HERITABLE, EPIGENETIC EFFECTS OF PATERNAL ALCOHOL USE ON FASD PHENOTYPES

About This Grant

Project Summary & Abstract PROJECT SUMMARY & ABSTRACT Despite evidence that poor paternal health increases the risk of pregnancy loss and that maternal alcohol use correlates with paternal drinking, all public health messaging addressing fetal alcohol spectrum disorders (FASDs) exclusively targets women. The Golding lab and other researchers examining paternal epigenetic effects propose that the exclusive emphasis on maternal health has created a significant blind spot in our efforts to understand the origins of FASDs and that paternal drinking is an entirely unexplored source of variation in alcohol-related birth defect penetrance and severity. Published preclinical studies from the Golding lab demonstrate that chronic preconception male alcohol exposures cause dose-dependent effects on offspring fetoplacental growth and craniofacial patterning. Emerging research reveals that these effects on offspring development arise as part of a heritable response to paternal oxidative stress, promoting the epigenetic inheritance of mitochondrial dysfunction. The offspring of alcohol-exposed fathers exhibit deficits in mitochondrial function, including alterations in mitochondrial structure, increased inflammatory cytokines, a reduced NAD+/NAHD ratio, and increased mitophagy, the removal of damaged mitochondria. Notably, these deficits interact with maternal alcohol exposures to exacerbate FASD outcomes and persist into adulthood. Individuals diagnosed with FASDs exhibit an increased incidence of age-related diseases and a reduced life expectancy. This proposal posits that some FASD adverse health outcomes are linked to paternal epigenetic effects on mitochondrial health. This proposal will test the hypothesis that paternal systemic mitochondrial stress induced by chronic alcohol exposure alters sperm-inherited noncoding RNAs, which provoke lasting epigenetic changes in offspring mitochondrial function and the emergence of FASD outcomes. The research outlined in this proposal will use transgenic mouse models to exacerbate and track the epigenetic transmission of mitochondrial dysfunction from parents to offspring, through fetal life and into adulthood. Published studies from the Golding lab demonstrate that chronic male alcohol use induces mitochondrial stress in the liver and epididymis – the portion of the male reproductive tract where sperm mature. This paternal mitochondrial stress correlates with the enrichment of sperm-inherited microRNAs, influencing the antioxidant response and mitochondrial function. This proposal will determine the function of these sperm-inherited noncoding RNAs and their relationship to the emergence of FASD phenotypes. Maternal education on the benefits of dietary folic acid intake and the dangers of drug use during pregnancy has helped significantly increase children's health. However, 50% of the information necessary to optimize the chances of achieving a healthy pregnancy may be missing because the father's lifestyle choices are not deemed important. The research outlined in this grant proposal will address this knowledge gap.