Paternal exposure alone induces alcohol-related birth defects in a mouse model: Implications of paternal drinking in FAS birth defects.

Prevailing dogma maintains that Fetal Alcohol Syndrome (FAS) craniofacial and neurological birth defects are the sole consequence of maternal alcohol use during pregnancy. Using a physiologically relevant mouse model, we contrasted the incidence of alcohol-related growth and craniofacial defects between offspring derived from maternal, paternal, and dual parental alcohol exposures. Geometric morphometric analyses reveal that maternal, paternal, and dual parental exposures each induce unique craniofacial malformations and program dose-dependent increases in microcephaly, particularly in male offspring. Notably, dual parental exposures do not exhibit additive or synergistic effects; instead, our transcriptomic analyses demonstrate that each treatment programs distinct sex-specific changes in gene expression within the developing brain. Our data are the first to demonstrate that male drinking is a plausible driver of alcohol- related birth defects and that epidemiological examination of male alcohol consumption may help explain the enormous variation in FAS clinical presentations and severity.