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Gestational Hypoxia Induces Sex-Differential Methylation of Crhr1 Linked to Anxiety-like Behavior

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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.

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Acknowledgments

This work was supported by grants from the Ministry Science and Technology of China, National Basic Research Program “973” of China (No. 2012CB518200 and No. 2006CB504100), and the National Natural Science Foundation of China (No. 31171145 and No. 30770807). We would also like to thank Prof. Gareth Leng (Centre for Integrative Physiology, University of Edinburgh) and Prof. IC Bruce (Department of Physiology, School of Medicine, Zhejiang University, China) for editing and commenting on the manuscript.

Conflict of Interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Division of Neurobiology and Physiology, Department of Basic Medical Sciences, School of Medicine, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China

    Xi Wang, Fan-Sen Meng, Jun-Ming Fan, Ke Hao, Xue-Qun Chen & Ji-Zeng Du

  2. Key Laboratory of Medical Neurobiology, Ministry of Health, Hangzhou, China

    Zong-Yun Liu, Xue-Qun Chen & Ji-Zeng Du

  3. Zhejiang Province Key Laboratory for Neurobiology, Hangzhou, 310058, China

    Xue-Qun Chen & Ji-Zeng Du

  4. School of Medicine, Zhejiang University, Research Building C507, 866 Yuhangtang Road, Hangzhou, Zhejiang, 310058, China

    Xue-Qun Chen & Ji-Zeng Du

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  1. Xi Wang
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Wang, X., Meng, FS., Liu, ZY. et al. Gestational Hypoxia Induces Sex-Differential Methylation of Crhr1 Linked to Anxiety-like Behavior. Mol Neurobiol 48, 544–555 (2013). https://doi.org/10.1007/s12035-013-8444-4

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