Effects of Genetics and Sex on Acute Gene Expression Changes in the Hippocampus Following Neonatal Ethanol Exposure in BXD Recombinant Inbred Mouse Strains

Abstract

Fetal alcohol spectrum disorders (FASD) are prevalent neurodevelopmental disorders. Genetics have been shown to have a role in the severity of alcohol’s teratogenic effects on the developing brain. We previously identified recombinant inbred BXD mouse strains that show high (HCD) or low cell death (LCD) in the hippocampus following ethanol exposure. The present study aimed to identify gene networks that influence this susceptibility. On postnatal day 7 (3rd-trimester-equivalent), male and female neonates were treated with ethanol (5.0 g/kg) or saline, and hippocampi were collected 7hrs later. Using the Affymetrix microarray platform, ethanol-induced gene expression changes were identified in all strains with divergent expression sets found between sexes. Genes, such as Bcl2l11, Jun, and Tgfb3, showed significant strain-by-treatment interactions and were involved in many apoptosis pathways. Comparison of HCD versus LCD showed twice as many ethanol-induced genes changes in the HCD. Interestingly, these changes were regulated in the same direction suggesting (1) more perturbed effects in HCD compared to LCD and (2) limited gene expression changes that confer resistance to ethanol-induced cell death in LCD. These results demonstrate that genetic background and sex are important factors that affect differential cell death pathways after alcohol exposure during development that could have long-term consequences.