title: Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus.
abstract: Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression.
authors.affiliation: a Oncology Department , The second affiliated hospital, Chongqing Medical University , No.76 Linjiang Road, Yuzhong District, Chongqing , China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: a Oncology Department , The second affiliated hospital, Chongqing Medical University , No.76 Linjiang Road, Yuzhong District, Chongqing , China.
authors.forename: Weidong
authors.initials: W
authors.lastname: Fan
authors.affiliation: a Oncology Department , The second affiliated hospital, Chongqing Medical University , No.76 Linjiang Road, Yuzhong District, Chongqing , China.
authors.forename: Xianquan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: a Oncology Department , The second affiliated hospital, Chongqing Medical University , No.76 Linjiang Road, Yuzhong District, Chongqing , China.|b The Psychiatric Institute , Department of Psychiatry , College of Medicine, University of Illinois at Chicago , Chicago , IL , USA.
authors.forename: Erbo
authors.initials: E
authors.lastname: Dong
mesh_terms: D000107:Acetylation; D000818:Animals; D001007:Anxiety / Q000235:genetics*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006624:Hippocampus / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics; D011401:Promoter Regions, Genetic; D013315:Stress, Psychological / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
keywords: Anxiety; BDNF; HDAC; depression; epigenetics; gestational stress; histone deacetylation; promoter methylation