Paternal medication dispensation around conception: A call to answer many unanswered questions

In this issue of Paediatric and Perinatal Epidemiology, McEwan and colleagues1 provide descriptive data on the most commonly used prescription medications by the father during the 90 days before conception as revealed by pharmacy dispensation claims from families in the MarketScan research database of commercially insured individuals in the United States (2011–2020). They report that prescription medication use is not uncommon during this period and that fathers were filling prescriptions that are known to be embryotoxic when taken by the pregnant person. These data make us consider the relevance of paternal exposures to prescription medications, and question what is and is not known about the role of paternal preconception exposures in fetal, infant and child development. While it has long been known that environmental exposures can induce mutations in sperm DNA, there is growing evidence that such exposures can also be encoded in the male germline without altering genetic information. This occurs through three main epigenetic mechanisms: DNA methylation, histone modifications and noncoding RNAs (e.g., microRNAs).2 Evidence from animal models and limited human studies demonstrate that through epigenetic alterations to sperm, paternal preconception exposures may affect offspring health and development.2 The evidence from animals and humans seems most well-developed concerning paternal stress, diet, and chemical and substance use exposures. Evidence from both animal models and humans indicates that high levels of stress before conception are associated with epigenetic alterations. A rat model of paternal preconceptual stress demonstrated altered brain structure and behaviour in offspring linked to extensive epigenetic changes.3 In mice, exposure to chronic stress before breeding resulted in altered noncoding microRNA profiles in sperm and hypothalamic–pituitary–adrenal stress axis dysregulation in offspring, a common underlying feature of neuropsychiatric disorders.4 Human studies involving Holocaust survivors have demonstrated how paternal traumatic stress can produce lasting effects through the paternal germline, including an increased prevalence of neuropsychiatric disorders and reduced cortisol levels and glucocorticoid receptor sensitivity in offspring whose fathers were holocaust survivors.5 Paternal diet at conception has also been established to impact offspring development via epigenetic changes. Mouse models of paternal low-protein and high-fat or high-sugar diets induced sperm DNA hypomethylation and altered sperm microRNA and transfer RNA profiles, respectively.6 Human epidemiological studies using historical food supply records from Sweden have shown intergenerational and transgenerational effects of famine transferred through male epigenetic factors, reporting that limited dietary resources during a father's or grandfather's pre-adolescence were associated with a reduced risk of cardiovascular and diabetes mortality in children.7 Paternal preconceptual exposures to endocrine-disrupting compounds, nicotine, alcohol and obesity have also been consistently linked to sperm epigenetic aberrations. For example, the offspring of nicotine-exposed male mice developed hyperactivity, attention deficits and cognitive inflexibility, with some of these behaviours persisting into the third generation.8 Together, animal and human research demonstrate that paternal preconception environmental exposures can be transmitted to offspring. By deepening our understanding of the role of sperm epigenetics, we may identify modifiable risk factors affecting offspring health and development. While it is tempting to take these examples as evidence of epigenetic alterations in sperm resulting in developmental impacts, there are, of course, other potential pathways related to the father that could explain these increased risks in offspring, including shared genetics and, in many cases, the shared environment between the child and the father during infancy and childhood. Our historical belief that sperm functioned essentially as a delivery vehicle for paternal DNA has also been proven incomplete. In spermiogenesis, histones are largely replaced by the more compact protamines (small basic proteins), enabling the DNA to become highly compact to fit into the head of the sperm. Previously, it was believed that almost all paternal histones were replaced by protamines in spermiogenesis and then replaced by maternal histones at fertilisation. More recently, however, research identified that approximately 4% of paternal histones are retained in spermiogenesis and transmitted along with the DNA.9 Not only that but the locations of the histones that were retained were found to be in areas of the genome containing genes that play critical roles in embryonic development.9 This landmark discovery inspired researchers to question some of their assumptions about paternal contributions to fetal development and is an increasingly studied area with calls to understand the role of sperm chromatin better. While we are focussing on better understanding the role of paternal exposures, let us also generate further evidence of a viable biological mechanism through which medication exposures in the 90 days before conception may result in alterations to fetal development. While it is theoretically possible that the use of medications by males could cause epigenetic changes in the developing sperm that are then transmitted to the developing embryo and that these epigenetic changes could harm the developing embryo, more data are needed on several fronts. First, more biological data for specific medications causing epigenetic changes in sperm would be of value. It will be essential to verify that relationships between specific medication exposures reported in other animals are likely to also occur in humans, given significant differences in epigenomic reprogramming in embryo development of humans compared with other animal models. Second, we need to understand better whether epigenetic changes in sperm caused by medication use are transmitted to the developing embryo. While the discovery by Hammoud et al. provides valuable data in support of this, it remains unclear whether these changes are transmitted only in the first days and weeks of embryogenesis and then replaced by histones of maternal origin, for example, or whether global reprogramming of DNA methylation across the embryo occurs before implantation.10 This connects to the final link in the chain of causality—we need a better understanding of whether epigenetic changes in developing sperm caused by paternal medication use are transmitted to the embryo and result in harm to that embryo. Huge gaps remain in our understanding of the embryonic epigenome. We do not yet know whether any epigenetic changes preconceptionally (by acetylation, e.g. in the case of paternal exposure to valproic acid) would influence the developing embryo beyond establishing initial viability. In the case of valproic acid, preliminary evidence from a Swedish population-based cohort study (n = 1,144,795) suggests this is not the case.11 Thus, we applaud McEwen and colleagues for providing these critical descriptive data, which can serve as a clear guide for future work in this area. We also caution readers that there is no clear evidence that male use of medications around the time of conception impacts fetal development. Importantly, psychotropics were the most commonly dispensed class of medications that McEwan et al. reported, and we know how challenging decision-making around psychotropic medication use is for pregnant people and their clinicians. We certainly do not want to extend these challenges to men trying to conceive without significant evidence of risk. We wholeheartedly agree with McEwen et al. that further research on prescription medication use around the time of conception is needed. The extremely dynamic nature of the embryonic epigenome presents a challenge to characterisation and understanding; its potent allure, however, is the possibility for change and a deepened understanding of the aetiology of complex developmental conditions. Let us all continue the science, but in the meantime, men should continue using their needed medications even when trying to conceive. CH, AN, and GH conceptualized, drafted, and critically reviewed and revised this commentary. Catriona Hippman is a postdoctoral fellow at the BC Women‘s Reproductive Mental Health Program and the UBC Department of Obstetrics and Gynaecology, and is a certified genetic counsellor. After specialising in psychiatric genetic counselling, she has focussed on reproductive mental health, including studies exploring perinatal use of psychotropic medications, and the use of population-based administrative datasets to investigate health service delivery related to reproductive mental health. Amanda S. Nitschke is a doctoral (PhD) student at the University of British Columbia, studying perinatal pharmacoepidemiology. She has worked with population-based administrative datasets to investigate the perinatal use of antibiotics, antidepressants, and more recently, ADHD stimulant medications. Gillian E. Hanley is an associate professor in Obstetrics and Gynaecology and Tier 2 Canada Research Chair in population-based gynaecologic and perinatal outcomes. She works in perinatal pharmacoepidemiology, with a specific focus on perinatal use of psychotropic medications and reproductive mental health. None. The authors report no conflicts of interest. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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