The Impact of Paternal Alcohol Consumption on Offspring Brain and Behavioral Development

Background Fetal alcohol spectrum disorders (FASD) describe the wide array of long‐lasting developmental abnormalities in offspring due to prenatal alcohol (ethanol [EtOH]) exposure via maternal gestational drinking. Although the teratogenic consequences of prenatal EtOH exposure, are apparent, the effects of preconception paternal EtOH exposure (PatEE) are still unclear. Previous research suggests that PatEE can induce molecular changes and abnormal behavior in the offspring. However, it is not known whether PatEE impacts the development of the neocortex and behavior in offspring as demonstrated in maternal consumption models of FASD (J Neurosci, 33, 2013, 18893). Methods In this study, we utilized a novel mouse model of PatEE where male mice self‐administered 25% EtOH for an extended period prior to conception, generating indirect exposure to the offspring through the paternal germline. Following mating, we examined the effects of PatEE on offspring neocortical development at postnatal day (P) 0 and evaluated several aspects of behavior at both P20 and P30 using a battery of behavioral assays. Results PatEE resulted in significant impact on neocortical development, including abnormal patterns of gene expression within the neocortex at P0 and subtle alterations in patterns of intraneocortical connections. Additionally, PatEE mice exhibited a sex‐specific increase in activity and sensorimotor integration deficits at P20, and decreased balance, coordination, and short‐term motor learning at P30. This suggests that PatEE may generate long‐lasting, sex‐specific effects on offspring behavior. Conclusions These results demonstrate that the developmental impact of preconception PatEE is more harmful than previously thought and provide additional insights into the biological mechanisms that may underlie atypical behavior observed in children of alcoholic fathers. Using a diverse combination of methodology, Conner et al., provide evidence for the potentially detrimental consequences of paternal ethanol exposure (PatEE) for offspring in a mouse model. In this study, approximately 2 to 3 weeks of PatEE prior to conception generated significant sex‐specific deficits in offspring behavior. Analysis of neocortical gene expression and intra‐neocortical connectivity revealed subtle deficits in the patterning of newborn neocortex, which may underlie the PatEE‐induced maladaptive behavioral phenotypes seen later in life.