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

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 (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alcohol Drinking / adverse effects*
  • Animals
  • Brain-Derived Neurotrophic Factor / genetics
  • Brain-Derived Neurotrophic Factor / metabolism
  • DNA Methylation / drug effects
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Ethanol / toxicity*
  • Female
  • Gene Expression Regulation, Developmental
  • Gene Expression Regulation, Enzymologic
  • Gestational Age
  • Hippocampus / drug effects*
  • Hippocampus / growth & development
  • Hippocampus / metabolism
  • Hypothalamus / drug effects*
  • Hypothalamus / growth & development
  • Hypothalamus / metabolism
  • Male
  • Maternal Exposure
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • RNA, Messenger / metabolism
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / metabolism*
  • Sex Factors


  • Brain-Derived Neurotrophic Factor
  • Early Growth Response Protein 1
  • Egr1 protein, rat
  • NR3C1 protein, rat
  • RNA, Messenger
  • Receptors, Glucocorticoid
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • Ethanol