Epidemiologic studies demonstrate that alcohol is the most prevalent teratogen to which humans are exposed. In the US, it is estimated that at least one percent of children suffer from fetal alcohol spectrum disorder (FASD) or alcohol-related birth defects associated with Fetal Alcohol Syndrome (FAS). FAS is associated with facial abnormalities, cognitive impairment, behavioral problems, and decreased birth weight. Over the past 40 years, clinical studies have reported multiple instances where infants were born with characteristic FAS symptoms to mothers who had not consumed alcohol during pregnancy; but whose fathers were either heavy drinkers or chronic alcoholics. These studies indicate that the father's lifestyle may be an unrecognized element in the genesis of this disorder. Studies of a wide-range of environmental exposures have demonstrated that changes in the male-inherited epigenetic program profoundly influence offspring development and health. Given that 70% of men drink and 40% drink heavily, we hypothesize that errors in the male-inherited developmental program drive several key FAS-associated birth defects. We examined how chronic preconception male alcohol exposure impacts fetal growth and development. We employed a mouse model that allowed us to quantitatively track parental patterns of inheritance. B6(Cast7) males were chronically exposed 10% ethanol for a period of 70 days, and then mated with non-exposed C57BL/6J dams. Our studies identified a significant decrease in the weight of the gestational sac and fetus, as well as a decrease in crown rump length. While placental weights were identical between the treatment groups, we did identify a significant increase in the relative placental weight of offspring sired by alcohol exposed males. In addition, we found that many of the growth defects exhibited a female sex-specific patterns of inheritance with three parameters that were measured. Molecular analysis of multiple candidate imprinted genes identified alteration in the expression of H19, Cdkn1c, Dio3 and Mirg. Of these, Dio3 displayed a sex-specific effect, where treated females exhibited increased expression compared to control females as well as male offspring from treated males. Collectively, our studies suggest that chronic preconception male alcohol exposure is associated with fetal growth restriction, a well-characterized FAS-associated birth defect.
