Mechanisms of Exposure

暴露机制

• 批准号: 10704013
• 负责人: Angela L Slitt
• 金额: $ 21.83万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704013
• 关键词: ABCG2 gene; Acids; Address; Apple; Binding; Binding Proteins; Biological; Biological Assay; Birds; Bispecific Antibody 2B1; Blood; Breast Epithelial Cells; Carrier Proteins; Cells; Chemical Engineering; Chemicals; Cods; Communication; Data; Detection; Development; Dietary Factors; Drug or chemical Tissue Distribution; Excretory function; Fatty Acid-Binding Protein 1; Fatty Acids; Fishes; Goals; Half-Life; Hazardous Substances; Health; Human; Human Milk; Impairment; In Vitro; Intestines; Juice; Kinetics; Knockout Mice; Knowledge; Lactation; Life; Liver; Marketing; Mediating; Methods; Milk; Modeling; Mus; OATP Transporters; Organism; Outcome; Permeability; Pharmaceutical Preparations; Pharmacy facility; Property; Proteins; Research; Risk Assessment; Rodent; Science; Serum; Serum Albumin; Signal Recognition Particle; Source; Techniques; Testing; Tissues; Toxic effect; Toxicokinetics; Toxicology; Training; Urine; Validation; Variant; Water; Whales; Work; Xenobiotics; absorption; bioaccumulation; biological development; community engagement; experience; fatty acid-binding proteins; genetic risk factor; high throughput screening; improved; in vitro Assay; in vitro Model; in vivo; in vivo Model; inhibitor; marine; method development; novel; offspring; perfluorooctanoic acid; pharmacologic; screening; tool; uptake; urinary; wasting

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).

项目摘要/摘要 – 项目 3 机制 项目 3（P3-Mechanisms）是一个生物医学项目，利用制药和化学工程专业知识 阐明全氟烷基物质和多氟烷基物质 (PFAS) 吸收、分布、 自 STEEP I 启动以来，已在人体血清和排泄物中检测到 PFAS。 很明显，PFAS 污染是全球性的，接触是无处不在的，并且需要了解 关于 PFAS 特性的认识存在很大差距，大约 7000 商业市场上的 PFAS 被生命系统吸收、保留和消除， 人们对 PFAS 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）和外源/药物转运蛋白（即有机 阴离子转运多肽 (OATP2B1) 和 ATP 结合盒亚家族 G 成员 2 (ABCG2)) 是 决定 PFAS 在体内吸收、分布和排泄的潜在机制将使用 P3 机制。 小鼠敲除模型和基于细胞的测定来检验蛋白质转运蛋白和蛋白质的假设 通过实现以下三个目标，结合是 PFAS ADE 和组织分布的关键因素： 目标 1：确定 OATP2B1 作为细胞 PFAS 摄取、组织摄取的关键摄取机制的贡献 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 PFAS 吸收、组织保留和消除的关键机制，以及目标 3：确定贡献； 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、啮齿动物工具和体外人源化工具验证关键机制。 该项目的进展将有助于指导可针对的关键毒理学机制的优先顺序和选择 在更大规模的筛查工作中，P3-机制确定的关键机制将为 P1-暴露、P2-提供信息。 关键效应和 P4 – 检测将被纳入生物累积模型 1、2 和 1。 4 将告知 P3-Mechanisms 有关新 PFAS 的信息，以在拟议的体外模型中进行表征。 机制将通过 STEEP 的 RETCC 提供跨学科培训经验，并将支持 社区参与核心（CEC），通过参与有关发现和结果的双向沟通 这项工作将显着增进我们对 PFAS ADE 的机制理解，特别是在 与新兴 PFAS 的预测理化特性的关系，解决了 SRP 任务 #2 （评估有害物质对人类健康影响的技术）它使用机械方法。 确定调节 PFAS ADE 的潜在遗传风险或饮食因素，从而解决广泛的 SRP 任务#3（制定评估有害物质对人类健康造成的风险的方法）和 SRP 指令 #4（开发减少有害物质的生物、化学和物理方法） 物质及其毒性）。