Paternal lineage effects of prenatal ethanol exposure: Offspring neuroanatomy and behavior in a multigenerational mouse model of FASD.

Abstract

BACKGROUND: Fetal alcohol spectrum disorders (FASD) encompass a range of phenotypes in offspring exposed to ethanol via maternal consumption during pregnancy. In a series of studies, our laboratory identified deleterious effects of prenatal ethanol exposure (PrEE) in our FASD mouse model. The first filial generation (F1) of PrEE offspring exhibited abnormal neocortical gene expression, ectopic intraneocortical connectivity, altered neuroanatomy, and disrupted behavior. Our results suggest that PrEE can induce transgenerational transmission of the abnormal phenotypes, potentially via epigenetic modifications. METHODS: Here, we investigated brain and behavioral development in the F1 (directly exposed), F2 (indirectly exposed), and F3 (non-exposed) generations of our PrEE model. Comparative analyses of body weight, brain weight, cortical length, thalamic nuclear areas, hippocampal structures, and corpus callosa were evaluated in control, F1, F2, and F3 newborn mice, with behavioral differences examined at wean age. RESULTS: All generations of PrEE newborns had decreased body weights, brain weights, and neocortical lengths compared with controls. Quantitative measures in F1, F2, and F3 newborn PrEE mice demonstrated altered neocortical thickness in F1 prelimbic, visual, and auditory cortices. Additionally, a transgenerational reduction was also observed in the auditory cortex in F3 mice when compared to controls. When compared to controls, all generations of PrEE mice demonstrated significant reductions in hippocampal CA3 thickness. While no control cases demonstrated corpus callosal agenesis, a majority of F1 cases did, as well as a lower but present percentage of F2 and F3 cases. Finally, we found that disrupted sensorimotor integration, motor control, and anxiety-like behavior persisted to at least the F2 generation. CONCLUSIONS: Our data suggest that PrEE can result in abnormal brain and behavioral development with heritable effects that persist transgenerationally.