A Father’s Day question: Why do fathers (epigenetically) treat their sons and daughters differently?
The frustrations and musings of an alcohol researcher working in the field of paternal epigenetic programming.
A Birth Defects Insights Blog by Michael Golding, PhD
Sociological research indicates that in the United States, parents desire families with a child of each gender. However, fathers spend more time with their sons than daughters and are more likely to support male offspring in reaching their academic and professional goals (1). Therefore, consciously or not, males preferentially invest more resources in their sons.
Our efforts to understand the developmental origins of birth defects and disease have recently expanded to include paternal exposures before conception, which emerging clinical and animal model research can link to a range of physiologic and behavioral changes in the next generation. Interestingly, here as well, alterations in the paternal epigenetic program appear to preferentially impact the male offspring, albeit with predominantly negative outcomes. For the past six years, my research group has focused on examining the impact of paternal alcohol exposures on offspring health and development (2–7). Through these studies, we have consistently identified adverse outcomes in placental development and long-term health measures in male offspring but less so in females. Others observe similar results in studies examining different drugs of abuse, including cocaine and cannabis (8–10). The transmission of a paternal memory that only affects male progeny, while interesting, is vexing and highlights the complexity of mammalian mechanisms of epigenetic inheritance.
Investigation into the impacts of preconception paternal alcohol exposures on offspring health was a challenging field to enter. After all, the cause of Fetal Alcohol Spectrum Disorders (FASDs) is defined by the warning label on the bottle. Furthermore, across the CDC, the NIH, and all levels of society, the perception that FASDs are the consequence of maternal drinking is thoroughly entrenched. The challenge of questioning this existing maternal-centric paradigm lies not in devising an elegant experimental design but in attempting to overhaul the maternal-centric view of study section. Yes, I understand maternal alcohol exposures are relevant to FASDs. Yes, I know that most men are unaware of non-genetic mechanisms of inheritance or their part in embryonic programming, and realistically, male alcohol use will not decrease. In fairness, messaging from the CDC and NIH-NIAAA cannot broadly achieve this in women either. Nevertheless! Although half of all pregnancies are unplanned, many male partners are heavily engaged in family planning — especially couples struggling with fertility. Importantly, we strongly suspect male alcohol use negatively impacts in vitro fertilization pregnancy rates. Further, our published data support not only an immediate effect of alcohol on sperm but also short-term effects on embryo growth and longer-term impacts on the metabolic health of the adult offspring (2–7). Therefore, determining the impact of paternal alcohol use on offspring growth and development is essential to defining the breadth of factors influencing FASD outcomes and potentially explaining the wide variation observed in the penetrance and variation of this disorder.
Part of the hesitation to adequately consider a male contribution to FASDs lies in two core misconceptions: that toxicological outcomes are an acute response (not programmed) and that sperm only transmit DNA. First, our research demonstrates that paternal alcohol exposures induce placental abnormalities and fetal growth restriction in the offspring (2, 3, 6, 7). As none of the dams ever see a drop of alcohol, the induced outcomes we observe do not follow a classic acute toxicological paradigm. Instead, they demonstrate that some aspects of teratogenesis are programmed and exert their effects in a subsequent life stage. Second, during the late 1980s, McGrath and Solter demonstrated that the sperm and egg contain information beyond the genetic code and make unequal contributions to the developing offspring (11). Specifically, their experiments revealed that information in sperm drives the development and differentiation of the placenta, and from this work, the field of genomic imprinting was born. Today, we know that sperm carry an expansive suite of epigenetic information, including DNA methylation, posttranslational histone modifications, and noncoding RNAs. Moving forward, we must recognize that toxicological outcomes do not need to entail cell death or other acute measures but can arise from changes in epigenetic programming that impact physiology during a subsequent life stage. Further, we must consider gametes the same as any other precursor cell type and recognize that epimutations acquired during the formation of sperm are likely to have just as much of an impact on the developmental program as exposures during preimplantation development.
However, although we can identify alcohol-induced changes in sperm-inherited epigenetic marks, we do not understand why these modifications predominantly impact the male offspring. Are females simply more adaptable than males? If so, sperm-inherited epigenetic memories may represent a transient stressor to which males and females respond differently. If this is the case, is everything else we observe a symptom of this early stressor? Perhaps the answer to my question is that females adapt to the abnormalities in the paternally inherited program and avoid the observed symptoms. Indeed, there is growing evidence that differences between male and female placentation confer different growth rates during different phases of pregnancy, which could influence sexually dimorphic disease outcomes (12). Previous studies have identified significant epigenetic differences between the male and female liver that confer differing abilities to metabolize drugs and predispositions to cancer (13, 14). However, we do not know if similar differences exist in the early embryo or placenta. To understand the basis of programmed sex differences, we need to carefully examine the epigenetic landscape of male and female embryos, especially the extraembryonic tissues, to determine the developmental basis of the different growth phenotypes. Doing so will shed light on the black box that exists between a range of male exposures and the sexually dimorphic outcomes we observe.
Working in this area of research and questioning the established dogma is fun, although, at times, it can be challenging. Nevertheless, our work is important and contributes evidence that we hope, one day, redresses the stigma that FASDs are exclusively of maternal origin. As Father’s Day approaches, the weather warms up, and we now reclaim our freedom from Covid, I will (consciously) spend more time with my daughter and contemplate the possibility that her physician may, instead of exclusively focusing on her, ask both her and her partner how much they drink.
More About The Society For Birth Defects Research And Prevention (BDRP)
To understand and prevent birth defects and disorders of developmental and reproductive origin, BDRP promotes multi-disciplinary research and exchange of ideas; communicates information to health professionals, decision-makers, and the public; and provides education and training.
Scientists interested in or already involved in research related to topics mentioned in this blog are encouraged to join BDRP and attend the 62nd Annual Meeting June 25–29, 2022. BDRP is the premier source for cutting-edge research and authoritative information related to birth defects and developmentally mediated disorders. Our members include those specializing in cell and molecular biology, developmental biology and toxicology, reproduction and endocrinology, epidemiology, nutritional biochemistry, and genetics, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counselling. In addition, BDRP publishes the scientific journal, Birth Defects Research. Learn more at http://www.birthdefectsresearch.org. Find BDRP on LinkedIn, Facebook, Twitter and YouTube.
References
1. Raley S, Bianchi S. Sons, daughters, and family processes: Does gender of children matter? Annu Rev Sociol 32: 401–421, 2006.
2. Bedi Y, Chang RC, Gibbs R, Clement TM, Golding MC. Alterations in sperm-inherited noncoding RNAs associate with late-term fetal growth restriction induced by preconception paternal alcohol use. Reproductive Toxicology 87: 11–20, 2019. doi: 10.1016/j.reprotox.2019.04.006.
3. Chang RC, Skiles WM, Chronister SS, Wang H, Sutton GI, Bedi YS, Snyder M, Long CR, Golding MC. DNA methylation-independent growth restriction and altered developmental programming in a mouse model of preconception male alcohol exposure. Epigenetics 12, 2017. doi: 10.1080/15592294.2017.1363952.
4. Chang RC, Wang H, Bedi Y, Golding MC. Preconception paternal alcohol exposure exerts sex-specific effects on offspring growth and long-term metabolic programming. Epigenetics and Chromatin 12, 2019. doi: 10.1186/s13072–019–0254–0.
5. Chang RC, Thomas KN, Bedi YS, Golding MC. Programmed increases in LXRα induced by paternal alcohol use enhance offspring metabolic adaptation to high-fat diet induced obesity. Molecular Metabolism 30: 161–172, 2019. doi: 10.1016/j.molmet.2019.09.016.
6. Mustapha TA, Chang RC, Garcia-Rhodes D, Pendleton D, Johnson NM, Golding MC. Gestational exposure to particulate air pollution exacerbates the growth phenotypes induced by preconception paternal alcohol use: a multiplex model of exposure. Environ Epigenet 6: dvaa011, 2020. doi: 10.1093/eep/dvaa011.
7. Thomas KN, Zimmel KN, Roach AN, Basel A, Mehta NA, Bedi YS, Golding MC. Maternal background alters the penetrance of growth phenotypes and sex-specific placental adaptation of offspring sired by alcohol-exposed males. FASEB J 35: e22035, 2021. doi: 10.1096/fj.202101131R.
8. Vassoler FM, White SL, Schmidt HD, Sadri-Vakili G, Pierce RC. Epigenetic inheritance of a cocaine-resistance phenotype. Nat Neurosci 16: 42–47, 2013. doi: 10.1038/nn.3280.
9. Schrott R, Murphy SK. Cannabis use and the sperm epigenome: a budding concern? Environ Epigenet 6: dvaa002, 2020. doi: 10.1093/eep/dvaa002.
10. Wimmer ME, Briand LA, Fant B, Guercio LA, Arreola AC, Schmidt HD, Sidoli S, Han Y, Garcia BA, Pierce RC. Paternal cocaine taking elicits epigenetic remodeling and memory deficits in male progeny. Mol Psychiatry 22: 1641–1650, 2017. doi: 10.1038/mp.2017.8.
11. McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37: 179–183, 1984.
12. Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJP. Boys live dangerously in the womb. Am J Hum Biol 22: 330–335, 2010. doi: 10.1002/ajhb.20995.
13. Rinn JL, Rozowsky JS, Laurenzi IJ, Petersen PH, Zou K, Zhong W, Gerstein M, Snyder M. Major molecular differences between mammalian sexes are involved in drug metabolism and renal function. Dev Cell 6: 791–800, 2004. doi: 10.1016/j.devcel.2004.05.005.
14. Waxman DJ, Holloway MG. Sex differences in the expression of hepatic drug metabolizing enzymes. Mol Pharmacol 76: 215–228, 2009. doi: 10.1124/mol.109.056705.
