The high-expression programming of SR-B1 mediates adrenal dysfunction in female offspring induced by prenatal caffeine exposure and its cholesterol accumulation mechanism

The cholesterol metabolism and homeostasis of adrenal are important for steroidogenesis. Our previous studies found that prenatal caffeine exposure (PCE) can inhibit adrenal steroidogenesis in offspring, but whether the mechanism is related to local imbalance of cholesterol metabolism remains unknown. Here, we found that PCE inhibited adrenal steroidogenesis and increased the expression of cell pyroptosis and inflammatory-related indicators (NLRP3, caspase-1 and IL-1β) in female adult offspring rats, and at the same time, the cholesterol levels in serum and adrenal gland also significantly increased. In vitro, the high level of cholesterol could inhibit adrenal corticosteroid synthesis through pyroptosis and an inflammatory response. It suggested that the low adrenal steroidogenesis in PCE female adult offspring is related to local cholesterol accumulation-mediated pyroptosis and inflammation. Furthermore, dating back to the intrauterine period, PCE increased the serum CORT level in female fetal rats, and increased the expression of the adrenal cholesterol intake gene SR-B1, which persisted after birth and even into adulthood. At the cellular level, silencing SR-B1 could reverse the increase of intracellular cholesterol content caused by high levels of cortisol in NCI-H295R cells. Finally, we confirmed that high concentrations of glucocorticoids increased the expression and H3K14ac level of the promoter region in SR-B1 by upregulating the GR/SREBP1/p300 pathway in vivo and in vitro. In conclusion, we clarified that the high-expression programming of SR-B1 mediates adrenal dysfunction in PCE female offspring and its cholesterol accumulation mechanism, which provided a favorable basis for finding novel targets to prevent and treat fetal-originated diseases.