Teratogenesis and the epigenetic programming of congenital defects: Why paternal exposures matter

Abstract

Until recently, clinicians and researchers did not realize paternal exposures could impact child developmental outcomes. Indeed, although there is growing recognition that sperm carry a large amount of non‐genomic information and that paternal stressors influence the health of the next generation, toxicologists are only now beginning to explore the role paternal exposures have in dysgenesis and the incidence of congenital malformations. In this commentary, I will briefly summarize the few studies describing congenital malformations resulting from preconception paternal stressors, argue for the theoretical expansion of teratogenic perspectives into the male preconception period, and discuss some of the challenges in this newly emerging branch of toxicology. I argue that we must consider gametes the same as any other malleable precursor cell type and recognize that environmentally‐induced epigenetic changes acquired during the formation of the sperm and oocyte hold equal teratogenic potential as exposures during early development. Here, I propose the term epiteratogen to reference agents acting outside of pregnancy that, through epigenetic mechanisms, induce congenital malformations. Understanding the interactions between the environment, the essential epigenetic processes intrinsic to spermatogenesis, and their cumulative influences on embryo patterning is essential to addressing a significant blind spot in the field of developmental toxicology.

Association between Maternal Birth Weight and Prevalence of Congenital Malformations in Offspring: The Japanese Environment and Children’s Study

“…Transgenerational effects were reported in the Dutch famine study, where famine exposure in utero was associated with poor health in the later life of the participants’ grandchildren [ 10 ]. Epigenetic changes are thought to be involved in shaping the health trajectory of offspring including teratogenesis, especially via the alteration of germ cell epigenome [ 11 , 12 ]. Of particular interest is the link between maternal birth weight and the occurrence of congenital malformations in offspring, underscoring the importance of elucidating the epigenetic mechanisms underlying intergenerational health disparities.…”