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

项目摘要 健康的骨骼对长期健康至关重要，不仅可以减少骨折风险，而且作为一个活跃的内分泌器官， 影响能量平衡、矿物质代谢和身体成分。重大的公共健康 骨骼健康不良的后果包括糖尿病相关的发病率和死亡率的风险增加，胰岛素 抵抗力和心血管疾病。然而，无处不在的干扰内分泌的化学物质的潜力 对骨骼健康的影响尚不清楚。邻苯二甲酸酯，用于塑料和个人护理产品的化学品， 与可能影响骨骼健康的生物学途径有关，包括激素的破坏 对骨稳态和PPARg的活化至关重要，指导间充质干细胞的分化 从成骨细胞到脂肪细胞。最近，尿邻苯二甲酸酯代谢物与 在NHANES中，绝经后妇女的骨密度（BMD）较低，骨质疏松症风险较高，但 尚未探讨不同生命阶段的暴露或对骨代谢功能的影响。一些 重金属还与骨密度降低和骨质疏松症和骨折风险增加有关。 例如，铅在骨基质中积累，损害骨完整性。怀孕和 围绝经期是对暴露相关的骨骼健康变化潜在敏感的生命阶段， 以强烈的骨重建和代谢及激素平衡的改变为特征。因此，我们认为， 我们的目标是调查邻苯二甲酸酯和金属暴露在怀孕和围绝经期之间的关系 测量中年人的骨骼健康这项拟议中的研究利用了墨西哥的早期生活暴露 环境毒物（ELEMENT）出生队列，作为参与母亲，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，并重复邻苯二甲酸酯和 在怀孕期间进行金属接触测量。在这项研究中，参与者将提供邻苯二甲酸酯的信息 以及围绝经期随访时的金属暴露、骨结构、骨代谢和身体成分 访视（n=400）。BMI和绝经状态将作为潜在的效应调节剂进行探索， 代谢物和金属将被视为单独和混合物。我们的目标是调查（1） 孕期BMI和孕期及围产期BMI轨迹与BMD的相关性， 使用双能X射线评估骨骼肌指数以及女性和男性脂肪组织分布 骨吸收测定法（iDXA）和定量超声评估的骨微结构; 2） 妊娠期和围绝经期邻苯二甲酸酯和金属暴露与骨显微结构、BMD和 肌肉和脂肪组织分布; 3）妊娠期间邻苯二甲酸酯和金属暴露的相关性 和围绝经期与中年骨代谢的生物标志物。这项工作的结果将提供洞察力 研究与骨质疏松症有关的骨健康变化的机制，对骨质疏松症有重要意义， 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.