MiR-133a-3p/Sirt1 epigenetic programming mediates hypercholesterolemia susceptibility in female offspring induced by prenatal dexamethasone exposure

Mounting evidence indicates that adverse intrauterine conditions increase offspring's hypercholesterolemia susceptibility in adulthood. This study aimed to confirm prenatal dexamethasone exposure (PDE)-induced hy-percholesterolemia susceptibility in female adult offspring rats, and elucidate its intrauterine programming mechanism. Pregnant Wistar rats were injected with dexamethasone subcutaneously (0, 0.1 and 0.2 mg/kgd) from gestational day (GD) 9 to 20. Serum and liver of the female offspring were collected at GD21 and postnatal week (PW) 12 and 28. PDE offspring showed elevated serum total cholesterol (TCH) levels and a cholesterol phenotype of high cardiovascular disease risk at PW12 and PW28. The histone acetylation levels of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) and its expression were consistently increased in the PDE offspring both in utero and after birth. Moreover, PDE promoted glucocorticoid receptor (GR) nuclear trans -location and miR-133a-3p expression and inhibited sirtuin-1 (Sirt1) expression in the fetal liver. In vitro , dexa-methasone increased intracellular and supernatant TCH levels and miR-133a-3p expression, decreased SIRT1 expression, and promoted HMGCR histone acetylation and expression in bone marrow mesenchymal stem cells (BMSCs) hepatoid differentiated cells and HepG2 cell line. GR siRNA, miR-133a-3p inhibitor or SIRT1 over -expression reversed dexamethasone-induced downstream molecular and phenotypic changes. Furthermore, elevated TCH levels in umbilical cord blood and increased HMGCR expression in peripheral blood mononuclear cells (PBMCs) were observed in human female neonates who had received dexamethasone treatment during pregnancy. In conclusion, PDE can cause persistent enhancement of hepatic cholesterol synthesis function before and after birth through GR/miR-133a-3p/Sirt1 pathway, eventually leading to increased hypercholesterolemia susceptibility in female offspring rats.

Automated summary

The study confirmed the increased risk of hypercholesterolemia in female adult offspring rats exposed to prenatal dexamethasone, and investigated its intrauterine programming mechanism. The results showed that PDE offspring exhibited elevated cholesterol levels, indicating a higher risk of cardiovascular diseases.