Paternal epigenetic influences on placental health and their impacts on offspring development and disease

Abstract

Our efforts to understand the developmental origins of birth defects and disease have primarily focused on maternal exposures and intrauterine stressors. Recently, research into non-genomic mechanisms of inheritance has led to the recognition that epigenetic factors carried in sperm also significantly impact the health of future generations. However, although researchers have described a range of potential epigenetic signals transmitted through sperm, we have yet to obtain a mechanistic understanding of how these paternally-inherited factors influence offspring development and modify life-long health. In this endeavor, the emerging influence of the paternal epigenetic program on placental development, patterning, and function may help explain how a diverse range of male exposures induce comparable intergenerational effects on offspring health. During pregnancy, the placenta serves as the dynamic interface between mother and fetus, regulating nutrient, oxygen, and waste exchange and coordinating fetal growth and maturation. Studies examining intrauterine maternal stressors routinely describe alterations in placental growth, histological organization, and glycogen content, which correlate with well-described influences on infant health and adult onset of disease. Significantly, the emergence of similar phenotypes in models examining preconception male exposures indicates that paternal stressors transmit an epigenetic memory to their offspring that also negatively impacts placental function. Like maternal models, paternally programmed placental dysfunction exerts life-long consequences on offspring health, particularly metabolic function. Here, focusing primarily on rodent models, we review the literature and discuss the influences of preconception male health and exposure history on placental growth and patterning. We emphasize the emergence of common placental phenotypes shared between models examining preconception male and intrauterine stressors but note that the direction of change frequently differs between maternal and paternal exposures. We posit that alterations in placental growth, histological organization, and glycogen content broadly serve as reliable markers of altered paternal developmental programming, predicting the emergence of structural and metabolic defects in the offspring. Finally, we suggest the existence of an unrecognized developmental axis between the male germline and the extraembryonic lineages that may have evolved to enhance fetal adaptation.

The application of epiphenotyping approaches to DNA methylation array studies of the human placenta

“…First, ethnicity is a social concept that can be related to but is fundamentally different from genetic ancestry. Further, if only maternal ethnicity is collected, it ignores the other parent’s contribution to the placental genome and epigenome [ 37 ]. In addition, genetic ancestry is interesting to study in its own right, as it may independently drive DNAme variation and/or confound other associations.…”

Prenatal paternal anxiety symptoms predict child DHEA levels and internalizing symptoms during adrenarche

“…As such, one preconception pathway may occur via paternal gene expression which drives placental development, the maternal-fetal interface which is necessary for fetal growth and survival ( Crespi, 2020 ; Dini et al, 2021 ). The field of genomic imprinting has revealed that sperm predominantly controls the growth and differentiation of extraembryonic tissues such as the placenta and yolk sac ( Bhadsavle and Golding, 2022 ). Studies have consistently shown that preconception paternal exposures such as age ( Denomme et al, 2020 ), obesity ( Mitchell et al, 2017 ; Jazwiec et al, 2022 ), toxicants ( Ding et al, 2018 ), cannabis ( Innocenzi et al, 2019 ) and alcohol ( De Cock et al, 2017 ; Thomas et al, 2022 ) result in sex-specific alterations of placental imprinted gene expression, as well as reduced placental weights and disruptions in placental histology.…”

Metabolic memory: mechanisms and diseases

“… 37 High-fat diet during early paternal years induces permanent alterations in testicular lipid content and leads to irreversible sperm quality damage, which can persist for up to two generations. 38 , 407 …”