• IDENTIFICATION OF p53-MEDIATED NEUROGENOMIC RESPONSES TO ETHANOL USING IN VIVO AND IN VITRO MODELS OF FETAL ALCOHOL SPECTRUM DISORDER

      Camargo, Maria (2016)
      Fetal Alcohol Spectrum Disorder (FASD) is a serious public health concern affecting 3.6% of the US population. One avenue to achieve a decrease in the prevalence of FASD is for scientific research to identify cellular mechanisms of action of imbibed alcohol and propose solutions to treat or prevent the damage done. Here we present our investigation into the molecular consequences of ethanol exposure in mouse brain cells and mouse neural stem cell cultures. Specifically, we tested the hypothesis that p53 mediates the neurogenomic response to ethanol exposure in brain cells in the somatosensory cortex, hippocampus and neural stem cells. p53 is a versatile transcription factor well known for inducing cell death in cancer cells. We identified the apoptosis pathway as being changed in a p53-related manner only in the CA1 subregion of the hippocampus, based on expression changes in Casp2, Cdk1, and Stat1. Overall, the regions interrogated revealed that p53’s cellular response is heterogeneous. In the somatosensory cortex and hippocampus a subset of gene expression changes occurred depending on both ethanol exposure and the presence of p53: Ephb1in layer 2/3; Ctgf in layer 5; Camk1 in layer 6; Cdk1, Casp2, Cdk1, and Stat1 in the CA1; and Camk1 in the DG. In regards to the specific mRNAs that changed, they differed in the brain regions and cell cultures, but we did observe that neuronal and developmental genes were the most significantly changed upon ethanol exposure. In addition, we also identified that the category of genes whose methylation pattern was changed after ethanol exposure are related to basic neuronal functions. Neural cells also appeared to be engaged in a challenging response to ethanol because DNA repair proteins Ercc1, Hus1, and Rad51 alter their DNA binding after ethanol exposure. In addition, we identified that p53 transcription factor changes its DNA binding in response to ethanol exposure. In conclusion, we identified that neural p53 signaling is measurably perturbed by ethanol exposure.