OMD activates BMPR2 involved in abnormal osteogenesis in male offspring mice exposed to fluoride during pregnancy.

The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that exposure to adverse environmental factors during pregnancy not only disturbs intrauterine fetal development but also exerts profound negative consequences on offspring. Previous studies have primarily focused on the health risks associated with direct individual exposure to fluoride (a common environmental exposure factor), while the effects of fluoride exposure on offspring during pregnancy have received little attention. In this study, we established the prenatal NaF exposure model by administering drinking water containing 100 mg/L sodium fluoride (NaF) to pregnant dams throughout gestation. We found that prenatal NaF exposure induced intrauterine hyper-osteogenesis and led to an abnormal and sustained, high bone mass phenotype in male offspring. Mechanistically, NaF exposure significantly upregulated osteomodulin (OMD) expression, which subsequently driven the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) via the activation of bone morphogenetic protein receptor type 2 (BMPR2). Notably, pharmacological intervention with CDD-1653, a selective BMPR2 inhibitor, effectively rescued the NaF-induced excessive BMSC osteogenesis and attenuated the abnormal bone accumulation in vivo. Taken together, our study demonstrates that prenatal fluoride exposure triggers aberrant activation of osteogenesis in male offspring through the OMD-BMPR2 signaling pathway. These findings uncover the potential molecular mechanisms by which early-life environmental fluoride exposure alters skeletal homeostasis in male offspring and highlight the imperative for public health strategies to mitigate gestational fluoride risks.