Multigenerational epigenetic inheritance in humans: DNA methylation changes associated with maternal exposure to lead can be transmitted to the grandchildren. Sci. Rep. 5, 14466 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rojas, D. et al. Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol. Sci. 143, 97–106 (2015).

    Article  CAS  PubMed  Google Scholar 

  43. Danielson, C. K., Hankin, B. L. & Badanes, L. S. Youth offspring of mothers with posttraumatic stress disorder have altered stress reactivity in response to a laboratory stressor. Psychoneuroendocrinology 53, 170–178 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Radtke, K. M. et al. Transgenerational impact of intimate partner violence on methylation in the promoter of the glucocorticoid receptor. Transl. Psychiatry 1, e21–e21 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Serpeloni, F. et al. Grandmaternal stress during pregnancy and DNA methylation of the third generation: an epigenome-wide association study. Transl. Psychiatry 7, e1202–e1202 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Heijmans, B. T. et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc. Natl Acad. Sci. USA 105, 17046 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Joubert, B. R. et al. DNA methylation in newborns and maternal smoking in pregnancy: genome-wide consortium meta-analysis. Am. J. Hum. Genet. 98, 680–696 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wilhelm-Benartzi Charlotte, S. et al. In utero exposures, infant growth, and DNA methylation of repetitive elements and developmentally related genes in human placenta. Env. Health Perspect. 120, 296–302 (2012).

    Article  CAS  Google Scholar 

  49. Geraghty, A. A., Lindsay, K. L., Alberdi, G., McAuliffe, F. M. & Gibney, E. R. Nutrition during pregnancy impacts offspring’s epigenetic status—evidence from human and animal studies. Nutr. Metab. Insights 8s1, NMI.S29527 (2015).

    Article  Google Scholar 

  50. Waterland, R. A. et al. Season of conception in rural Gambia affects DNA methylation at putative human metastable epialleles. PLoS Genet. 6, e1001252 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Loke, Y. J. et al. Association of maternal and nutrient supply line factors with DNA methylation at the imprinted IGF2/H19 locus in multiple tissues of newborn twins. Epigenetics 8, 1069–1079 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. McCullough, L. E. et al. Maternal B vitamins: effects on offspring weight and DNA methylation at genomically imprinted domains. Clin. Epigenet. 8, 8 (2016).

    Article  Google Scholar 

  53. Pauwels, S. et al. Maternal intake of methyl-group donors affects DNA methylation of metabolic genes in infants. Clin. Epigenet. 9, 16 (2017).

    Article  Google Scholar 

  54. Steegers-Theunissen, R. P. et al. Periconceptional maternal folic acid use of 400 µg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS One 4, e7845 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  55. McCullough, L. E. et al. Associations between prenatal physical activity, birth weight, and DNA methylation at genomically imprinted domains in a multiethnic newborn cohort. Epigenetics 10, 597–606 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Houfflyn, S., Matthys, C. & Soubry, A. Male obesity: epigenetic origin and effects in sperm and offspring. Curr. Mol. Biol. Rep. 3, 288–296 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Soubry, A. et al. Opposing epigenetic signatures in human sperm by intake of fast food versus healthy food. Front. Endocrinol. https://doi.org/10.3389/fendo.2021.625204 (2021).

    Article  Google Scholar 

  58. Robledo, C. A. et al. Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE study. Env. Health Perspect. 123, 88–94 (2015).

    Article  Google Scholar 

  59. Wu, H. et al. Parental contributions to early embryo development: influences of urinary phthalate and phthalate alternatives among couples undergoing IVF treatment. Hum. Reprod. 32, 65–75 (2017).

    CAS  PubMed  Google Scholar 

  60. Wu, H. et al. Preconception urinary phthalate concentrations and sperm DNA methylation profiles among men undergoing IVF treatment: a cross-sectional study. Hum. Reprod. 32, 2159–2169 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Fayomi, A. P. & Orwig, K. E. Spermatogonial stem cells and spermatogenesis in mice, monkeys and men. Stem Cell Res. 29, 207–214 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. de Rooij, D. G. The nature and dynamics of spermatogonial stem cells. Development 144, 3022 (2017).

    Article  PubMed  Google Scholar 

  63. Campion, S. et al. Male reprotoxicity and endocrine disruption. Exp. Suppl. 101, 315–360 (2012).

    PubMed  Google Scholar 

  64. Skakkebæk, N. E., Rajpert-De Meyts, E. & Main, K. M. Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects: opinion. Hum. Reprod. 16, 972–978 (2001).

    Article  PubMed  Google Scholar 

  65. Guo, J. et al. The dynamic transcriptional cell atlas of testis development during human puberty. Cell Stem Cell 26, 262–276.e264 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Wu, H., Hauser, R., Krawetz, S. A. & Pilsner, J. R. Environmental susceptibility of the sperm epigenome during windows of male germ cell development. Curr. Env. Health Rep. 2, 356–366 (2015).

    Article  Google Scholar 

  67. Pilsner, J. R., Parker, M., Sergeyev, O. & Suvorov, A. Spermatogenesis disruption by dioxins: epigenetic reprograming and windows of susceptibility. Reprod. Toxicol. 69, 221–229 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kubo, N. et al. DNA methylation and gene expression dynamics during spermatogonial stem cell differentiation in the early postnatal mouse testis. BMC Genomics 16, 624 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yamazaki, Y. et al. Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning. Proc. Natl Acad. Sci. USA 100, 12207–12212 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gkountela, S. et al. DNA demethylation dynamics in the human prenatal germline. Cell 161, 1425–1436 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Marques, C. J. et al. DNA methylation imprinting marks and DNA methyltransferase expression in human spermatogenic cell stages. Epigenetics 6, 1354–1361 (2011).

    Article  CAS  PubMed  Google Scholar 

  72. McKinnell, C. et al. Perinatal germ cell development and differentiation in the male marmoset (Callithrix jacchus): similarities with the human and differences from the rat. Hum. Reprod. 28, 886–896 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Langenstroth-Röwer, D. et al. De novo methylation in male germ cells of the common marmoset monkey occurs during postnatal development and is maintained in vitro. Epigenetics 12, 527–539 (2017).

    Article  PubMed  Google Scholar 

  74. Moosavi, A. & Motevalizadeh Ardekani, A. Role of epigenetics in biology and human diseases. Iran. Biomed. J. 20, 246–258 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. Cattanach, B. M. & Kirk, M. Differential activity of maternally and paternally derived chromosome regions in mice. Nature 315, 496–498 (1985).

    Article  CAS  PubMed  Google Scholar 

  76. Millership, S. J., Van de Pette, M. & Withers, D. J. Genomic imprinting and its effects on postnatal growth and adult metabolism. Cell. Mol. Life Sci. 76, 4009–4021 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Peters, J. The role of genomic imprinting in biology and disease: an expanding view. Nat. Rev. Genet. 15, 517–530 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Grafodatskaya, D., Choufani, S., Basran, R. & Weksberg, R. An update on molecular diagnostic testing of human imprinting disorders. J. Pediatr. Genet. 6, 3–17 (2017).

    Article  PubMed  Google Scholar 

  79. Guo, F. et al. The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell 161, 1437–1452 (2015).

    Article  CAS  PubMed  Google Scholar 

  80. Gonzalez-Nahm, S. et al. DNA methylation of imprinted genes at birth is associated with child weight status at birth, 1 year, and 3 years. Clin. Epigenet. 10, 90 (2018).

    Article  Google Scholar 

  81. Lorgen-Ritchie, M. et al. Imprinting methylation in SNRPN and MEST1 in adult blood predicts cognitive ability. PLoS One 14, e0211799 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Soubry, A. et al. Obesity-related DNA methylation at imprinted genes in human sperm: results from the TIEGER study. Clin. Epigenet. 8, 51 (2016).

    Article  Google Scholar 

  83. Ouko, L. A. et al. Effect of alcohol consumption on CpG methylation in the differentially methylated regions of H19 and IG-DMR in male gametes: implications for fetal alcohol spectrum disorders. Alcohol. Clin. Exp. Res. 33, 1615–1627 (2009).

    Article  CAS  PubMed  Google Scholar 

  84. Dong, H. et al. Abnormal methylation of imprinted genes and cigarette smoking: assessment of their association with the risk of male infertility. Reprod. Sci. 24, 114–123 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Liu, Y. et al. Effects of paternal exposure to cigarette smoke on sperm DNA methylation and long-term metabolic syndrome in offspring. Epigenet Chromat. 15, 3 (2022).

    Article  CAS  Google Scholar 

  86. Alkhaled, Y. et al. Impact of cigarette-smoking on sperm DNA methylation and its effect on sperm parameters. Andrologia https://doi.org/10.1111/and.12950 (2018).

    Article  PubMed  Google Scholar 

  87. Laqqan, M. et al. Aberrant DNA methylation patterns of human spermatozoa in current smoker males. Reprod. Toxicol. 71, 126–133 (2017).

    Article  CAS  PubMed  Google Scholar 

  88. Jenkins, T. G. et al. Cigarette smoking significantly alters sperm DNA methylation patterns. Andrology 25, 1089–1099 (2017).

    Article  Google Scholar 

  89. Murphy, S. K. et al. Cannabinoid exposure and altered DNA methylation in rat and human sperm. Epigenetics 13, 1208–1221 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Schrott, R. et al. Refraining from use diminishes cannabis-associated epigenetic changes in human sperm. Environ. Epigenetics 7, dvab009 (2021).

    Article  Google Scholar 

  91. Jazayeri, M., Eftekhari-Yazdi, P., Sadighi Gilani, M. A., Sharafi, M. & Shahverdi, A. Epigenetic modifications at DMRs of imprinting genes in sperm of type 2 diabetic men. Zygote https://doi.org/10.1017/S0967199422000107 (2022).

    Article  PubMed  Google Scholar 

  92. Kelsey, K. T. et al. Serum dioxin and DNA methylation in the sperm of operation ranch hand veterans exposed to agent orange. Environ. Health 18, 91 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Soubry, A. et al. Human exposure to flame-retardants is associated with aberrant DNA methylation at imprinted genes in sperm. Environ. Epigenet. 3, dvx003 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Consales, C. et al. Exposure to persistent organic pollutants and sperm DNA methylation changes in Arctic and European populations. Environ. Mol. Mutagen. 57, 200–209 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Walczak-Jedrzejowska, R., Wolski, J. K. & Slowikowska-Hilczer, J. The role of oxidative stress and antioxidants in male fertility. Cent. European J. Urol. 66, 60–67 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Darbandi, M. et al. Reactive oxygen species-induced alterations in H19-Igf2 methylation patterns, seminal plasma metabolites, and semen quality. J. Assist. Reprod. Genet. 36, 241–253 (2019).

    Article  PubMed  Google Scholar 

  97. Aquilina, N. J. et al. Environmental and biological monitoring of exposures to PAHs and ETS in the general population. Env. Int. 36, 763–771 (2010).

    Article  CAS  Google Scholar 

  98. Agency for Toxic Substances and Disease Registry. Toxicological profile for polycyclic aromatic hydrocarbons (PAHs). Agency for Toxic Substances and Disease Registry https://www.atsdr.cdc.gov/toxprofiles/tp69.pdf (1995).

  99. Lewtas, J. Air pollution combustion emissions: characterization of causative agents and mechanisms associated with cancer, reproductive, and cardiovascular effects. Mutat. Res. 636, 95–133 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Mumtaz, M. & George, J. Toxicological profile for polycyclic aromatic hydrocarbons. Vol. 458 (US Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, 1995).

  101. Ma, Y., Lu, Z., Wang, L. & Qiang, M. Correlation of internal exposure levels of polycyclic aromatic hydrocarbons to methylation of imprinting genes of sperm DNA. Int. J. Environ. Res. Public Health https://doi.org/10.3390/ijerph16142606 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Yang, J., Lu, Z., Liu, Z., Wang, L. & Qiang, M. Methylation of imprinted genes in sperm DNA correlated to urinary polycyclic aromatic hydrocarbons (PAHs) exposure levels in reproductive-aged men and the birth outcomes of the offspring. Front. Genet. https://doi.org/10.3389/fgene.2020.611276 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Nye, M. D. et al. Maternal blood lead concentrations, DNA methylation of MEG3 DMR regulating the DLK1/MEG3 imprinted domain and early growth in a multiethnic cohort. Environ. Epigenet https://doi.org/10.1093/eep/dvv009 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Li, Y. et al. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Env. Health Perspect. 124, 666–673 (2016).

    Article  CAS  Google Scholar 

  105. Smeester, L. et al. Imprinted genes and the environment: links to the toxic metals arsenic, cadmium and lead. Genes 5, 477–496 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Zheng, P.-Z. et al. Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc. Natl Acad. Sci. USA 102, 7653–7658 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Lunghi, P., Costanzo, A., Levrero, M. & Bonati, A. Treatment with arsenic trioxide (ATO) and MEK1 inhibitor activates the p73-p53AIP1 apoptotic pathway in leukemia cells. Blood 104, 519–525 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Wu, X. et al. Arsenic trioxide-mediated growth inhibition of myeloma cells is associated with an extrinsic or intrinsic signaling pathway through activation of TRAIL or TRAIL receptor 2. Cancer Biol. Ther. 10, 1201–1214 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhao, S., Zhang, J., Zhang, X., Dong, X. & Sun, X. Arsenic trioxide induces different gene expression profiles of genes related to growth and apoptosis in glioma cells dependent on the p53 status. Mol. Biol. Rep. 35, 421–429 (2008).

    Article  CAS  PubMed  Google Scholar 

  110. Glienke, W., Chow, K. U., Bauer, N. & Bergmann, L. Down-regulation of wt1 expression in leukemia cell lines as part of apoptotic effect in arsenic treatment using two compounds. Leuk. Lymphoma 47, 1629–1638 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Choi, Y.-J. et al. Involvement of E2F1 transcriptional activity in cadmium-induced cell-cycle arrest at G1 in human lung fibroblasts. Env. Mol. Mutagen. 52, 145–152 (2011).

    Article  CAS  Google Scholar 

  112. Åsenius, F., Danson, A. F. & Marzi, S. J. DNA methylation in human sperm: a systematic review. Hum. Reprod. Update 26, 841–873 (2020).

    Article  PubMed  Google Scholar 

  113. Soubry, A. et al. Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort. BMC Med. 11, 29 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Soubry, A. et al. Newborns of obese parents have altered DNA methylation patterns at imprinted genes. Int. J. Obes. 39, 650–657 (2015).

    Article  CAS  Google Scholar 

  115. Potabattula, R. et al. Male obesity effects on sperm and next-generation cord blood DNA methylation. PLoS One 14, e0218615 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sharp, G. C. et al. Paternal body mass index and offspring DNA methylation: findings from the PACE consortium. Int. J. Epidemiol. 50, 1297–1315 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Noor, N. et al. Association of periconception paternal body mass index with persistent changes in DNA methylation of offspring in childhood. JAMA Netw. Open 2, e1916777 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Ding, T., Mokshagundam, S., Rinaudo, P. F., Osteen, K. G. & Bruner-Tran, K. L. Paternal developmental toxicant exposure is associated with epigenetic modulation of sperm and placental Pgr and Igf2 in a mouse model. Biol. Reprod. 99, 864–876 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Guerrero-Bosagna, C., Settles, M., Lucker, B. & Skinner, M. K. Epigenetic transgenerational actions of vinclozolin on promoter regions of the sperm epigenome. PLoS One 5, e13100 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Siklenka, K. et al. Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science 350, aab2006 (2015).

    Article  PubMed  Google Scholar 

  121. Skinner, M. K. & Anway, M. D. Epigenetic transgenerational actions of vinclozolin on the development of disease and cancer. Crit. Rev. Oncog. 13, 75–82 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Skinner, M. K. et al. Transgenerational sperm DNA methylation epimutation developmental origins following ancestral vinclozolin exposure. Epigenetics 14, 721–739 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Dias, B. G. & Ressler, K. J. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat. Neurosci. 17, 89–96 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Anway, M. D., Cupp, A. S., Uzumcu, M. & Skinner, M. K. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Buck Louis, G. M. et al. Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE study. Andrology 4, 639–647 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Hoyo, C. et al. Methylation variation at IGF2 differentially methylated regions and maternal folic acid use before and during pregnancy. Epigenetics 6, 928–936 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Agency for Toxic Substances and Disease Registry. Polychlorinated Biphenyls (PCBs). Agency for Toxic Substances and Disease Registry https://wwwn.cdc.gov/TSP/substances/ToxSubstance.aspx?toxid=26 (2021).

  128. Georgiadis, P. et al. DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia. Environ. Int. 126, 24–36 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Leung, Y.-K. et al. Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort. Epigenetics 13, 290–300 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Di Persio, S. et al. Whole-genome methylation analysis of testicular germ cells from cryptozoospermic men points to recurrent and functionally relevant DNA methylation changes. Clin. Epigenet. 13, 160 (2021).

    Article  Google Scholar 

  131. Rotondo, J. C. et al. Methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples of infertile couples correlates with recurrent spontaneous abortion. Hum. Reprod. 27, 3632–3638 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Rotondo, J. C. et al. Methylation loss at H19 imprinted gene correlates with methylenetetrahydrofolate reductase gene promoter hypermethylation in semen samples from infertile males. Epigenetics 8, 990–997 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Tang, L. et al. Imprinting alterations in sperm may not significantly influence ART outcomes and imprinting patterns in the cord blood of offspring. PLoS One 12, e0187869 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Carrell, D. T. in Genetic Damage in Human Spermatozoa (eds Baldi, E. & Muratori, M.) 47–56 (Springer International Publishing, 2019).

  135. Rotondo, J. C., Lanzillotti, C., Mazziotta, C., Tognon, M. & Martini, F. Epigenetics of male infertility: the role of DNA methylation. Front. Cell Dev. Biol. https://doi.org/10.3389/fcell.2021.689624 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Sanz, L. A. et al. A mono-allelic bivalent chromatin domain controls tissue-specific imprinting at Grb10. EMBO J. 27, 2523–2532 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Cook, R. J. & Farewell, V. T. Guidelines for monitoring efficacy and toxicity responses in clinical trials. Biometrics 50, 1146–1152 (1994).

    Article  CAS  PubMed  Google Scholar 

  139. Senaldi, L. & Smith-Raska, M. Evidence for germline non-genetic inheritance of human phenotypes and diseases. Clin. Epigenet. 12, 136 (2020).

    Article  CAS  Google Scholar 

  140. Kader, F. & Ghai, M. DNA methylation-based variation between human populations. Mol. Genet. Genomics 292, 5–35 (2017).

    Article  CAS  PubMed  Google Scholar 

  141. Shea, J. M. et al. Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev. Cell 35, 750–758 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Berletch, J. B., Yang, F. & Disteche, C. M. Escape from X inactivation in mice and humans. Genome Biol. 11, 213 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Soncin, F. et al. Comparative analysis of mouse and human placentae across gestation reveals species-specific regulators of placental development. Development https://doi.org/10.1242/dev.156273 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Dolinoy, D. C. & Faulk, C. Introduction: the use of animals models to advance epigenetic science. ILAR J. 53, 227–231 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Hubrecht, R. C. & Carter, E. The 3Rs and humane experimental technique: implementing change. Animals https://doi.org/10.3390/ani9100754 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Grimm, D. US EPA to eliminate all mammal testing by 2035. Science https://doi.org/10.1126/science.aaz4593 (2019).

    Article  PubMed  Google Scholar 

  147. Díez-Solinska, A., Vegas, O. & Azkona, G. Refinement in the European union: a systematic review. Animals 12, 3263 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Vasbinder, M. A. & Locke, P. Introduction: global laws, regulations, and standards for animals in research. ILAR J. 57, 261–265 (2017).

    Article  Google Scholar 

  149. Yin, L. et al. High-content image-based single cell phenotypic analysis for the testicular toxicity prediction induced by bisphenol A and its analogs bisphenol S, bisphenol AF, and tetrabromobisphenol A in a three-dimensional testicular cell co-culture model. Toxicol. Sci. https://doi.org/10.1093/toxsci/kfz233 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Alves-Lopes, J. P., Söder, O. & Stukenborg, J.-B. Testicular organoid generation by a novel in vitro three-layer gradient system. Biomaterials 130, 76–78 (2017).

    Article  CAS  PubMed  Google Scholar 

  151. Sakib, S., Voigt, A., Goldsmith, T. & Dobrinski, I. Three-dimensional testicular organoids as novel in vitro models of testicular biology and toxicology. Env. Epigenet. 5, dvz011 (2019).

    Article  Google Scholar 

  152. Baert, Y. et al. Primary human testicular cells self-organize into organoids with testicular properties. Stem Cell Rep. 8, 30–38 (2017).

    Article  CAS  Google Scholar 

  153. Strange, D. P. et al. Human testicular organoid system as a novel tool to study Zika virus pathogenesis. Emerg. Microbes Infect. 7, 82 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Edenfield, R. C. & Easley, C. A. 4th Implications of testicular ACE2 and the renin-angiotensin system for SARS-CoV-2 on testis function. Nat. Rev. Urol. 19, 116–127 (2022).

    Article  CAS  PubMed  Google Scholar 

  155. National Institutes of Health. NIH stem cell information: stem cell basics. NIH https://stemcells.nih.gov/info/basics/stc-basics (2016).

  156. Zhang, B., Korolj, A., Lai, B. F. L. & Radisic, M. Advances in organ-on-a-chip engineering. Nat. Rev. Mater. 3, 257–278 (2018).

    Article  Google Scholar 

  157. Ravi, M., Paramesh, V., Kaviya, S. R., Anuradha, E. & Solomon, F. D. P. 3D cell culture systems: advantages and applications. J. Cell. Physiol. 230, 16–26 (2015).

    Article  CAS  PubMed  Google Scholar 

  158. Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).

    Article  CAS  PubMed  Google Scholar 

  159. WiCell. Stem cells. WiCell https://www.wicell.org/home/stem-cells/stem-cells.cmsx (2021).

  160. Edenfield, C., Siracusa, J., Wang, R. & Yu, X. in iPSCs from Diverse Species (ed Birbrair, A.) 1–44 (Academic Press, 2021).

  161. Luo, Y. & Yu, Y. Research advances in gametogenesis and embryogenesis using pluripotent stem cells. Front. Cell Dev. Biol. https://doi.org/10.3389/fcell.2021.801468 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  162. Easley, C. A. et al. Direct differentiation of human pluripotent stem cells into haploid spermatogenic cells. Cell Rep. 2, 440–446 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhao, Y. et al. In vitro modeling of human germ cell development using pluripotent stem cells. Stem Cell Rep. 10, 509–523 (2018).

    Article  Google Scholar 

  164. Easley, C. A. et al. Assessing reproductive toxicity of two environmental toxicants with a novel in vitro human spermatogenic model. Stem Cell Res. 14, 347–355 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Steves, A. N. et al. Ubiquitous flame-retardant toxicants impair spermatogenesis in a human stem cell model. iScience 3, 161–176 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Steves, A. N. et al. Per- and polyfluoroalkyl substances impact human spermatogenesis in a stem-cell-derived model. Syst. Biol. Reprod. Med. 64, 225–239 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Schrott, R. et al. Cannabis alters DNA methylation at maternally imprinted and autism candidate genes in spermatogenic cells. Syst. Biol. Reprod. Med. 68, 357–369 (2022).

    Article  CAS  PubMed  Google Scholar 

  168. Khampang, S. et al. Blastocyst development after fertilization with in vitro spermatids derived from nonhuman primate embryonic stem cells. F. S Sci. 2, 365–375 (2021).

    PubMed  PubMed Central  Google Scholar 

  169. Alonso-Magdalena, P., Rivera, F. J. & Guerrero-Bosagna, C. Bisphenol-A and metabolic diseases: epigenetic, developmental and transgenerational basis. Environ. Epigenet. 2, dvw022 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  170. St-Pierre, J. et al. IGF2 DNA methylation is a modulator of newborn’s fetal growth and development. Epigenetics 7, 1125–1132 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cao-Lei, L. et al. DNA methylation signatures triggered by prenatal maternal stress exposure to a natural disaster: Project Ice Storm. PLoS One 9, e107653 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Hompes, T. et al. Investigating the influence of maternal cortisol and emotional state during pregnancy on the DNA methylation status of the glucocorticoid receptor gene (NR3C1) promoter region in cord blood. J. Psychiatr. Res. 47, 880–891 (2013).

    Article  PubMed  Google Scholar 

  173. Mulligan, C. J., D’Errico, N. C., Stees, J. & Hughes, D. A. Methylation changes at NR3C1 in newborns associate with maternal prenatal stress exposure and newborn birth weight. Epigenetics 7, 853–857 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Oberlander, T. F. et al. Prenatal exposure to maternal depression, neonatal methylation of human glucocorticoid receptor gene (NR3C1) and infant cortisol stress responses. Epigenetics 3, 97–106 (2008).

    Article  PubMed  Google Scholar 

  175. Chang, C.-J. et al. Serum concentrations of polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in the Michigan PBB Registry 40 years after the PBB contamination incident. Environ. Int. 137, 105526 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Jacobs, L. W., Chou, S. F. & Tiedje, J. M. Field concentrations and persistence of polybrominated biphenyls in soils and solubility of PBB in natural waters. Environ. Health Perspect. 23, 1–8 (1978).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Small, C. M. et al. Maternal exposure to a brominated flame retardant and genitourinary conditions in male offspring. Environ. Health Perspect. 117, 1175–1179 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Blanck, H. M. et al. Age at menarche and Tanner stage in girls exposed in utero and postnatally to polybrominated biphenyl. Epidemiology 11, 641–647 (2000).

    Article  CAS  PubMed  Google Scholar 

  179. Small, C. M., Murray, D., Terrell, M. L. & Marcus, M. Reproductive outcomes among women exposed to a brominated flame retardant in utero. Arch. Environ. Occup. Health 66, 201–208 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Curtis, S. W. et al. Exposure to polybrominated biphenyl (PBB) associates with genome-wide DNA methylation differences in peripheral blood. Epigenetics 14, 52–66 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Landrigan, P. J. et al. Cohort study of Michigan residents exposed to polybrominated biphenyls: epidemiologic and immunologic findings. Ann. N. Y. Acad. Sci. 320, 284–294 (1979).

    Article  CAS  PubMed  Google Scholar 

  182. US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration. National Survey on Drug Use and Health www.datafiles.samhsa.gov (2018).

  183. Charalambous, M. et al. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc. Natl Acad. Sci. USA 100, 8292–8297 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. El-Maarri, O. et al. Maternal alleles acquiring paternal methylation patterns in biparental complete hydatidiform moles. Hum. Mol. Genet. 12, 1405–1413 (2003).

    Article  CAS  PubMed  Google Scholar 

  185. Huang, J. M. & Kim, J. DNA methylation analysis of the mammalian PEG3 imprinted domain. Gene 442, 18–25 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Kim, J. et al. Peg3 mutational effects on reproduction and placenta-specific gene families. PLoS One 8, e83359 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Xie, T. et al. PEG10 as an oncogene: expression regulatory mechanisms and role in tumor progression. Cancer Cell Int. 18, 112 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  188. Peall, K. J. et al. SGCE and myoclonus dystonia: motor characteristics, diagnostic criteria and clinical predictors of genotype. J. Neurol. 261, 2296–2304 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Peall, K. J. et al. SGCE mutations cause psychiatric disorders: clinical and genetic characterization. Brain 136, 294–303 (2013).

    Article  PubMed  Google Scholar 

  190. Simons Foundation Autism Research Initiative. SFARI Human Gene Module gene.sfari.org (2022).

  191. Court, F. & Arnaud, P. An annotated list of bivalent chromatin regions in human ES cells: a new tool for cancer epigenetic research. Oncotarget 8, 4110–4124 (2017).

    Article  PubMed  Google Scholar 

  192. Marini, C. et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain 141, 3160–3178 (2018).

    Article  PubMed  Google Scholar 

  193. Seo, H., Seol, M. J. & Lee, K. Differential expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits during hippocampal development in the mouse. Mol. Brain 8, 13 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Levy, J. et al. NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder. Clin. Genet. 94, 264–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  195. Reuter, M. S. et al. Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment. Am. J. Med. Genet. A 173, 2231–2234 (2017).

    Article  CAS  PubMed  Google Scholar 

  196. Zhang, J., Zhou, W., Liu, Y. & Li, N. Integrated analysis of DNA methylation and RNA sequencing data in Down syndrome. Mol. Med. Rep. 14, 4309–4314 (2016).

    Article  CAS  PubMed  Google Scholar 

  197. Rovida, C., Vivier, M., Garthoff, B. & Hescheler, J. ESNATS conference — the use of human embryonic stem cells for novel toxicity testing approaches. Altern. Lab. Anim. 42, 97–113 (2014).

    Article  CAS  PubMed  Google Scholar 

  198. Palmer, J. R. et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero. Epidemiology 16, 583–586 (2005).

    Article  PubMed  Google Scholar 

  199. Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Ishihara, T., Griffith, O. W., Suzuki, S. & Renfree, M. B. Presence of H3K4me3 on paternally expressed genes of the paternal genome from sperm to implantation. Front. Cell Dev. Biol. 10, 838684 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Janssen, S. M. & Lorincz, M. C. Interplay between chromatin marks in development and disease. Nat. Rev. Genet. 23, 137–153 (2022).

    Article  CAS  PubMed  Google Scholar 

  202. Pepin, A.-S., Lafleur, C., Lambrot, R., Dumeaux, V. & Kimmins, S. Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction. Mol. Metab. 59, 101463 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Sharma, U. Paternal contributions to offspring health: role of sperm small RNAs in intergenerational transmission of epigenetic information. Front. Cell Dev. Biol. https://doi.org/10.3389/fcell.2019.00215 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Chen, Q., Yan, W. & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat. Rev. Genet. 17, 733–743 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Lee, G. S. & Conine, C. C. The transmission of intergenerational epigenetic information by sperm microRNAs. Epigenomes https://doi.org/10.3390/epigenomes6020012 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  206. Kretschmer, M. & Gapp, K. Deciphering the RNA universe in sperm in its role as a vertical information carrier. Environ. Epigenet. 8, dvac011 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Bohacek, J. & Rassoulzadegan, M. Sperm RNA: quo vadis? Semin. Cell Dev. Biol. 97, 123–130 (2020).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Environmental Health Science, College of Public Health, University of Georgia, Athens, GA, USA

    Katherine W. Greeson, Krista M. S. Crow, R. Clayton Edenfield & Charles A. Easley IV

  2. Regenerative Bioscience Center, University of Georgia, Athens, GA, USA

    Katherine W. Greeson, Krista M. S. Crow, R. Clayton Edenfield & Charles A. Easley IV

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K.W.G., K.M.S.C. and R.C.E. researched data for the article. C.A.E. contributed substantially to discussion of the content. K.W.G. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Greeson, K.W., Crow, K.M.S., Edenfield, R.C. et al. Inheritance of paternal lifestyles and exposures through sperm DNA methylation. Nat Rev Urol 20, 356–370 (2023). https://doi.org/10.1038/s41585-022-00708-9

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