Epigenetic Toxicity: Preconception Paternal Alcohol Exposure and the Programming of Offspring Birth Defects

Abstract

Paternally inherited alterations in epigenetic programming are emerging as a relevant factor in numerous developmental disorders. Despite the exclusive association of fetal alcohol spectrum disorders (FASDs) with maternal drinking, research from our lab indicates that paternal alcohol use is a relevant factor in this debilitating condition. Using an established mouse model, our group has linked preconception paternal alcohol use to sex-specific patterns of both fetal and postnatal growth restriction, as well as long-term metabolic defects in the next generation. These phenotypic changes associate with altered placentation and programmed changes in gene expression that arise during fetal gestation and persist into adulthood. In addition to growth restriction, FASD patients exhibit distinctive craniofacial malformations and central nervous system defects. Although primarily examined in the context of early-life exposures, research now suggests that altered epigenetic programming may drive the emergence of several FASD phenotypes. Accordingly, we hypothesized that within the offspring of ethanol-exposed males, inherited epigenetic changes may negatively influence the transcriptional programs regulating the structural organization and developmental patterning of the face. Using a C57BL/6J mouse model of chronic paternal alcohol exposure, we find that preconception paternal ethanol exposure is associated with reductions in ocular diameter and abnormalities in the patterning of the eye. These defects associate with differential expression of crucial homeobox genes driving craniofacial development, including Msh Homeobox 1 and Msh Homeobox 2 (Msx1 and Msx2) as well as the transcriptional regulators Bone Morphogenic Protein 4 (BMP4) and Twist Family BHLH Transcription Factor 1 (Twist1). Preliminary data indicate that alterations in craniofacial patterning correlate with long-term suppression of the genetic pathways controlling oxidative phosphorylation and the oxidative stress response. These persistent epigenetic changes transmit to the offspring via paternally-inherited changes in histone post-translational modifications and the non-coding RNA profile of sperm. In this talk, I will describe our ongoing efforts to identify the epigenetic mechanisms by which paternally-inherited phenotypes transmit to the offspring and how these alterations in paternal programming influence fetal development. Our observations challenge the prevailing paradigm that alcohol-related congenital disabilities are exclusively attributable to maternal alcohol consumption and reveal paternal life history is relevant to FASD developmental defects.