Sex Differences in Fetal Neural Stem Cells’ Response to Ethanol

Abstract

Fetal Alcohol Spectrum Disorders (FASDs) can result from prenatal exposure to alcohol. Alcohol is a known teratogen and in utero exposure is the leading non-genetic cause of neurodevelopmental disabilities. Neural stem cells (NSCs) generate a majority of neurons in the adult brain during the mid-first to second trimester of gestation, a time at which pregnancy may not yet be recognized, resulting in a window of vulnerability for alcohol exposure. Our previous data shows that ethanol induces loss of stem cell capacity in NSCs but does not induce cell death. One cellular mechanism through which ethanol exerts its effects on NSCs is through actions on miR-9, a critical regulator of NSC differentiation. Ethanol exposure increases methylation at the miR-9 locus and subsequently reduces its expression in NSCs. Interestingly, previous studies have shown genetic sex-specific cellular behaviors within endogenous stem cells. Our study is the first to investigate sex-differences in the NSC response to ethanol. Using an ex vivo neurosphere culture of NSCs derived from mouse gestational day 12.5 fetal dorsal neuroepithelium, we assessed the effects of ethanol on neurosphere formation, cell cycle kinetics, as well as on NSC maturation in sex segregated cultures. Our data indicates that there is a sexually dimorphic response to ethanol in terms of its effects on neurosphere formation, cell cycle kinetics, and NSC maturation. Further studies characterizing these sex differences in the NSC response to ethanol will help elucidate the pathophysiology of FASD.