title: Prenatal alcohol exposure alters methyl metabolism and programs serotonin transporter and glucocorticoid receptor expression in brain.
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.
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Ying Fai
authors.initials: YF
authors.lastname: Ngai
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Dian C
authors.initials: DC
authors.lastname: Sulistyoningrum
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia; and.
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Neill
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Innis
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia; and Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: Joanne
authors.initials: J
authors.lastname: Weinberg
authors.affiliation: Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Child and Family Research Institute, Vancouver, British Columbia, Canada adevlin@cfri.ubc.ca.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Devlin
mesh_terms: D000367:Age Factors; D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D008297:Male; D018811:Maternal Exposure; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; C542344:NR3C1 protein, rat; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D000431:Ethanol
keywords: developmental programming; fetal alcohol spectrum disorder; glucocorticoid receptor; hypothalamo-pituitary axis; methyl metabolism; prenatal alcohol exposure; serotonin transporter