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

• 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
• 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

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 全氟和多氟烷基物质(PFAS)广泛存在于日常生活中。它们在消费者中的广泛使用 产品、工业流程和灭火泡沫导致饮用水和 导致人类普遍接触的食物。虽然许多研究已经调查了脂类的破坏 关于PFAS的代谢和免疫系统功能，对其不良影响的关注较少 全氟辛烷磺酸对骨骼健康的影响。鉴于全氟辛烷磺酸与低骨密度之间的流行病学关系 儿童和成人以及缺乏研究全氟辛烷磺酸的因果关系和/或机制 干扰骨代谢，这项研究的目的是开始确定全氟辛酸的影响 酸(PFOA)对骨骼质量的影响。我们的研究集中在PFAS与核受体的相互作用上，这可能是一种 PFAS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不良健康效应的模型：表达人过氧化物酶体增殖物的小鼠 激活的受体α(PPARα)根据NHANES中关于我们在美国吃什么的分析喂食。我们的 工作假说是，PFAS通过与多个核受体相互作用而降低骨质量 骨细胞类型。生成支持关联的原则证明所需的初步数据 在PFAS暴露和骨骼健康之间，为了完善我们的工作假设，我们提出了以下建议 明确目标。我们将确定长期接触全氟辛烷磺酸对皮质和骨小梁结构的影响， 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 从人源化PPARα中采集的骨和血清样本的优势 小鼠，PPARα缺失小鼠和PPARα野生型小鼠：研究1-年轻的雌性和雄性小鼠，喂养青少年 美国饮食，暴露于饮用水中的全氟辛烷磺酸6周，研究2-成年雌性和雄性小鼠，喂食 一种暴露于饮用水中全氟辛烷磺酸14周的美国成年人饮食。对肝脏和血清的生物学效应 这些小鼠的血清全氟辛酸浓度与职业性相似，其体内的脂质平衡是明显的。 暴露的人。将对骨骼结构、组织学、生化和转录数据进行分析。 基因型间的比较将开始确定PPARα在PFAS诱导的不良反应中的作用 对骨骼质量的影响。这项研究的结果将提供关于PFAS如何负面影响的重要新数据 影响骨骼健康并提供必要的基础，以开始解决全氟辛烷磺酸研究中的关键差距， 确定全氟辛烷磺酸与人类骨质量丧失之间存在因果关系的可能性。