UC Riverside

Fetal Alcohol Spectrum Disorders (FASD) represent a wide range of

developmental conditions caused by in utero ethanol exposure. Today, FASD affects nearly 1% of the total population, a number likely to be underestimated. Cognitive, perceptual and behavioral deficits following prenatal ethanol exposure arise from underlying neurobiological damage in developing brain structures, including the neocortex, which is involved in higher level cognitive and behavioral function. Current research indicates that alcohol-mediated alterations to epigenetic function could underlie some aspects of FASD, and that these changes may be heritable (Govorko et al., 2012; Bekdash et al., 2013). To determine the impact of prenatal ethanol exposure (PrEE) on functional organization of the neocortex, we first generated an FASD mouse model in CD-1 mice. Preliminary work with this model demonstrated a correlation between gross anatomical changes, and altered gene expression patterns of RZRβ, Cad8 and Id2 at birth along with extensive disruption in neocortical targeting within the neocortex of PrEE offspring (El Shawa et al., 2013; Abbott et al., in review). We extend these findings transgenerationally, identifying numerous stable modifications transmitted via the male germline to unexposed offspring including significant upregulation of RZRβ and Id2, as well as downregulated ephrin A5 expression in cortex. Associated with this change was a significant decrease in global DNA methylation levels in cortex. Absolute methylation levels of CpG islands in promoter regions of RZRβ and Id2 revealed significant hypomethylation in PrEE mice and their offspring. These assays established a strong inverse correlation between gene expression and DNA hypomethylation. Expression of DNMTs 1, 3A and 3B was suppressed in PrEE cortex, providing further insight into possible points at which ethanol perturbs DNA methylation, ultimately resulting in altered gene transcription. The anatomical and behavioral phenotype described in the first generation PrEE mice were also observed in the subsequent generations. These alterations in brain development could be responsible for cognitive, sensorimotor and behavioral deficits seen in our model and children with FASD and may generate phenotypes in the offspring of exposed humans. Thus, understanding the epigenetic means by which this phenotype is generated may reveal novel targets for therapeutic intervention of FASD.