19 Paternal drinking and the epigenetic influences on mitochondrial function, placental dysfunction, and structural birth defects

Abstract Emerging research reveals that epigenetic mechanisms of paternal inheritance are a significant driver of adverse developmental outcomes, including those associated with fetal alcohol spectrum disorders (FASD). In recognition of the urgent need to understand the combined effects of maternal and paternal alcohol consumption, our laboratory established a preclinical multiplex mouse model to compare alcohol-induced developmental defects in offspring resulting from maternal, paternal, and dual parental exposures. Our findings reveal that both maternal and paternal alcohol consumption independently impair placental development and alter craniofacial patterning in a dose-dependent manner. Strikingly, in the male offspring, we observed an interaction between maternal and paternal alcohol use, with adverse developmental outcomes in the dual-parental offspring exceeding those induced by either maternal or paternal alcohol use alone. Our ongoing experiments reveal that parental alcohol exposure heritably disrupts offspring mitochondrial complex I activity in the placenta and fetal brain. These deficits persist into adulthood, resulting in elevated oxidative stress, chronic inflammation, and premature cellular aging in the brain and liver. Our results underscore that chronic toxicant-induced mitochondrial stress, ­particularly in males, programs enduring bioenergetic dysfunction that elevates the risk of birth defects and long-term disease. These findings emphasize the critical importance of considering both maternal and paternal health in preconception planning.