Abstract
While genetics impacts the type and severity of damage following developmental ethanol exposure, little is currently known about the molecular pathways that mediate these effects. Traditionally, research in this area has used a candidate gene approach and evaluated effects on a gene-by-gene basis. Recent studies, however, have begun to use unbiased approaches and genetic reference populations to evaluate the roles of genotype and epigenetic modifications in phenotypic changes following developmental ethanol exposure, similar to studies that evaluated numerous alcohol-related phenotypes in adults. Here, we present work assessing the role of genetics and chromatin-based alterations in mediating ethanol-induced apoptosis in the developing nervous system. Utilizing the expanded family of BXD recombinant inbred mice, animals were exposed to ethanol at postnatal day 7 via subcutaneous injection (5.0 g/kg in 2 doses). Tissue was collected 7 h after the initial ethanol treatment and analyzed by activated caspase-3 immunostaining to visualize dying cells in the cerebral cortex and hippocampus. In parallel, the levels of two histone modifications relevant to apoptosis, γH2AX and H3K14 acetylation, were examined in the cerebral cortex using protein blot analysis. Activated caspase-3 staining identified marked differences in cell death across brain regions between different mouse strains. Genetic analysis of ethanol susceptibility in the hippocampus led to the identification of a quantitative trait locus on chromosome 12, which mediates, at least in part, strain-specific differential vulnerability to ethanol-induced apoptosis. Furthermore, analysis of chromatin modifications in the cerebral cortex revealed a global increase in γH2AX levels following ethanol exposure, but did not show any change in H3K14 acetylation levels. Together, these findings provide new insights into the molecular mechanisms and genetic contributions underlying ethanol-induced neurodegeneration.
Highlights
Alcohol exposure during development induces a number of lasting physiological changes that result in a host of abnormalities in brain function
GENETIC BACKGROUND ALTERED LEVELS OF ETHANOL-INDUCED CELL DEATH In spite of the similarity observed between by crossing the C57BL/6J (B6) and D2 progenitor strains, considerable differences in susceptibility to apoptosis were observed between various BXD recombinant inbred strains following ethanol treatment at postnatal day 7 (P7)
In the present study, lines of recombinant inbred mice were examined to determine if genetic variation influences the extent and localization of ethanol-induced cell death in the developing cerebral cortex and hippocampus at P7
Summary
Alcohol exposure during development induces a number of lasting physiological changes that result in a host of abnormalities in brain function. The central nervous system (CNS) is especially susceptible to developmental defects following alcohol exposure, with ethanol causing aberrant mitosis and cell migration, as well as alterations in neuronal process outgrowth and connectivity (as reviewed in Sulik et al, 1988; Kumada et al, 2007; Sadrian et al, 2013). Ethanol was administered to mice postnatally during the time of the brain growth spurt (Dobbing, 1974). The equivalent stage of brain growth in humans begins during www.frontiersin.org the third trimester and continues the first 1–2 years after birth (Dobbing and Sands, 1979)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
