Work

Abnormal chenodexycholic acid metabolism programming promotes cartilage matrix degradation in male adult offspring rats induced by prenatal caffeine exposure

Year: 2025

Type: article

Abstract: Epidemiological evidence links osteoarthritis to fetal origins. Our study shows prenatal caffeine exposure (PCE) in rats predisposes adult offspring to osteoarthritis, associated with elevated intrauterine glucocorticoid levels. Previous research indicates that chenodeoxycholic acid (CDCA), a bile acid, can slow osteoarthritis progression when administered intra-articularly. This study explored if disrupted bile acid metabolism in cartilage affects osteoarthritis risk in adult offspring with PCE. Our findings indicate that the expression of MMP3/MMP13 was upregulated, while endogenous CDCA levels were reduced in the cartilage of PCE-exposed offspring. Furthermore, we observed a persistent reduction in H3K27ac levels at the CYP7B1 promoter and its expression in the cartilage of PCE offspring from fetus to adulthood. Moreover, a sub-physiological level of CDCA promoted NF-κB phosphorylation and the expression of MMP3/MMP13 in chondrocytes in vitro. High levels of glucocorticoids reduced H3K27ac levels and CYP7B1 expression in the promoter region of CYP7B1 through the glucocorticoid receptor and histone deacetylase 4, consequently leading to decreased CDCA levels. In summary, our findings suggest that intrauterine low-expression programming of CYP7B1, induced by elevated glucocorticoid levels, reduces local CDCA levels in the cartilage of PCE offspring, ultimately leading to increased matrix degradation and susceptibility to osteoarthritis.

Source: Toxicology Research

DOI: 10.1093/toxres/tfaf063