| Osteoblasts and osteoclasts are crucial to maintaining bone homeostasis. These specialized cells rely on various environmental signals and cross talk from one another in order to model, remodel and repair bone. Exogenous chemicals such as the therapeutic drug rosiglitazone, a peroxisome proliferator activated receptor gamma (PPARgamma) agonist, can interfere with bone-forming and bone-resorbing pathways, causing osteoporosis and increasing the risk of bone fracture. Evidence is emerging that environmental toxicants induce similar toxic endpoints in bone, both through PPARgamma-dependent and PPARgamma-independent mechanisms. To date, these toxicants have only ever been considered in isolation or in limited co-exposure studies. This comprehensive review relating these toxicants and their effect on bone health will help guide future studies and illuminate gaps in our knowledge. Five toxicant classes (organotins---mainly tributyltin; TBT, heavy metals---lead, cadmium, and arsenic, dioxin-like chemicals, phthalates, and perfluoroalkyl compounds; PFAs) were examined, with emphasis on molecular targets, osteoclast- and osteoblast-specific effects, animal models and epidemiological data. It was concluded that organotins (TBT) act via PPARgamma and RXR agonism, phthalates act via PPARgamma agonism, heavy metals act at least through ERK-mediated pathways, and dioxin-like chemicals act through aryl hydrocarbon receptor interaction. The molecular targets of PFAs remain unknown. Additional targets are still being investigated. These findings emphasize the importance of co-exposures, as these toxicants act through diverse molecular mechanisms that may share toxic endpoints, making co-exposure consequences particularly severe. While the evidence available strongly suggests that lead, cadmium, and dioxin-like chemicals are negative modulators of human bone health, evidence supporting this conclusion for organotins, phthalates, arsenic, and PFAs is somewhat lacking. There are still significant gaps in our understanding that must be filled to gain a holistic understanding of these threats to human bone health. |
