Advertisement

Current Epidemiology Reports

, Volume 4, Issue 1, pp 46–55 | Cite as

Fathers Matter: Why It’s Time to Consider the Impact of Paternal Environmental Exposures on Children’s Health

  • Joseph M. Braun
  • Carmen Messerlian
  • Russ Hauser
Environmental Epidemiology (J Braun, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Environmental Epidemiology

Abstract

Purpose

Despite accumulating evidence from experimental animal studies showing that paternal environmental exposures induce genetic and epigenetic alterations in sperm which in turn increase the risk of adverse health outcomes in offspring, there is limited epidemiological data on the effects of human paternal preconception exposures on children’s health. We summarize animal and human studies showing that paternal preconception environmental exposures influence offspring health. We discuss specific approaches and designs for human studies to investigate the health effects of paternal preconception exposures, the specific challenges these studies may face, and how we might address them.

Recent Findings

In animal studies, paternal preconception diet, stress, and chemical exposures have been associated with offspring health and these effects are mediated by epigenetic modifications transmitted through sperm DNA, histones, and RNA. Most epidemiological studies have examined paternal preconception occupational exposures and their effect on the risk of birth defects and childhood cancer; few have examined the effects of low-level general population exposure to environmental toxicants. While the design and execution of epidemiological studies of paternal preconception exposures face challenges, particularly with regard to selection bias and recruitment, we believe these are tractable and that preconception studies are feasible.

Summary

New or augmented prospective cohort studies would be the optimal method to address the critical knowledge gaps on the effect of paternal preconception exposures on prevalent childhood health outcomes. Determining if this period of life represents a window of heightened vulnerability would improve our understanding of modifiable risk factors for children’s health and wellbeing.

Keywords

Children’s health Chemical exposures Epidemiology Epigenetics Paternal Preconception Prenatal 

Notes

Acknowledgements

NIEHS grants R00 ES020346, R01 ES024381, R01 ES025214, R01 ES022955, P01 ES000002, and R01 ES009718. We thank David Savitz for his helpful feedback on an earlier version of this commentary.

Compliance with Ethical Standards

Conflict of Interest

Joseph M. Braun, Carmen Messerlian, and Russ Hauser each declare no potential conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Olshan AF, Faustman EM. Male-mediated developmental toxicity. Annu Rev Public Health. 1993;14:159–81.CrossRefPubMedGoogle Scholar
  2. 2.
    Daxinger L, Whitelaw E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat Rev Genet. 2012;13:153–62.CrossRefPubMedGoogle Scholar
  3. 3.
    Fernandez-Twinn DS, Constancia M, Ozanne SE. Intergenerational epigenetic inheritance in models of developmental programming of adult disease. Semin Cell Dev Biol. 2015;43:85–95.CrossRefPubMedGoogle Scholar
  4. 4.
    Szyf M. Nongenetic inheritance and transgenerational epigenetics. Trends Mol Med. 2015;21:134–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Rando OJ. Daddy issues: paternal effects on phenotype. Cell. 2012;151:702–8.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Puri D, Dhawan J, Mishra RK. The paternal hidden agenda: epigenetic inheritance through sperm chromatin. Epigenetics. 2010;5:386–91.CrossRefPubMedGoogle Scholar
  7. 7.
    Krawetz SA. Paternal contribution: new insights and future challenges. Nat Rev Genet. 2005;6:633–42.CrossRefPubMedGoogle Scholar
  8. 8.
    Kay VR, Bloom MS, Foster WG. Reproductive and developmental effects of phthalate diesters in males. Crit Rev Toxicol. 2014;44:467–98.CrossRefPubMedGoogle Scholar
  9. 9.
    Snijder CA, te Velde E, Roeleveld N, Burdorf A. Occupational exposure to chemical substances and time to pregnancy: a systematic review. Hum Reprod Update. 2012;18:284.CrossRefPubMedGoogle Scholar
  10. 10.
    Jenkins TG, Carrell DT. The sperm epigenome and potential implications for the developing embryo. Reproduction. 2012;143:727–34.CrossRefPubMedGoogle Scholar
  11. 11.
    Krawetz SA, Kruger A, Lalancette C, et al. A survey of small RNAs in human sperm. Human reproduction (Oxford, England). 2011;26:3401–12.CrossRefGoogle Scholar
  12. 12.
    Huang HB, Chen HY, Su PH, et al. Fetal and childhood exposure to phthalate diesters and cognitive function in children up to 12 years of age: Taiwanese Maternal and Infant Cohort Study. PLoS One. 2015;10:e0131910.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gapp K, Jawaid A, Sarkies P, et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci. 2014;17:667–9.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Grandjean V, Fourre S, De Abreu DA, Derieppe MA, Remy JJ, Rassoulzadegan M. RNA-mediated paternal heredity of diet-induced obesity and metabolic disorders. Sci Rep. 2015;5:18193.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    • Chen O, Yan W, Duan E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet. 2016. A review of the biological mechanisms that paternal exposures might be transmitted to offspring via sperm.Google Scholar
  16. 16.
    •• Rodgers AB, Morgan CP, Bronson SL, Revello S, Bale TL. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation. J Neurosci. 2013;33:9003–12. Animal study showing that paternal preconception stress exposure can induce epigenetic changes in father’s sperm and phenotypic changes in offspringCrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    •• Rodgers AB, Morgan CP, Leu NA, Bale TL. Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress. Proc Natl Acad Sci USA. 2015. Animal study showing that offspring phenotypic changes observed in response to paternal stress could be created by injecting sperm miRNAs from stressed fathers into zygotes created from control animals.Google Scholar
  18. 18.
    •• Dias BG, Ressler KJ. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nat Neurosci. 2014;17:89–96. This series of elegant experiments in animals showed that paternal fear of a specific scent could be transmitted to offspring via father’s spermCrossRefPubMedGoogle Scholar
  19. 19.
    Yehuda R, Bell A, Bierer LM, Schmeidler J. Maternal, not paternal, PTSD is related to increased risk for PTSD in offspring of Holocaust survivors. J Psychiatr Res. 2008;42:1104–11.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lehrner A, Bierer LM, Passarelli V, et al. Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. Psychoneuroendocrinology. 2014;40:213–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Bierer LM, Bader HN, Daskalakis NP, et al. Elevation of 11beta-hydroxysteroid dehydrogenase type 2 activity in Holocaust survivor offspring: evidence for an intergenerational effect of maternal trauma exposure. Psychoneuroendocrinology. 2014;48:1–10.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Yehuda R, Halligan SL, Bierer LM. Cortisol levels in adult offspring of Holocaust survivors: relation to PTSD symptom severity in the parent and child. Psychoneuroendocrinology. 2002;27:171–80.CrossRefPubMedGoogle Scholar
  23. 23.
    Yehuda R, Daskalakis NP, Lehrner A, et al. Influences of maternal and paternal PTSD on epigenetic regulation of the glucocorticoid receptor gene in Holocaust survivor offspring. Am J Psychiatry. 2014;171:872–80.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Yehuda R, Schmeidler J, Wainberg M, Binder-Brynes K, Duvdevani T. Vulnerability to posttraumatic stress disorder in adult offspring of Holocaust survivors. Am J Psychiatry. 1998;155:1163–71.CrossRefPubMedGoogle Scholar
  25. 25.
    Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA, Morris MJ. Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature. 2010;467:963–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Sharma U, Conine CC, Shea JM, et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science. 2015.Google Scholar
  27. 27.
    Fullston T, McPherson NO, Owens JA, Kang WX, Sandeman LY, Lane M. Paternal obesity induces metabolic and sperm disturbances in male offspring that are exacerbated by their exposure to an "obesogenic" diet. Physiological reports. 2015;3Google Scholar
  28. 28.
    Anderson LM, Riffle L, Wilson R, Travlos GS, Lubomirski MS, Alvord WG. Preconceptional fasting of fathers alters serum glucose in offspring of mice. Nutrition. 2006;22:327–31.CrossRefPubMedGoogle Scholar
  29. 29.
    Carone BR, Fauquier L, Habib N, et al. Paternally induced transgenerational environmental reprogramming of metabolic gene expression in mammals. Cell. 2010;143:1084–96.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sharma U, Conine CC, Shea JM, et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science (New York, NY). 2016;351:391–6.CrossRefGoogle Scholar
  31. 31.
    Wei Y, Yang CR, Wei YP, et al. Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals. Proc Natl Acad Sci U S A. 2014;111:1873–8.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kaati G, Bygren LO, Edvinsson S. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet. 2002;10:682–8.CrossRefPubMedGoogle Scholar
  33. 33.
    Pembrey ME, Bygren LO, Kaati G, et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet. 2006;14:159–66.CrossRefPubMedGoogle Scholar
  34. 34.
    Rocheleau CM, Romitti PA, Dennis LK. Pesticides and hypospadias: a meta-analysis. J Pediatr Urol. 2009;5:17–24.CrossRefPubMedGoogle Scholar
  35. 35.
    Chia SE, Shi LM. Review of recent epidemiological studies on paternal occupations and birth defects. Occup Environ Med. 2002;59:149–55.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Olshan AF, van Wijngaarden E. Paternal occupation and childhood cancer. Adv Exp Med Biol. 2003;518:147–61.CrossRefPubMedGoogle Scholar
  37. 37.
    Anderson D, Schmid TE, Baumgartner A. Male-mediated developmental toxicity. Asian J Androl. 2014;16:81–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Nassar N, Abeywardana P, Barker A, Bower C. Parental occupational exposure to potential endocrine disrupting chemicals and risk of hypospadias in infants. Occup Environ Med. 2010;67:585–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Morales-Suarez-Varela MM, Toft GV, Jensen MS, et al. Parental occupational exposure to endocrine disrupting chemicals and male genital malformations: a study in the Danish National Birth Cohort study. Environ Health. 2011;10:3.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Pierik FH, Burdorf A, Deddens JA, Juttmann RE, Weber RF. Maternal and paternal risk factors for cryptorchidism and hypospadias: a case-control study in newborn boys. Environ Health Perspect. 2004;112:1570–6.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Carran M, Shaw IC. New Zealand Malayan war veterans’ exposure to dibutylphthalate is associated with an increased incidence of cryptorchidism, hypospadias and breast cancer in their children. N Z Med J. 2012;125:52–63.PubMedGoogle Scholar
  42. 42.
    De Roos AJ, Olshan AF, Teschke K, et al. Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring. Am J Epidemiol. 2001;154:106–14.CrossRefPubMedGoogle Scholar
  43. 43.
    Feingold L, Savitz DA, John EM. Use of a job-exposure matrix to evaluate parental occupation and childhood cancer. Cancer Causes & Control: CCC. 1992;3:161–9.CrossRefPubMedGoogle Scholar
  44. 44.
    van Wijngaarden E, Stewart PA, Olshan AF, Savitz DA, Bunin GR. Parental occupational exposure to pesticides and childhood brain cancer. Am J Epidemiol. 2003;157:989–97.CrossRefPubMedGoogle Scholar
  45. 45.
    Carlos-Wallace FM, Zhang L, Smith MT, Rader G, Steinmaus C. Parental, in utero, and early-life exposure to benzene and the risk of childhood leukemia: a meta-analysis. Am J Epidemiol. 2016;183:1–14.CrossRefPubMedGoogle Scholar
  46. 46.
    Bailey HD, Fritschi L, Infante-Rivard C, et al. Parental occupational pesticide exposure and the risk of childhood leukemia in the offspring: findings from the childhood leukemia international consortium. Int J Cancer. 2014;135:2157–72.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Shah NR, Bracken MB. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet Gynecol. 2000;182:465–72.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Savitz DA, Whelan EA, Kleckner RC. Effect of parents’ occupational exposures on risk of stillbirth, preterm delivery, and small-for-gestational-age infants. Am J Epidemiol. 1989;129:1201–18.PubMedGoogle Scholar
  49. 49.
    Robledo CA, Yeung E, Mendola P, et al. Preconception maternal and paternal exposure to persistent organic pollutants and birth size: the LIFE Study. Environ health Perspect. 2014.Google Scholar
  50. 50.
    •• Buck Louis GM, Barr DB, Kannan K, Chen Z, Kim S, Sundaram R. Paternal exposures to environmental chemicals and time-to-pregnancy: overview of results from the LIFE Study. Andrology. 2016. A population-based prospective cohort of couples enrolled before conception with extensive collection of questionnaires, fertility/pregnancy outcomes, and biospecimens, including semen.Google Scholar
  51. 51.
    Smarr MM, Grantz KL, Sundaram R, Maisog JM, Kannan K, Louis GM. Parental urinary biomarkers of preconception exposure to bisphenol A and phthalates in relation to birth outcomes. Environ Health. 2015;14:73.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Graversen L, Sorensen TI, Gerds TA, et al. Prediction of adolescent and adult adiposity outcomes from early life anthropometrics. Obesity (Silver Spring, Md). 2015;23:162–9.CrossRefGoogle Scholar
  53. 53.
    Fourth national report on human exposure to environmental chemicals, updated tables. 2012. at http://www.cdc.gov/exposurereport/pdf/FourthReport_UpdatedTables_Feb2012.pdf.
  54. 54.
    Needham LL, Calafat AM, Barr DB. Assessing developmental toxicant exposures via biomonitoring. Basic & clinical pharmacology & toxicology. 2008;102:100–8.CrossRefGoogle Scholar
  55. 55.
    Smith KW, Braun JM, Williams PL, et al. Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy. Environ Health Perspect. 2012;120:1538–43.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Selevan SG, Stanford JB. Workshop recommendations for the preconception cohort of the National Children’s Study. Paediatr Perinat Epidemiol. 2006;20(Suppl 1):60–5.CrossRefPubMedGoogle Scholar
  57. 57.
    Stanford JB, Brenner R, Fetterer D, Palmer L, Schoendorf KC. Study USNCs. Impact of preconception enrollment on birth enrollment and timing of exposure assessment in the initial vanguard cohort of the U.S. National Children’s Study. BMC Med Res Methodol. 2015;15:75.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Buck GM, Lynch CD, Stanford JB, et al. Prospective pregnancy study designs for assessing reproductive and developmental toxicants. Environ Health Perspect. 2004;112:79–86.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Buck Louis GM, Schisterman EF, Sweeney AM, et al. Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development—the LIFE Study. Paediatr Perinat Epidemiol. 2011;25:413–24.CrossRefPubMedGoogle Scholar
  60. 60.
    •• Wise LA, Rothman KJ, Mikkelsen EM, et al. Design and conduct of an internet-based preconception cohort study in North America: pregnancy study online. Paediatr Perinat Epidemiol. 2015;29:360–71. A large epidemiological study using internet based enrollment and data collection to study preconception risk factors in couplesCrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    CDC. Fertility clinic success rate report: 2014. Atlanta, GA: Centers for Disease Control and Prevention; 2016.Google Scholar
  62. 62.
    •• Braun JM, Smith KW, Williams PL, et al. Variability of urinary phthalate metabolite and bisphenol A concentrations before and during pregnancy. Environ Health Perspect. 2012;120:739–45. A clinic-based prospective cohort of couples enrolled before conception with extensive collection of questionnaires, fertility/pregnancy outcomes, child healht outcomes, and biospecimens, including semenCrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    • Verner MA, Gaspar FW, Chevrier J, et al. Increasing sample size in prospective birth cohorts: back-extrapolating prenatal levels of persistent organic pollutants in newly enrolled children. Environmental science & technology. 2015;49:3940–8. An epidemiological study demonstrating that prenatal exposure to persistent pollutants can be accurately estimated using children’s levels measured up to 9 years laterCrossRefGoogle Scholar
  64. 64.
    Verner MA, Hart JE, Sagiv SK, Bellinger DC, Altshul LM, Korrick SA. Measured prenatal and estimated postnatal levels of polychlorinated biphenyls (PCBs) and ADHD-related behaviors in 8-year-old children. Environ Health Perspect. 2015;123:888–94.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Olshan AF, Perreault SD, Bradley L, et al. The healthy men study: design and recruitment considerations for environmental epidemiologic studies in male reproductive health. Fertil Steril. 2007;87:554–64.CrossRefPubMedGoogle Scholar
  66. 66.
    Bonde JP, Hjollund NH, Jensen TK, et al. A follow-up study of environmental and biologic determinants of fertility among 430 Danish first-pregnancy planners: design and methods. Reprod Toxicol. 1998;12:19–27.CrossRefPubMedGoogle Scholar
  67. 67.
    Curtin SC, Abma JC, Ventura SJ, Henshaw SK. Pregnancy rates for U.S. women continue to drop. NCHS data brief. 2013:1–8.Google Scholar
  68. 68.
    Mosher WD, Jones J, Abma JC. Intended and unintended births in the United States. National health statistics reports. 1982-2010;2012:1–28.Google Scholar
  69. 69.
    • Hatch EE, Hahn KA, Wise LA, et al. Evaluation of selection bias in an internet-based study of pregnancy planners. Epidemiology (Cambridge, Mass). 2016;27:98–104. This epidemiological analysis shows that selection bias does not greatly influence the results of well-established associations between perinatal risk factors and maternal/neonatal health in a Danish CohortCrossRefGoogle Scholar
  70. 70.
    Nohr EA, Frydenberg M, Henriksen TB, Olsen J. Does low participation in cohort studies induce bias? Epidemiology (Cambridge, Mass). 2006;17:413–8.CrossRefGoogle Scholar
  71. 71.
    Nilsen RM, Vollset SE, Gjessing HK, et al. Self-selection and bias in a large prospective pregnancy cohort in Norway. Paediatr Perinat Epidemiol. 2009;23:597–608.CrossRefPubMedGoogle Scholar
  72. 72.
    Liew Z, Olsen J, Cui X, Ritz B, Arah OA. Bias from conditioning on live birth in pregnancy cohorts: an illustration based on neurodevelopment in children after prenatal exposure to organic pollutants. Int J Epidemiol. 2015.Google Scholar
  73. 73.
    Werler MM, Parker SE. Bias from conditioning on live-births in pregnancy cohorts: an illustration based on neurodevelopment in children after prenatal exposure to organic pollutants (Liew et al. 2015). Int J Epidemiol. 2015;44:1079–80.CrossRefPubMedGoogle Scholar
  74. 74.
    Basso O. Implications of using a fetuses-at-risk approach when fetuses are not at risk. Paediatr Perinat Epidemiol. 2016;30:3–10.CrossRefPubMedGoogle Scholar
  75. 75.
    Rothman KJ. Six persistent research misconceptions. J Gen Intern Med. 2014;29:1060–4.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Doll R, Hill AB. The mortality of doctors in relation to their smoking habits; a preliminary report. Br Med J. 1954;1:1451–5.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Lu YH, Wang N, Jin F. Long-term follow-up of children conceived through assisted reproductive technology. J Zhejiang Univ Sci B. 2013;14:359–71.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Sandin S, Nygren KG, Iliadou A, Hultman CM, Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization. JAMA. 2013;310:75–84.CrossRefPubMedGoogle Scholar
  79. 79.
    Jodar M, Sendler E, Krawetz SA. The protein and transcript profiles of human semen. Cell Tissue Res. 2016;363:85–96.CrossRefPubMedGoogle Scholar
  80. 80.
    Wu H, Hauser R, Krawetz SA, Pilsner JR. Environmental susceptibility of the sperm epigenome during windows of male germ cell development. Curr Environ Health Rep. 2015;2:356–66.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Joseph M. Braun
    • 1
  • Carmen Messerlian
    • 2
  • Russ Hauser
    • 2
    • 3
  1. 1.Department of EpidemiologyBrown UniversityProvidenceUSA
  2. 2.Department of Environmental HealthHarvard TH Chan School of Public HealthBostonUSA
  3. 3.Department of EpidemiologyHarvard TH Chan School of Public HealthBostonUSA

Personalised recommendations