LDLR H3K27ac in PBMCs: An Early Warning Biomarker for Hypercholesterolemia Susceptibility in Male Newborns Treated...

Dexamethasone, widely used as an exogenous glucocorticoid in clinical and animal practice, has recently been recognized as an environmental contaminant of concern. Existing evidence documents its ability to induce persistent dyslipidemia in adult offspring. In this study, plasma cholesterol levels in male rats exposed to dexamethasone prenatally (PDE) were increased. Meanwhile, developmental tracking revealed a reduction in hepatic low-density lipoprotein receptor (LDLR) promoter H3K27 acetylation (H3K27ac) and corresponding transcriptional activity across gestational-to-postnatal stages. Mechanistic investigations established glucocorticoid receptor/histone deacetylase2 (GR/HDAC2) axis-mediated epigenetic programming of LDLR through H3K27ac modulation in PDE offspring, potentiating susceptibility to hypercholesterolemia. Additionally, in peripheral blood mononuclear cells (PBMC) of PDE male adult offspring, LDLR H3K27ac level and expression were also decreased and positively correlated with those in the liver. Clinical studies further substantiated that male newborns prenatally treated with dexamethasone exhibited increased serum cholesterol levels and consistent reductions in LDLR H3K27ac levels and corresponding transcriptional activity in PBMC. This study establishes a complete evidence chain linking PDE with epigenetic programming and cholesterol metabolic dysfunction, proposing PBMC epigenetic biomarkers as a novel non-invasive monitoring tool for assessing the developmental toxicity of chemical exposures during pregnancy. This has significant implications for improving environmental health risk assessment systems.