Relating phthalate and metals exposure during pregnancy and perimenopause to bone health and body composition in midlife

PROJECT SUMMARY Healthy bone is critical for long term health not only to minimize fracture risk, but as an active endocrine organ with influence on energy homeostasis, mineral metabolism, and body composition. Significant public health consequences of poor bone health include increased risk of fracture-related morbidity and mortality, insulin resistance, and cardiovascular disease. However, the potential for ubiquitous endocrine-disrupting chemicals to affect bone health is unknown. Phthalates, chemicals used in plastics and personal care products, have been associated with biological pathways that may affect bone health, including disruption of hormones essential to bone homeostasis and activation of PPARg, directing differentiation of mesenchymal stem cells from osteoblasts to adipocytes. Recently, urinary phthalate metabolites were cross-sectionally associated with lower bone mineral density (BMD) and higher osteoporosis risk in post-menopausal women in NHANES, but the effects of exposure at different life stages or on bone metabolic function have not been explored. Some heavy metals have also been associated with decreased BMD and increased risk of osteoporosis and fracture. For example, lead accumulates in the bone matrix, compromising bone integrity. Pregnancy and perimenopause are life stages potentially sensitive to exposure related changes in bone health, as they are characterized by intense bone remodeling and changes in metabolic and hormone homeostasis. Therefore, our goal is to investigate relationships of phthalate and metals exposure across pregnancy and perimenopause with measures of bone health in midlife. The proposed research leverages the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) birth cohort, as participating mothers, who are now 40-65 years of age, provided extensive demographic, anthropometric, and health information, and repeated phthalate and metal exposure measures, during pregnancy. In this study, participants will provide information on phthalate and metal exposure, bone structure, bone metabolism, and body composition at a perimenopausal follow-up visit (n=400). BMI and menopausal status will be explored as potential effect modifiers, and phthalate metabolites and metals will be considered individually and as mixtures. Our aims are to investigate 1) associations of BMI during pregnancy and BMI trajectory through pregnancy and perinatal periods with BMD, skeletal muscle index, and gynoid and android adipose tissue distribution assessed using dual energy x-ray absorptiometry (iDXA), and bone microstructure assessed by quantitative ultrasound, in midlife; 2) associations of phthalate and metals exposure during pregnancy and perimenopause with bone microstructure, BMD, and muscle and adipose tissue distribution; 3) associations of phthalate and metals exposure during pregnancy and perimenopause with biomarkers of bone metabolism in midlife. Findings from this work will provide insight into mechanisms of exposure-related changes in bone health, with important implications for osteoporosis, fracture risk, and long-term metabolic and cardiovascular health.