Epidemiology suggests that adverse environmental exposure during pregnancy may predispose children to hypercholesterolemia in adulthood. This study aimed to demonstrate hypercholesterolemia induced by prenatal dexamethasone exposure (PDE) in adult male offspring rats and explore the intrauterine programming mechanisms. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0, 0.1, 0.2, and 0.4 mg/kg∙d) from gestational days (GD) 9 to 21, and the serum and liver of the male offsprings were collected at GD21, postnatal week (PW) 12 and 28. Furthermore, the effects of dexamethasone on the expression of low-density lipoprotein receptor (LDLR) and its epigenetic mechanism was confirmed in the bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and continuous hepatocyte line. PDE could reduce the birth weight of male offsprings, increase the serum total cholesterol (TCH) level in adult rats, and decrease the liver low-density lipoprotein receptor (LDLR) expression. Serum TCH level and liver LDLR expression were decreased in PDE male fetuses in utero (GD21). Moreover, PDE increased the translocation of the glucocorticoid receptor (GR) in the fetal liver, the expression of DiGeorge syndrome critical region 8 gene (DGCR8), the pre- and post-natal expression of miR-148a. The results of PDE offspring in vivo and in vitro exhibited similar changes. These changes could be reversed by overexpressing LDLR, inhibiting miR-148a or GR. PDE caused hypercholesterolemia in male adult offspring rats, which was mediated via dexamethasone activated intrauterine hepatic GR, enhanced the expression of DGCR8 and miR-148a, thereby reducing the expression of LDLR, leading to impaired liver cholesterol reverse transport function, and finally causing hypercholesterolemia in adult rats.

流行病学表明，怀孕期间不良的环境暴露可能会使儿童成年后患上高胆固醇血症。这项研究旨在证明成年雄性后代大鼠中产前地塞米松暴露（PDE）诱发的高胆固醇血症，并探讨宫内编程机制。从妊娠第9至21天向怀Wistar大鼠皮下注射地塞米松（0、0.1、0.2和0.4 mg / kg∙d），并在出生后第21天GD21收集雄性后代的血清和肝脏。 PW）12和28.此外，在骨髓间充质干细胞（BMSCs）肝样分化细胞和连续肝细胞系中，证实了地塞米松对低密度脂蛋白受体（LDLR）表达及其后生机制的影响。PDE可以减轻雄性后代的出生体重，增加成年大鼠的血清总胆固醇（TCH）水平，并降低肝脏低密度脂蛋白受体（LDLR）的表达。PDE男性胎儿的血清TCH水平和肝脏LDLR表达降低在子宫内（GD21）。此外，PDE增加了胎肝中糖皮质激素受体（GR）的转运，DiGeorge综合征关键区域8基因（DGCR8）的表达，miR-148a的出生前和产后表达。PDE后代在体内和体外的结果显示出相似的变化。这些变化可以通过过量表达LDLR，抑制miR-148a或GR来逆转。PDE引起雄性成年后代大鼠高胆固醇血症，这是通过地塞米松激活的宫内肝GR介导的，增强了DGCR8和miR-148a的表达，从而降低了LDLR的表达，导致肝胆固醇反向转运功能受损，最终导致高胆固醇血症。成年大鼠。