Differential Effects of Prenatal Alcohol Exposure in Mice on Brain Growth and Gene Expression Reveals Early Effects on Cell Cycle and Apoptosis and Delayed Effects on Metabolism in Affected Offspring

Fetal Alcohol Spectrum Disorder (FASD) encompasses the deleterious consequences of Prenatal Alcohol Exposure (PAE), including developmental delay, dysmorphologies, cognitive and behavioral issues. The dose and timing of alcohol exposure, maternal and environmental factors, and genetics all impact FASD outcomes, but differential susceptibility to PAE remains poorly understood. In this study, we examined the differential effects of PAE on mouse brain development by measuring brain weight in embryos (embryonic day 14, E14) and neonatal pups (postnatal day 0, P0) exposed alcohol during early development. We used transcriptomics to determine whether offspring differentially affected by PAE also differ in gene expression. PAE offspring were classified as normal, middle, and low-weight brains relative to controls. The normal-weight brains showed no differences in gene expression, suggesting these offspring were both phenotypically and transcriptionally unaffected by PAE. While both middle- and low-weight brains showed changes in gene expression, the middle-weight brains showed the most robust transcriptome differences. In affected E14 offspring, we saw an upregulation of cell cycle and apoptosis by PAE, whereas at P0, we saw a downregulation of metabolic processes. Overall, these findings highlight variability in response to PAE and demonstrate the molecular processes involved in offspring affected by alcohol.