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

项目总结 健康的骨骼对长期健康至关重要，不仅可以将骨折风险降到最低，还可以作为一个活跃的内分泌器官。 对能量平衡、矿物质代谢和身体成分有影响。重大公共卫生 骨骼健康不良的后果包括增加与骨折相关的发病率和死亡率，胰岛素 抵抗力和心血管疾病。然而，无处不在的内分泌干扰化学物质的可能性 影响骨骼健康的因素尚不清楚。邻苯二甲酸酯，用于塑料和个人护理产品的化学物质，具有 与可能影响骨骼健康的生物途径有关，包括荷尔蒙的干扰 对骨稳态和PPARg的激活至关重要，指导骨髓间充质干细胞的分化 从成骨细胞到脂肪细胞。最近，尿邻苯二甲酸盐代谢产物与 NHANES中绝经后女性的骨密度(BMD)较低，骨质疏松风险较高，但 不同生命阶段的暴露或对骨代谢功能的影响尚未被探索。一些人 重金属还与骨密度降低、骨质疏松症和骨折风险增加有关。 例如，铅在骨骼基质中积累，损害骨骼的完整性。怀孕和 围绝经期是生命阶段，可能对暴露相关的骨骼健康变化敏感，因为它们是 以剧烈的骨骼重塑以及代谢和激素稳态的变化为特征。因此， 我们的目标是调查怀孕和围绝经期邻苯二甲酸盐和金属暴露的关系。 对中年的骨骼健康进行测量。这项拟议的研究利用了墨西哥的早年生活暴露 以环境毒物(元素)出生的队列，作为参与的母亲，她们现在40-65岁 年龄，提供了广泛的人口统计学、人体测量学和健康信息，并重复邻苯二甲酸盐和 金属暴露措施，在怀孕期间。在这项研究中，参与者将提供有关邻苯二甲酸盐的信息 围绝经期随访时的金属暴露、骨结构、骨代谢和身体成分 访问(n=400)。BMI和更年期状态将作为潜在的效果修饰剂进行探索，邻苯二甲酸盐 代谢物和金属将作为混合物单独考虑。我们的目标是调查1) 孕期BMI和孕期及围产期BMI轨迹与BMD的关系 用双能x射线评估骨骼肌指数以及雌雄和安卓脂肪组织的分布 中年的骨密度测定(IDXA)和定量超声评估的骨微结构；2)相关性 妊娠和围绝经期邻苯二甲酸盐和金属暴露与骨显微结构、骨密度和 肌肉和脂肪组织的分布；3)孕期邻苯二甲酸盐和金属暴露的关系 以及围绝经期中年骨代谢的生物标记物。这项工作的发现将提供洞察力 探讨与暴露有关的骨骼健康变化的机制，对骨质疏松有重要影响， 骨折风险，以及长期代谢和心血管健康。

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.