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Prenatal alcohol exposure programs steady-state gene expression and the gene expression response to inflammation in the adult rat brain Stepien, Katarzyna Anna


Prenatal alcohol exposure results in alterations in numerous physiological systems, including neuroendocrine and neuroimmune systems. The purpose of this study was to determine whether prenatal ethanol exposure results in long-term alteration of neural gene expression, particularly in genes related to neuroendocrine and neuroimmune function. Utilizing a well-established animal model of prenatal ethanol exposure, ethanol was administered to pregnant Sprague-Dawley dams throughout gestation in a liquid diet fed ad libitum (36% calories derived from ethanol). Maltose-dextrin was isocalorically substituted for ethanol in a liquid control diet for a pair-fed group, and a control group received a pelleted control diet ad libitum. In young adulthood, an adjuvant-induced arthritis paradigm was utilized, where female offspring were injected with either saline or complete Freund’s adjuvant, to induce an inflammatory response and elucidate dysregulated neuroimmune pathways. Gene expression was analyzed in the prefrontal cortex and hippocampus at both the peak and resolution of arthritis using whole genome gene expression microarrays. Within saline-injected animals, prenatal alcohol exposure alone resulted in significant changes in gene expression in both the prefrontal cortex and hippocampus. Included were multiple genes related to, cell death, transcriptional regulation, neuronal signaling and neurodevelopment. Among the genes involved in neurodevelopment, Acs13 has also been shown to be variably methylated in humans according to in utero exposure to environmental factors. Prenatal alcohol exposure also altered the gene expression response to adjuvant-induced arthritis. Many genes showed a significantly different pattern of expression in ethanol-exposed animals compared to both pair-fed and control, in both prefrontal cortex and hippocampus. These genes were either differentially up- or downregulated in ethanol-exposed compared to control animals or failed to show the adjuvant-induced change in regulation shown by controls. As well, several of these genes were mediators of the response to immune or stress challenge, such as Lcn2 and Bhlhe40. Genes found to be differentially expressed in this study are potential mediators contributing to the long-term alterations in neuroendocrine and neuroimmune function observed in prenatal alcohol exposure.

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