title: Molecular pathways underpinning ethanol-induced neurodegeneration.
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.
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute - Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada.
authors: Dan
authors: D
authors: Goldowitz
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute - Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada.
authors: Alexandre A
authors: AA
authors: Lussier
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute - Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada.
authors: Julia K
authors: JK
authors: Boyle
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute - Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada.
authors: Kaelan
authors: K
authors: Wong
authors: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center Memphis, TN, USA.
authors: Scott L
authors: SL
authors: Lattimer
authors: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center Memphis, TN, USA.
authors: Candis
authors: C
authors: Dubose
authors: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center Memphis, TN, USA.
authors: Lu
authors: L
authors: Lu
authors: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute - Department of Medical Genetics, University of British Columbia Vancouver, BC, Canada ; Human Early Learning Partnership, School of Population and Public Health, University of British Columbia Vancouver, BC, Canada.
authors: Michael S
authors: MS
authors: Kobor
authors: Department of Anatomy and Neurobiology, University of Tennessee Health Science Center Memphis, TN, USA.
authors: Kristin M
authors: KM
authors: Hamre
keywords: QTL; apoptosis; cerebral cortex; chromosome modifications; hippocampus; histone marks