PFAS and bone health over the life course in Hispanic/Latinos: emerging risk factors and underlying mechanisms - ABSTRACT Latinos, one of the largest and fastest growing ethnic groups in the country, face a disproportionate burden of osteoporosis, with over 40% estimated to have low bone mass. The underlying environmental factors contributing to these disparities remain unclear. Per- and polyfluoroalkyl substances (PFAS) are ubiquitous, persistent chemicals and are emerging as potential risk factors for bone toxicity. Animal and autopsy studies have shown that PFAS can accumulate in skeletal tissues, potentially influencing bone metabolism through alterations in osteoclast and osteoblast activities and bone remodeling pathways. However, evidence from human studies is limited, often hindered by small sample sizes, cross-sectional designs, and a lack of focus on the Latino population, which bears a disproportionate burden of metabolic and bone diseases. Additionally, no studies have utilized omics biomarkers to explore the biological mechanisms through which PFAS may affect bone health. To address these critical knowledge gaps, we propose the first prospective study to investigate the effects of PFAS on bone mass, metabolism, and structural quality in a high-risk, overweight/obese Latino population. This study will integrate data from three longitudinal cohorts spanning the life course to understand the impact of PFAS at various stages of bone development and deterioration. Given the challenges of observing a single population over 70 years, this multi-cohort design provides the most effective approach for life course analyses. We will employ robust longitudinal assessments, including bone mineral density (BMD), markers of bone turnover (BTM), and trabecular bone score (TBS), to document the effects of PFAS across different life stages in overweight/obese Latinos. Additionally, we will use proteomics to comprehensively characterize dysregulated pathways affecting bone health, focusing on inflammation and metabolism-regulating proteins. Our specific aims are: 1) Determine the associations between plasma PFAS concentrations (individual PFAS and PFAS mixtures) and measures of bone health (BMD, BTM, and TBS) in Latino adolescents, young adults, and older adults; 2) Investigate the association between plasma PFAS concentrations and plasma protein abundance related to inflammation, bone morphogenic, and maintenance pathways across different age groups; and 3) Develop integrated risk profiles of impaired bone health in Latino populations across the life course. By leveraging three distinct, well-phenotyped cohorts and employing state-of-the-art omics and data science methodologies, this study aims to elucidate the impact of PFAS on bone health throughout the life course. The findings have the potential to inform the development of precision environmental health strategies to identify high-risk individuals and mitigate adverse effects on bone health, thus reducing the overall risk of osteoporosis.
