title: Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior.
abstract: Stress during gestation increases vulnerability to disease and changes behavior in offspring. We previously reported that hypoxia and restraint during pregnancy sensitized the hypothalamic-pituitary-adrenal (HPA) axis and induced anxiety-like behavior in the adult offspring. Here, we report that gestational intermittent hypoxia (GIH) elicited a sex-dependent anxiety-like behavior in male P90 offspring and activation of corticotropin-releasing hormone (CRH) and CRH type-1 receptor (CRHR1) mRNA in the hypothalamic paraventricular nucleus (PVN) and in male E19 hypothalamus. These linked to demethylation at several specific sites of CpG island of Crhr1 promoter in P90 PVN and E19 embryo hypothalamus in GIH groups. Crhr1 DNA demethylation is more crucial in CpG island 1 than island 2 for activation of CRHR1 mRNA. DNMT3b is required for the Crhr1 DNA methylation than DNMT1 and DNMT3a in increased CRHR1 mRNA. We first address a novel hypothesis that GIH-induced male-sex-dependent demethylation at CpG sites of Crhr1 DNA in promoter triggers elevation of CRHR1 mRNA in PVN and anxiety-like behavior in adult offspring.
authors.affiliation: Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Fan-Sen
authors.initials: FS
authors.lastname: Meng
authors.forename: Zong-Yun
authors.initials: ZY
authors.lastname: Liu
authors.forename: Jun-Ming
authors.initials: JM
authors.lastname: Fan
authors.forename: Ke
authors.initials: K
authors.lastname: Hao
authors.forename: Xue-Qun
authors.initials: XQ
authors.lastname: Chen
authors.forename: Ji-Zeng
authors.initials: JZ
authors.lastname: Du
mesh_terms: D000679:Amygdala / Q000201:enzymology; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D001522:Behavior, Animal; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000860:Hypoxia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D000099052:CRF Receptor, Type 1
chemical_list: C101531:CRF receptor type 2; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D008156:Luciferases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619382:Dnmt1 protein, rat