Mechanisms of Exposure

项目摘要/摘要--项目3机制 项目3(P3-机械)是一个生物医学项目，利用制药和化学工程的专业知识来 阐明全氟烷基物质和多氟烷基物质(PFAS)吸收、分布、 和排泄物(ADE)。已在人的血清和排泄物中检测到全氟辛烷磺酸。自从陡峭的一号开始， 很明显，全氟辛烷磺酸的污染是全球性的，暴露是无处不在的，需要了解 全氟辛烷磺酸的性能是迫切的。关于~7000的作用机制，人们的认识存在很大差距。 商业市场上的全氟辛烷磺酸被生活系统吸收、保留和淘汰， 对决定全氟辛烷磺酸ADE的机制知之甚少。基于细胞的研究表明，这两种蛋白质 结合(即血清白蛋白和脂肪酸结合蛋白)和异物/药物转运体(即有机转运体 阴离子转运多肽(OATP2B1)和三磷酸腺苷结合盒G亚家族成员2(ABCG2)) 决定PFAS在体内吸收、分布和排泄的潜在机制。P3-机构将使用 小鼠基因敲除模型和基于细胞的分析来检验蛋白质转运体和蛋白质 通过实现以下三个目标，结合是影响PFAS、ADE和组织分布的关键因素： 目的1：确定OATP2B1作为细胞摄取PFAS的关键摄取机制的贡献，组织 分布和消除；目标2：确定血清白蛋白和脂肪酸结合蛋白的贡献 作为全氟辛烷磺酸摄取、组织保留和消除的关键机制；和目标3：确定 ABCG2作为影响PFAS ADE的关键外排机制。拟议工作的结果将是 使用体内、基于啮齿动物的工具和体外人性化工具对关键机制进行验证。调查结果 该项目的实施将有助于指导确定优先次序和选择可作为目标的关键毒理学机制 在更大规模的筛选工作中。由P3确定的关键机制-机制将通知P1-暴露，P2- 临界效应和P4-检测，并将纳入生物累积模型。项目1、2和 4将告知P3-关于新的PFAS的机制，以在所提出的体外模型中进行表征。P3- 各机制将通过START的RETCC提供跨学科培训体验，并将支持 社区参与核心(CEC)，通过参与有关调查结果和 全氟化氢科学。这项工作将极大地促进我们对PFAS ADE的机械性理解，特别是在 与新出现的全氟辛烷磺酸的预测性物理化学性质的关系，它涉及SRP任务#2 (评估有害物质对人类健康影响的技术)。它使用机械论的方法 确定潜在的遗传风险或调节全氟辛烷磺酸ADE的饮食因素，以解决广泛的SRP 任务3(制定评估危险物质对人类健康构成的风险的方法)和 战略行动方案任务#4(发展减少危险的生物、化学和物理方法 物质及其毒性)。

PROJECT SUMMARY/ABSTRACT – PROJECT 3 MECHANISMS Project 3 (P3–Mechanisms) is a biomedical project utilizing expertise in pharmacy and chemical engineering to elucidate mechanisms that underlie per- and polyfluorinated alkyl substances (PFAS) absorption, distribution, and excretion (ADE). PFAS have been detected in human serum and excreta. Since the inception of STEEP I, it has become evident that PFAS contamination is global, exposure is ubiquitous, and the need to understand PFAS properties is urgent. There is a large gap in knowledge regarding the mechanisms by which the ~7000 PFAS that are on the commercial market are absorbed, retained, and are eliminated by the living system, with very little understood about the mechanisms that dictate PFAS ADE. Cell-based studies suggest both protein binding (i.e., Serum Albumin and Fatty Acid Binding Proteins) and xenobiotic/drug transporters (i.e., Organic Anion Transporting Polypeptide (OATP2B1) and ATP-Binding Cassette Subfamily G Member 2 (ABCG2)) are potential mechanisms that dictate PFAS absorption, distribution, and excretion in vivo. P3–Mechanisms will use mouse knock-out models and cell-based assays to test the hypothesis that protein transporters and protein binding are critical factors for PFAS ADE and tissue distribution through accomplishing the following three aims: Aim 1: Determine the contribution of OATP2B1 as a critical uptake mechanism for cellular PFAS uptake, tissue distribution and elimination; Aim 2: Determine the contribution of Serum Albumin and Fatty Acid Binding Proteins as critical mechanisms for PFAS uptake, tissue retention, and elimination; and Aim 3: Determine the contribution of ABCG2 as a critical efflux mechanism that influences PFAS ADE. The outcome of the proposed work will be the validation of critical mechanisms using in vivo, rodent based tools and in vitro humanized tools. The findings of the project will help guide the prioritization and selection of key toxicological mechanisms that can be targeted in larger screening efforts. Key mechanisms identified by P3–Mechanisms will inform P1–Exposure, P2– Critical Effects, and P4–Detection and will be incorporated into bioaccumulation modeling. Projects 1, 2, and 4 will inform P3–Mechanisms about new PFAS to characterize in the proposed in vitro models. P3– Mechanisms will provide an interdisciplinary training experience through STEEP’s RETCC and will support the Community Engagement Core (CEC) through participation in bidirectional communications about findings and PFAS science. This work will significantly advance our mechanistic understanding of PFAS ADE, especially in relationship to predicative physiochemical properties of emerging PFAS, which addresses SRP Mandate #2 (techniques of assessing the effects of hazardous substances on human health). It uses a mechanistic approach to identify underlying genetic risk or dietary factors that modulate PFAS ADE, which addresses the broad SRP Mandate # 3 (development of methods of assessing the risks hazardous substances pose to human health) and SRP Mandate #4 (development of biological, chemical, and physical methods of decreasing hazardous substances and their toxicity).