期刊
AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
卷 309, 期 5, 页码 R613-R622出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpregu.00075.2015
关键词
fetal alcohol spectrum disorder; prenatal alcohol exposure; methyl metabolism; developmental programming; hypothalamo-pituitary axis; glucocorticoid receptor; serotonin transporter
类别
资金
- National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism (NIH/NIAAA) [R21 AA016683]
- NIH/NIAAA [R37 AA007789]
- NeuroDevNet (Networks of Centres of Excellence) [20R64153]
- Canadian Foundation on Fetal Alcohol Research
- Child and Family Research Institute
Prenatal alcohol exposure (PAE) programs the fetal hypothalamic-pituitaryadrenal (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.
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