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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. [ABSTRACT FROM AUTHOR]

Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CORT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4 g/kg·d). In PEE fetus, increased serum CORT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3β-hydroxysteroid dehydrogenase (3β-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CORT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3β-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a “two-programming” mechanism for PEE-induced adrenal developmental toxicity: “the first programming” is a lower functional programming of adrenal steroidogenesis, and “the second programming” is GC-metabolic activation system-related GC-IGF1 axis programming. [ABSTRACT FROM AUTHOR]

Our previous study proposed a glucocorticoid-insulin-like growth factor 1 (GC-IGF1) axis programming mechanism for prenatal caffeine exposure (PCE)-induced adrenal developmental dysfunction. Here, we focused on PCE-induced cell proliferation changes of the adrenal cortex in male offspring rats before and after birth and clarified the intrauterine programming mechanism. On gestational day (GD) 20, the PCE group had an elevated serum corticosterone level reduced fetal bodyweight, maximum adrenal sectional area, and elevated adrenal corticosterone and aldosterone contents. However, in postnatal week (PW) 6, the serum corticosterone level was decreased, and the bodyweight, with catch-up growth, adrenal cortex maximum cross-sectional area and aldosterone content were relatively increased, while the adrenal corticosterone content was lower. On GD20, the expression of adrenal IGF1, IGF1R and proliferating cell nuclear antigen (PCNA) were decreased, while the expression of these factors at PW6 were increased in the PCE group. Fetal adrenal gene chip analysis suggested that the mitogen-activated protein kinase/extracellular regulated protein kinase (MAPK/ERK) signal pathway was suppressed in the PCE group. Moreover, in the rat primary adrenal cells, corticosterone (rather than caffeine) was shown to significantly inhibit cell proliferation, IGF1 and PCNA expression, and ERK phosphorylation, which could be reversed by exogenous IGF1. Meanwhile, the effects of exogenous IGF1 were reversed by the ERK pathway inhibitor (PD184161). In conclusion, PCE could induce programming alterations in adrenal cortical cell proliferation before and after birth in male offspring rats. The underlying mechanism is associated with the inhibition of fetal adrenal IGF1-related MAPK/ERK signaling pathway caused by high glucocorticoid levels. [ABSTRACT FROM AUTHOR]