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Uncovering the Mechanisms of PFAS-induced Immunotoxicity

揭示 PFAS 诱导免疫毒性的机制

基本信息

批准号：
10115847
负责人：
Seth William Kullman
金额：
$ 9.71万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-28 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10115847
关键词：
Acids Adaptive Immune System Address Affect Air Animal Model Animals Antibodies Antibody Formation Antigens B-Cell Development B-Lymphocytes Bioenergetics Biological Biological Assay Biomedical Research Cause of Death Cell Line Cell physiology Cells Chemical Structure Chemicals Chemotaxis Chronic Disease Communities Data Deposition Dermal Development Disease Embryo Environment Environmental Health Environmental Pollution Environmental Risk Factor Event Experimental Animal Model Exposure to Flow Cytometry Food Frequencies Future Goals Hazardous Substances Health Hepatotoxicity Human Human Cell Line Immune Immune System Diseases Immune response Immune system Immunize Immunosuppression Immunotherapy Impairment In Vitro Individual Industrial Product Industrialization Infection Innate Immune System Knowledge Malignant Neoplasms Measures Mediating Metabolic Metabolism Mitochondria Modeling Molecular Mus Natural Immunity North Carolina Organism Outcome Phagocytes Phagocytosis Plasma Cells Production Public Health Reactive Oxygen Species Research Research Project Grants Resistance Respiration Risk Sampling Serum Signal Pathway Signaling Protein Site Source Stains Superfund T-Lymphocyte Testing Toxic effect Toxicology United States Universities Water Work Zebrafish adaptive immunity base bioaccumulation consumer product developmental toxicity disorder risk drinking water experience exposed human population hazard immune function immune health immunoregulation immunotoxicity improved in vivo in vivo Model macrophage metabolome metabolomics mouse model neutrophil novel perfluorooctane sulfonate programs rapid technique reproductive toxicity response tool transcriptome vaccine response

项目摘要

ABSTRACT (Biomedical Research) Research Project 2 Biomedical Research Project 2 is one of two biomedical research projects proposed for the “Center for Environmental and Health Effects of PFAS” being led by North Carolina State University (NC State). The primary goal of the proposed Center is to provide highly relevant data and information to help the Superfund Research Program (SRP) address the growing problem of per- and polyfluoroalkyl substance (PFAS) contamination across the United States (US). PFAS are considered contaminants of emerging concern for myriad reasons, but one of the most pressing is that only a handful of the nearly 5,000 PFAS that are known to exist have been evaluated for their toxicologic potential, even though numerous communities are being impacted by their presence in environmental media, especially drinking water. Studies of humans exposed to perfluoroocatonic acid (PFOA) and perfluorooctane sulfonate (PFOS), two PFAS detected with high frequency and concentration in human and environmental samples, have provided compelling evidence that the immune system is a sensitive target of PFAS. Additional work with experimental animal models supports the hypothesis that PFAS induce immunotoxicity and alter responses of both the adaptive and innate immune systems. While PFOA and PFOS are presumed to be immune hazards to humans, several gaps in knowledge exist: notably, the mechanism(s) by which these PFAS induce immunotoxicity remain elusive, and the extent to which most PFAS of emerging concern perturb immune function is largely unknown. Therefore, the objectives of Project 2 are twofold: i) explore molecular changes underlying PFAS-induced immunotoxicity in select animal models as well as human cell lines to identify impacted signaling pathways and networks, and ii) determine the immunotoxicological profile, including mechanistic underpinnings, of PFAS of emerging concern relative to the few well-studied PFAS. Our global hypothesis is that PFAS-mediated immune suppression results from modulation of immune cell metabolic functions. This hypothesis will be evaluated by (Aim 1) quantifying the impact of PFAS exposure on B cell development and antibody production in a mouse model and (Aim 2) identifying the impact of PFAS exposure on phagocytotic cell function using a zebrafish in vivo model and human in vitro cell line models. This project will address significant gaps in what is known about the mechanisms by which PFAS induce immunotoxicity, which will improve management of a known PFAS health risk, immune suppression, and accelerate development of immune therapies for affected individuals. Additionally, the large number of untested PFAS also means that methods for rapid prioritization are critical for informing appropriate regulatory measures; our project will uncover molecular initiating events underlying altered immune responses to facilitate novel, immune-mechanism-based prioritization strategies for PFAS recently detected in North Carolina and elsewhere.

摘要