Mechanisms of Exposure

暴露机制

• 批准号: 10352512
• 负责人: Angela L Slitt
• 金额: $ 26.85万
• 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/10352512
• 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; Mediating; Methods; Milk; Modeling; Mus; OATP Transporters; Organism; Outcome; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacy facility; Property; Proteins; Research; Research Project Grants; Risk; 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; base; 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; method development; novel; offspring; perfluorooctanoic acid; 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 - 机械）是一个利用药学和化学工程专业知识的生物医学项目 阐明构成人类和多氟化烷基物质（PFAS）抽象的机制，分布， 和极端（ADE）。 PFA在人血清和极端中被检测到。自从陡峭的I开始以来 它已成为PFAS污染是全球性，暴露量无处不在的证据，并且需要了解 PFAS属性很紧急。关于〜7000的机制的知识差距很大 商业市场上的PFA被吸收，保留，并被生活系统淘汰，并与 对决定PFAS ADE的机制几乎没有理解。基于细胞的研究表明两种蛋白 结合（即血清白蛋白和脂肪酸结合蛋白）和异生元/药物转运蛋白（即有机 阴离子运输多肽（OATP2B1）和ATP结合盒子亚家族G成员2（ABCG2）为 在体内决定PFA的抽象，分布和排泄的潜在机制。 P3 - 机械性将使用 小鼠敲除模型和基于细胞的测定，以检验蛋白质转运蛋白和蛋白质的假设 通过完成以下三个目的，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PFA摄取，组织的关键吸收机制的贡献 分配和消除；目标2：确定血清白蛋白和脂肪酸结合蛋白的贡献 作为PFA摄取，组织保留和消除的关键机制；和目标3：确定贡献 ABCG2是影响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的关键机制的验证。发现 该项目将有助于指导可以针对的关键毒理学机制的优先级和选择 在更大的筛选工作中。 P3 –机制确定的关键机制将告知P1-暴露，P2 – 关键效应和P4检测，并将纳入生物积累建模。项目1、2和 4将告知有关新PFA的P3机制，以表征在拟议的体外模型中。 P3– 机制将通过陡峭的RETCC提供跨学科的培训经验，并将支持 社区参与核心（CEC）通过参与有关发现的双向交流 PFAS科学。这项工作将大大提高我们对PFAS ADE的机械理解，尤其是在 与新兴PFA的谓词生理化学特性的关系，该特性解决了SRP授权＃2 （评估危险物质对人类健康的影响的技术）。它使用机械方法 确定调节PFA的潜在遗传风险或饮食因素，以解决广泛的SRP 授权＃3（开发评估风险危险物质对人类健康构成的方法）和 SRP授权＃4（生物学，化学和物理方法的发展降低了危险 物质及其毒性）。