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Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67

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An Erratum to this article was published on 03 August 2017

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Abstract

The intrauterine programming of hypothalamic–pituitary–adrenal (HPA) axis hypersensitivity is associated with chronic adult diseases. Our previous studies demonstrated the HPA-axis hypersensitivity in offspring rats induced by prenatal nicotine exposure. The goal of the present study is to further investigate the intrauterine programming mechanism. Pregnant Wistar rats were subcutaneously administered with 2.0 mg/kg day of nicotine from gestational day (GD) 9–20. A group of the pregnant rats was euthanized at GD20, and the fetal rats were extracted. The remaining rats were left to come to term, and the adult offspring were exposed to chronic stress. For adult offspring rats, prenatal nicotine exposure induced HPA-axis hypersensitivity after chronic stress, accompanied by imbalanced glutamatergic/GABAergic afferent inputs. Moreover, prenatal nicotine exposure enhanced the expression of hippocampal glutamic acid decarboxylase 67 (GAD67), accompanied by a decreased methylation ratio within nt −1019 to −689 of the GAD67 promoter, decreased expression of Dnmt1, and an increased GABA content and density of GABAergic neurons. The fetal rats exhibited changes consistent with the adult rats. Similar effects were also observed by treating the fetal hippocampal cell line H19-7 with 1−100 μM nicotine, while dihydro-β-erythroidine hydrobromide (DHβE), the specific inhibitor of α4β2nAChR, can reverse the effects caused by nicotine. These results indicate that prenatal nicotine exposure can enhance the potential excitability of the hypothalamus via the intrauterine programming of up-regulation of hippocampal GAD67. All of these results contribute to the HPA-axis hypersensitivity in adult offspring.

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  • 03 August 2017

    An erratum to this article has been published.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81371483, 81220108026, 81430089, 81202240).

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Authors and Affiliations

  1. Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, 430071, China

    Xia He, Juan Lu, Wanting Dong, Zhexiao Jiao, Chong Zhang, Hui Wang & Dan Xu

  2. Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China

    Hui Wang & Dan Xu

  3. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Ying Yu & Zhaohui Zhang

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  1. Xia He
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  2. Juan Lu
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An erratum to this article is available at https://doi.org/10.1007/s00204-017-2039-1.

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He, X., Lu, J., Dong, W. et al. Prenatal nicotine exposure induces HPA axis-hypersensitivity in offspring rats via the intrauterine programming of up-regulation of hippocampal GAD67. Arch Toxicol 91, 3927–3943 (2017). https://doi.org/10.1007/s00204-017-1996-8

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