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  2. Prenatal dexamethasone exposure caused fetal rats liver dysplasia by inhibiting autophagy-mediated cell proliferation

Prenatal dexamethasone exposure caused fetal rats liver dysplasia by inhibiting autophagy-mediated cell proliferation

  • Toxicology. 2021 Feb 15;449:152664. doi: 10.1016/j.tox.2020.152664.
Dingmei Zhang 1 Kexin Liu 1 Wen Hu 1 Xiaoqian Lu 1 Li Li 1 Qi Zhang 1 Hegui Huang 2 Hui Wang 3
Affiliations

Affiliations

  • 1 Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China.
  • 2 Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China; Wuhan No.1 Hospital, Wuhan, 430071, China.
  • 3 Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan, 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan, 430071, China. Electronic address: wanghui19@whu.edu.cn.
Abstract

As a synthetic glucocorticoid, dexamethasone has been widely used in the clinical treatment of premature birth and related pregnant diseases, but its clinical use is still controversial due to developmental toxicity. This study aimed to confirm the proliferation inhibitory effect of pregnant dexamethasone exposure (PDE) on fetal liver development and elucidate its molecular mechanism. In vitro studies, we found that dexamethasone inhibited hepatocyte proliferation through Autophagy activated by Glucocorticoid Receptor (GR)-forkhead protein O1 (FOXO1) pathway. Subsequently, in vivo, we confirmed in a PDE rat model that male fetal liver proliferation was inhibited, and the expression of the GR-FOXO1 pathway and Autophagy were increased. Taken together, PDE induces Autophagy by activating the GR-FOXO1 pathway, which leads to fetal liver proliferation inhibition and dysplasia in offspring rats. This study confirmed that dexamethasone activates cell Autophagy in utero through the GR-FOXO1 pathway, thereby inhibiting hepatocyte proliferation and liver development, which provides theoretical basis for understanding the developmental toxicity of dexamethasone and guiding the rational clinical use.

Keywords

Autophagy; Glucocorticoid receptor; Prenatal dexamethasone exposure; Proliferation.

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