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

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 dexamet...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2021-02, Vol.449, p.152664, Article 152664
Main Authors: Zhang, Dingmei, Liu, Kexin, Hu, Wen, Lu, Xiaoqian, Li, Li, Zhang, Qi, Huang, Hegui, Wang, Hui
Format: Article
Language:English
Subjects:
Animals
Autophagy
Autophagy - drug effects
Autophagy - physiology
Cell Proliferation - drug effects
Cell Proliferation - physiology
Dexamethasone - administration & dosage
Dexamethasone - toxicity
Dose-Response Relationship, Drug
Female
Fetal Development - drug effects
Fetal Development - physiology
Glucocorticoid receptor
Glucocorticoids - toxicity
Liver - drug effects
Liver - embryology
Liver - pathology
Male
Pregnancy
Prenatal dexamethasone exposure
Prenatal Exposure Delayed Effects - chemically induced
Prenatal Exposure Delayed Effects - pathology
Proliferation
Rats
Rats, Wistar
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Summary: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.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2020.152664