Ambient [Formula: see text] Exposure and Bone Homeostasis: Analysis of UK Biobank Data and Experimental Studies in Mice and in Vitro

BACKGROUND: Previous evidence has identified exposure to fine ambient particulate matter ([Formula: see text]) as a leading risk factor for adverse health outcomes. However, to date, only a few studies have examined the potential association between long-term exposure to [Formula: see text] and bone homeostasis. OBJECTIVE: We sought to examine the relationship between long-term [Formula: see text] exposure and bone health and explore its potential mechanism. METHODS: This research included both observational and experimental studies. First, based on human data from UK Biobank, linear regression was used to explore the associations between long-term exposure to [Formula: see text] (i.e., annual average [Formula: see text] concentration for 2010) and bone mineral density [BMD; i.e., heel BMD ([Formula: see text]) and femur neck and lumbar spine BMD ([Formula: see text])], which were measured during 2014–2020. For the experimental animal study, C57BL/6 male mice were assigned to ambient [Formula: see text] or filtered air for 6 months via a whole-body exposure system. Micro-computed tomography analyses were applied to measure BMD and bone microstructures. Biomarkers for bone turnover and inflammation were examined with histological staining, immunohistochemistry staining, and enzyme-linked immunosorbent assay. We also performed tartrate-resistant acid phosphatase (TRAP) staining and bone resorption assay to determine the effect of [Formula: see text] exposure on osteoclast activity in vitro. In addition, the potential downstream regulators were assessed by real-time polymerase chain reaction and western blot. RESULTS: We observed that long-term exposure to [Formula: see text] was significantly associated with lower BMD at different anatomical sites, according to the analysis of UK Biobank data. In experimental study, mice exposed long-term to [Formula: see text] exhibited excessive osteoclastogenesis, dysregulated osteogenesis, higher tumor necrosis factor-alpha ([Formula: see text]) expression, and shorter femur length than control mice, but they demonstrated no significant differences in femur structure or BMD. In vitro, cells stimulated with conditional medium of [Formula: see text] macrophages had aberrant osteoclastogenesis and differences in the protein/mRNA expression of members of the [Formula: see text] pathway, which could be partially rescued by [Formula: see text] inhibition. DISCUSSION: Our prospective observational evidence suggested that long-term exposure to [Formula: see text] is associated with lower BMD and further experimental results demonstrated exposure to [Formula: see text] could disrupt bone homeostasis, which may be mediated by inflammation-induced osteoclastogenesis. https://doi.org/10.1289/EHP11646