Investigating the Perturbation of Bone Health by Per/Polyfluoroalkyl Substances

项目摘要 全氟烷基和多氟烷基物质（PFAS）在日常生活中普遍存在。广泛应用于消费者 产品、工业过程和消防泡沫的使用导致饮用水受到严重污染， 导致人类普遍接触的食物。虽然许多研究已经调查了脂质的破坏， PFAS对新陈代谢和免疫系统功能的影响，人们对PFAS的不良影响关注较少 PFAS对骨骼健康的影响。根据PFAS和低骨密度之间的流行病学联系， 儿童和成人，缺乏研究调查的因果关系和/或机制， 干扰骨代谢，本研究的目的是开始确定全氟辛酸的影响 PFOA（PFOA）对骨质的影响我们的研究重点是PFAS与核受体的相互作用，这可能是一种新的机制。 PFAS可以干扰骨细胞功能的机制。我们开发了一种新颖的，与人类相关的 研究PFAS不良健康影响的模型：表达人过氧化物酶体增殖物的小鼠 激活受体α（PPARα）的饮食基于NHANES的“我们在美国吃什么”分析。我们 工作假设是PFAS通过与多个核受体相互作用降低骨质量， 骨细胞类型生成支持关联原理证明所需的初步数据 PFAS暴露与骨骼健康之间的关系，并完善我们的工作假设，我们提出以下建议 具体目标。我们将确定长期暴露于PFOA对皮质和小梁结构的影响， 成骨细胞和破骨细胞的数量和功能，以及骨转录组。我们建议采取 从已经在人源化PPARα中进行的实验中收集的骨和血清样本的优势 小鼠、PPARα敲除小鼠和PPARα野生型小鼠：研究1 -年轻雌性和雄性小鼠，喂食青春期 美国饮食，暴露于饮用水中的PFOA 6周，研究2 -成年雌性和雄性小鼠，喂食 一个成年美国人的饮食暴露于饮用水中的PFOA 14周。对肝脏和血清的生物学效应 脂质体内平衡在这些小鼠中是明显的，其血清PFOA浓度与职业性 暴露的人。将分析骨结构、组织学、生化和转录组学数据。 基因型之间的比较将开始，以确定PPARα在PFAS诱导的不良反应中的作用。 对骨质量的影响。这项研究的结果将提供有关PFAS如何负面影响的重要新数据 影响骨骼健康，并为开始解决PFAS研究中的关键空白提供所需的基础， 建立PFAS与人类骨质量损失之间的因果关系。

Project Summary Per- and polyfluoroalkyl substances (PFAS) are pervasive in everyday life. Their extensive use in consumer products, industrial processes and fire-fighting foam has led to significant contamination of drinking water and food resulting in universal human exposure. While many studies have investigated the disruption of lipid metabolism and immune system function by PFAS, less attention has been paid to the adverse effects of PFAS on bone health. In light of the epidemiological associations between PFAS and lower bone density in children and adults and the lack of studies investigating the causality and/or mechanisms by which PFAS could interfere with bone metabolism, the objective of this study is to begin to define the effects of perfluorooctanoic acid (PFOA) on bone quality. Our research focuses on the interaction of PFAS with nuclear receptors, a likely mechanism through which PFAS could perturb bone cell function. We have developed a novel, human-relevant model in which to study the adverse health effects of PFAS: mice expressing human peroxisome proliferator activated receptor α (PPARα) fed a diet based on the What We Eat In America analysis in NHANES. Our working hypothesis is that PFAS reduce bone quality through their interaction with nuclear receptors in multiple bone cell types. To generate the preliminary data needed to support the proof-of-principle for an association between PFAS exposure and bone health and to hone our working hypothesis, we propose the following specific aim. We will define the effect of long term PFOA exposure on cortical and trabecular structure, osteoblast and osteoclast number and function, and the bone transcriptome. We propose to take advantage of bone and serum samples collected from experiments already conducted in humanized PPARα mice, PPARα null mice and PPARα wildtype mice: Study 1 – young female and male mice, fed an adolescent American diet, exposed to PFOA in drinking water for 6 weeks and Study 2 – adult female and male mice, fed an adult American diet exposed to PFOA in drinking water for 14 weeks. Biological effects on liver and serum lipid homeostasis are evident in these mice, which have serum PFOA concentrations similar to occupationally exposed people. Bone structural, histological, biochemical and transcriptomic data will be analyzed. Comparison between genotypes will begin to define the contribution of PPARα in PFAS-induced adverse effects on bone quality. The results of this research will provide essential new data on how PFAS negatively impact bone health and provide the needed foundation to begin to address a critical gap in PFAS research, establishing the potential for causality in associations between PFAS and loss of bone quality in humans.