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Maternal and fetal methionine metabolism and the implications on programming of the hypothalamic pituitary adrenal axis by prenatal alcohol exposure O'Neill, Ryan Patrick


Chronic ethanol exposure is known to disrupt the methionine cycle in liver of adult rats. Alterations in the methionine cycle are associated with changes in tissue methylation capacity and may affect DNA and histone methylation thereby altering epigenetic regulation of gene expression, causing long-term phenotypic changes. Data from our lab and others have shown that prenatal alcohol exposure (PAE) reprograms the hypothalamic-pituitary-adrenal (HPA) axis such that HPA tone is increased throughout life. That is, PAE animals show increased HPA responsiveness and/or delayed or deficient recovery to basal levels following exposure to stressors. These alterations persist into adulthood, can have negative consequences for health, and may be mediated by metabolic changes induced by prenatal ethanol exposure. To explore this hypothesis, mass-spectrometry and real time PCR were used to quantify several of the primary metabolites and enzymes involved in methionine metabolism using plasma and liver samples from pregnant dams and fetuses from ethanol (E), pair-fed (PF) and ad lib fed control (C) groups on gestation day 21. Mass spectrometry analysis of plasma revealed increases (p<0.05) in homocysteine levels in E dams and increases (p<0.02) in methionine levels in both E dams and fetuses compared to their PF and C counterparts. Quantification of hepatic enzymes by real-time PCR showed significantly decreased mRNA levels (p≤0.05) of maternal methionine adenosyltransferase (MAT) 1A, MAT2A, methionine synthase (MS), and phosphatidylethanolamine N-methyl transferase (PEMT)in addition to decreased fetal MAT1A mRNA. Together these data demonstrate marked alterations in methionine metabolism during prenatal exposure to ethanol.

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