Exploring plasticisers-osteoporosis links and mechanisms: a cohort and network toxicology study

Background Plasticisers, widely present in daily life, have been linked to osteoporosis (OP), though the precise mechanisms remain unclear. Methods This study examined the association between mono (2-ethylhexyl) phthalate (MEHP) and OP using multivariate logistic regression based on NHANES data. Network toxicology identified key targets and pathways involved in MEHP-induced OP. Molecular docking and dynamics simulations validated the stability of MEHP-target interactions. The effects of MEHP on osteogenic differentiation were further assessed in mouse bone marrow stromal cells (BMSCs). Results All logistic regression models confirmed a significant positive correlation between MEHP levels and OP. Network toxicology analysis identified CTSD, SOAT1, and VCP as key targets and the apoptosis pathway as a key mechanism in MEHP-induced OP. Molecular simulations demonstrated stable MEHP binding to these targets. Cellular experiments revealed that MEHP significantly inhibited BMSC osteogenesis by downregulating CTSD and VCP, while SOAT1 showed a weaker correlation. Conclusion MEHP exposure is positively associated with OP risk, with CTSD, VCP, and the apoptosis pathway potentially playing key roles in impairing BMSC osteogenesis.