AUTHOR=Yang Xingyao , Wang Xin , Bao Shifu , Li Zhengjiang , Xing Shuxing , Du Zhangzhen 

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

JOURNAL=Frontiers in Toxicology

VOLUME=Volume 7 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/toxicology/articles/10.3389/ftox.2025.1617663

DOI=10.3389/ftox.2025.1617663

ISSN=2673-3080

ABSTRACT=BackgroundPlasticisers, widely present in daily life, have been linked to osteoporosis (OP), though the precise mechanisms remain unclear.MethodsThis 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).ResultsAll 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.ConclusionMEHP exposure is positively associated with OP risk, with CTSD, VCP, and the apoptosis pathway potentially playing key roles in impairing BMSC osteogenesis.