Mechanisms of Exposure

暴露机制

基本信息

  • 批准号:
    10352512
  • 负责人:
  • 金额:
    $ 26.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

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Angela L Slitt其他文献

Angela L Slitt的其他文献

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{{ truncateString('Angela L Slitt', 18)}}的其他基金

Mechanisms of Exposure
暴露机制
  • 批准号:
    10704013
  • 财政年份:
    2017
  • 资助金额:
    $ 26.85万
  • 项目类别:
Sources, Transport, Exposure and Effects of PFASs (STEEP)
PFAS 的来源、传输、暴露和影响 (STEEP)
  • 批准号:
    9258544
  • 财政年份:
    2017
  • 资助金额:
    $ 26.85万
  • 项目类别:
Research Experience and Training Coordination Core (RETCC)
研究经验和培训协调核心(RETCC)
  • 批准号:
    10704031
  • 财政年份:
    2017
  • 资助金额:
    $ 26.85万
  • 项目类别:
Research Experience and Training Coordination Core (RETCC)
研究经验和培训协调核心(RETCC)
  • 批准号:
    10352517
  • 财政年份:
    2017
  • 资助金额:
    $ 26.85万
  • 项目类别:
Developmental exposure to Bisphenol A and susceptibility to liver injury
发育时期接触双酚 A 和对肝损伤的易感性
  • 批准号:
    8879721
  • 财政年份:
    2015
  • 资助金额:
    $ 26.85万
  • 项目类别:
RESVERATROL INDUCTION OF GENE EXPRESSION VIA ACTIVATION OF CAR AND NRF2
白藜芦醇通过激活 CAR 和 NRF2 诱导基因表达
  • 批准号:
    7960141
  • 财政年份:
    2009
  • 资助金额:
    $ 26.85万
  • 项目类别:
Effect of nutritional status on MRP2 expression and biliary excretion of bispheno
营养状况对MRP2表达和双酚胆汁排泄的影响
  • 批准号:
    7911148
  • 财政年份:
    2009
  • 资助金额:
    $ 26.85万
  • 项目类别:
Effect of nutritional status on MRP2 expression and biliary excretion of bispheno
营养状况对MRP2表达和双酚胆汁排泄的影响
  • 批准号:
    8282836
  • 财政年份:
    2008
  • 资助金额:
    $ 26.85万
  • 项目类别:
RESVERATROL INDUCTION OF GENE EXPRESSION VIA ACTIVATION OF CAR AND NRF2
白藜芦醇通过激活 CAR 和 NRF2 诱导基因表达
  • 批准号:
    7725156
  • 财政年份:
    2008
  • 资助金额:
    $ 26.85万
  • 项目类别:
Effect of nutritional status on MRP2 expression and biliary excretion of bispheno
营养状况对MRP2表达和双酚胆汁排泄的影响
  • 批准号:
    7684045
  • 财政年份:
    2008
  • 资助金额:
    $ 26.85万
  • 项目类别:

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