Investigating the Perturbation of Bone Health by Per/Polyfluoroalkyl Substances

研究全氟烷基/多氟烷基物质对骨骼健康的干扰

基本信息

批准号：
10589459
负责人：
Jennifer J Schlezinger
金额：
$ 8.25万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589459
关键词：
Address Adolescent Adult Adverse effects Age American American diet Attention Biochemical Biological Blood Bone Density Carboxylic Acids Cell physiology Chemical Exposure Chemistry Child Data Databases Detection Diagnosis Diet Eating Epidemiology Estrogen Receptors Ethers Etiology Exposure to Female Food Foundations Genotype Health Histologic Homeostasis Human Impairment In Vitro Industrialization Investigation Knockout Mice Life Light Lipids Liver Long-Term Effects Longevity Measures Mental Health Metabolic Modeling Monitor Mus National Health and Nutrition Examination Survey Natural regeneration Nature Nuclear Receptors Occupational Exposure Osteoblasts Osteoclasts Osteoporosis Outcome PPAR alpha Pathway interactions Perinatal Persons Phenotype Play Poly-fluoroalkyl substances Population Positioning Attribute Process Public Health Quality of life Receptor Signaling Reporting Research Risk Role Sampling Serum Source Structure Sulfonic Acids Testing Therapeutic Effect Tissues Toxic Environmental Substances Wild Type Mouse Woman aged aging population bone bone cell bone health bone loss bone metabolism bone quality cell type constitutive androstane receptor consumer product contaminated drinking water defined contribution drinking water epidemiologic data epidemiology study experience experimental study exposed human population fracture risk healthy aging immune system function improved in vivo in vivo Model lipid metabolism male mathematical model men mortality novel osteoporosis with pathological fracture perfluorooctanoic acid physical conditioning pregnane X receptor toxicant interaction transcriptome transcriptomics

项目摘要

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.

项目摘要在日常生活中，每日和多氟烷基物质（PFA）普遍存在。他们在消费者中的广泛使用产品，工业过程和消防泡沫已导致饮用水和食物导致人类普遍接触。尽管许多研究调查了脂质的破坏 PFA的代谢和免疫系统功能，对骨骼健康的PFA。鉴于PFA和较低的骨密度之间的流行病学关联儿童和成人以及缺乏研究PFA的因果关系和/或机制的研究干扰骨骼代谢，这项研究的目的是开始定义全氟的影响酸（PFOA）骨质质量。我们的研究重点是PFA与核接收器的相互作用，这可能是 PFA可以扰动骨细胞功能的机制。我们已经开发了一部小说，与人类相关的小说研究PFA的不良健康影响的模型：表达人过氧化物体增殖物的小鼠活化的受体α（PPARα）根据我们在NHANES中的美国分析中喂养饮食。我们的工作假设是PFA通过与多个核接收器的相互作用来降低骨骼质量骨细胞类型。生成支持协会的原则证明所需的初步数据在PFAS暴露和骨骼健康和磨练我们的工作假设之间，我们提出以下具体目标。我们将定义长期PFOA暴露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中进行的实验收集的骨骼和血清样品的优势小鼠，PPARα无效小鼠和PPARα野生型小鼠：研究1 - 年轻雌性和雄性小鼠，喂养青少年美国饮食，暴露于饮用水中的PFOA 6周，研究2 - 成年雌性和雄性小鼠，喂养美国成年饮食在饮用水中暴露于PFOA 14周。生物学对肝脏和系列的影响脂质稳态是这些小鼠的证据，这些小鼠的PFOA浓度与占有率相似暴露的人。将分析骨结构，组织学，生化和转录组数据。基因型之间的比较将开始定义PPARα在PFA诱导的不良方面的贡献对骨质质量的影响。这项研究的结果将提供有关PFA如何负面影响的重要新数据影响骨骼健康，并提供所需的基础，以解决PFAS研究中的关键差距，在PFA与人类骨质丧失之间建立偶然性的潜力。