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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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Autophagy plays a vital role in embryonic development and cell differentiation. Our previous study demonstrated that prenatal ethanol exposure (PEE) resulted in intrauterine growth retardation (IUGR) and adrenal developmental toxicities in rat offspring. The present study focused on PEE-induced autophagy as an underlying mechanism and its biological significance in female fetal rats. Female fetuses in the PEE group exhibited lower body weights and suffered adrenal structural abnormalities compared to the controls. Cell proliferation was inhibited, the insulin-like growth factor 1 (IGF1) pathway was reduced, and autophagy was activated in the glands of female fetal rats. Ethanol increased the ratio of microtubule-associated protein light chain 3 beta-II (LC3β-II) to LC3β-I in vitro, and it reduced cortisol levels in time- and concentration-dependent manners in human adrenocortical carcinoma cells (NCI-H295A). Bafilomycin A1 inhibited autophagy, steroidogenic factor 1 (SF1) protein and steroidogenesis in the present study. Rapamycin with ethanol up-regulated autophagy and SF1 expression and activated steroidogenesis when compared with ethanol alone. In addition, ethanol inhibited IGF1 receptor (IGF1R) and phospho-mTOR (Ser2448) expression in a concentration-dependent manner. These results demonstrate that PEE activated autophagy in fetal adrenal glands, and the underlying mechanism may be associated with inhibition of the IGF1R/phospho-mTOR (Ser2448) pathway. Autophagy may be a compensatory mechanism for the PEE-induced inhibition of fetal adrenal steroidogenesis to maintain fetal adrenal development., (Copyright © 2018. Published by Elsevier Inc.)

Epidemiological evidence has revealed that non-alcoholic fatty liver disease (NAFLD) harbors an intrauterine origin. Autophagy is known to be involved in the protective mechanism in the development of adult NAFLD, but whether it engages in the occurrence of fetal-originated NAFLD remains unclear. In this study, a rat model of fetal-originated NAFLD was established by giving a high-fat diet or chronic stress after birth on prenatal caffeine exposure (PCE) male offspring. The alterations of liver morphologic analysis, lipid metabolism, and autophagy before and after birth were determined to confirm autophagy mechanism, NAFLD susceptibility, and intrauterine origin in PCE male adult offspring. Our results revealed that PCE-induced intrauterine high concentration of corticosterone exposure blocked autophagic flux by inhibiting cathepsin D expression in hepatocytes, leading to β-oxidation inhibition and lipid accumulation in the liver. Moreover, high concentration of corticosterone upregulated miR-665 by activating the glucocorticoid receptor to suppress cathepsin D, thus causing lysosomal degradation dysfunction and autophagy flux blockade. Notably, hepatic overexpression of cathepsin D could reverse PCE-induced postnatal NAFLD susceptibility in male rat offspring. This study elucidates the epigenetic programming mechanism of intrauterine autophagy-related fetal-originated NAFLD susceptibility, and identifies cathepsin D as its early intervention target, providing an experimental basis for exploring early prevention and treatment strategies for fetal-originated NAFLD. [Display omitted] • PCE induced NAFLD susceptibility in male rat offspring via blocking autophagic flux. • Intrauterine hyperglucocorticoid exposure impairs autophagy by upregulating miR-665 to inhibit CTSD. • CTSD is a potential intervention target for fetal-originated NAFLD susceptibility. [ABSTRACT FROM AUTHOR]