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Am J Physiol Regul Integr Comp Physiol. 2015 Sep;309(5):R613-22. doi: 10.1152/ajpregu.00075.2015. Epub 2015 Jul 15.

Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.

Author information

1
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada.
2
Department of Cellular and Physiological Sciences, University of British Columbia; and.
3
Department of Cellular and Physiological Sciences, University of British Columbia; and Child and Family Research Institute, Vancouver, British Columbia, Canada.
4
Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada adevlin@cfri.ubc.ca.

Abstract

Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitary-adrenal (HPA) axis, resulting in HPA dysregulation and hyperresponsiveness to stressors in adulthood. Molecular mechanisms mediating these alterations are not fully understood. Disturbances in one-carbon metabolism, a source of methyl donors for epigenetic processes, contributes to alcoholic liver disease. We assessed whether PAE affects one-carbon metabolism (including Mtr, Mat2a, Mthfr, and Cbs mRNA) and programming of HPA function genes (Nr3c1, Nr3c2, and Slc6a4) in offspring from ethanol-fed (E), pair-fed (PF), and ad libitum-fed control (C) dams. At gestation day 21, plasma total homocysteine and methionine concentrations were higher in E compared with C dams, and E fetuses had higher plasma methionine concentrations and lower whole brain Mtr and Mat2a mRNA compared with C fetuses. In adulthood (55 days), hippocampal Mtr and Cbs mRNA was lower in E compared with C males, whereas Mtr, Mat2a, Mthfr, and Cbs mRNA were higher in E compared with C females. We found lower Nr3c1 mRNA and lower nerve growth factor inducible protein A (NGFI-A) protein in the hippocampus of E compared with PF females, whereas hippocampal Slc6a4 mRNA was higher in E than C males. By contrast, hypothalamic Slc6a4 mRNA was lower in E males and females compared with C offspring. This was accompanied by higher hypothalamic Slc6a4 mean promoter methylation in E compared with PF females. These findings demonstrate that PAE is associated with alterations in one-carbon metabolism and has long-term and region-specific effects on gene expression in the brain. These findings advance our understanding of mechanisms of HPA dysregulation associated with PAE.

KEYWORDS:

developmental programming; fetal alcohol spectrum disorder; glucocorticoid receptor; hypothalamo-pituitary axis; methyl metabolism; prenatal alcohol exposure; serotonin transporter

PMID:
26180184
PMCID:
PMC4591382
DOI:
10.1152/ajpregu.00075.2015
[Indexed for MEDLINE]
Free PMC Article

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