Early Life Phthalate and Perfluoroalkyl Substance Exposures and Childhood Bone Health

摘要 邻苯二甲酸酯和全氟烷基物质（PFAS）是人类广泛接触的合成化学品 降低动物的骨密度。我们的初步数据和有限的流行病学研究报告， 这些化学物质会导致儿童身材矮小、骨密度降低和维生素D改变 成年人的新陈代谢青春期低峰值骨量是骨质疏松症的一个强可改变的危险因素， 影响数百万美国老年人的骨骼疾病。虽然生命早期是骨骼生长的关键时期 和骨量增加，目前还没有关于邻苯二甲酸酯或PFAS暴露与 儿童时期的骨密度因此，我们的目标是测试新的假设，即早期生活邻苯二甲酸酯和PFAS 暴露对儿童的骨骼生长、骨强度和维生素D代谢产生不利影响。我们高度 有效的建议利用健康成果和环境措施（HOME）研究， 一项在辛辛那提，俄亥俄州入组的前瞻性、种族多样性妊娠队列研究， 从妊娠期到8岁的生物标志物、混杂因素和身高测量。双能x线 骨密度的吸收测定法测量值目前正在进行12年的随访 访问我们还将测量经验证的维生素D和邻苯二甲酸酯暴露生物标志物， 邻苯二甲酸酯或PFAS暴露是否与从出生到12岁的身高轨迹相关（目的 1）、12岁时的骨密度（Aim 2）和8岁和12岁时的维生素D生物标志物浓度（Aim 3）。此外，我们还将通过检查身高或体重是否与化学和营养共同暴露有关来探讨化学和营养共同暴露的作用。 维生素D生物标志物浓度或钙摄入量改变或介导了骨密度相关性 (Aim 4）。使用丰富的纵向数据和复杂的贝叶斯建模方法，我们将调查 潜在的易感窗口（产前、幼儿期、儿童中期和青春期早期）以及 累积暴露和暴露混合物的影响。这项研究将构成第一个系统的 评估邻苯二甲酸酯和PFAS在改变骨骼健康方面的作用，这是一个重要但未充分研究的问题。 这是儿童福祉的一个组成部分，对骨折和骨质疏松症的终身风险至关重要。在 此外，该NIEHS ONES奖将支持一个特殊的早期研究人员建立一个 创新的研究计划，专门从事儿童的环境健康。最后，我们的发现将催化 未来的研究检查环境对青春期后期骨骼健康的影响，阐明生物学 机制，调查其他环境骨毒物，并开发化学或营养 干预措施，目标是让儿童走上一生更健康、更强壮的骨骼之路。

Abstract Phthalates and perfluoroalkyl substances (PFAS) are synthetic chemicals with widespread human exposures that lower bone density in animals. Our preliminary data and limited epidemiologic studies report associations of these chemicals with shorter stature in children as well as lower bone density and altered vitamin D metabolism in adults. Low peak bone mass in adolescence is a strong modifiable risk factor for osteoporosis, a bone disease impacting millions of older Americans. Although early life is a critical period of skeletal growth and bone mass accrual, there are currently no longitudinal studies of phthalate or PFAS exposures in relation to childhood bone density. Therefore, our goal is to test the novel hypothesis that early life phthalate and PFAS exposures adversely impact skeletal growth, bone strength, and vitamin D metabolism in children. Our highly efficient proposal leverages the Health Outcomes and Measures of the Environment (HOME) Study, a prospective, racially-diverse pregnancy cohort study enrolled in Cincinnati, Ohio with existing exposure biomarker, confounder, and height measures from gestation through 8 years of age. Dual-energy X-ray absorptiometry measurements of bone density are currently being collected at an ongoing 12-year follow-up visit. We will additionally measure validated vitamin D and phthalate exposure biomarkers to investigate whether phthalate or PFAS exposures are associated with height trajectories from birth to age 12 years (Aim 1), bone density at age 12 years (Aim 2), and vitamin D biomarker concentrations at ages 8 and 12 years (Aim 3). Further, we will explore the role of chemical and nutritional co-exposures by examining whether height or bone density associations are modified or mediated by vitamin D biomarker concentrations or calcium intake (Aim 4). Using rich longitudinal data and a sophisticated Bayesian modeling approach, we will investigate potential windows of susceptibility (prenatal, early childhood, mid childhood, and early adolescence) as well as effects of cumulative exposures and exposure mixtures. This research will constitute the first systematic assessment of the role of phthalates and PFAS in altering bone health, a significant but understudied component of child well-being with critical importance for life-long risk of fractures and osteoporosis. In addition, this NIEHS ONES Award will support an exceptional Early Stage Investigator to establish an innovative research program specializing in children's environmental health. Finally, our findings will catalyze future research examining environmental impacts on bone health in later adolescence, elucidating biological mechanisms, investigating other environmental bone toxicants, and developing chemical or nutritional interventions with the goal of setting children on a path to healthier, stronger bones throughout life.