Uncovering the Mechanisms of PFAS-induced Immunotoxicity

揭示 PFAS 诱导免疫毒性的机制

• 批准号: 10559567
• 负责人: Seth William Kullman
• 金额: $ 15.94万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-03 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559567
• 关键词: Acceleration; Acids; Adaptive Immune System; Address; Affect; Air; Animal Experiments; Animal Model; Antibodies; Antibody Formation; Antigens; Assessment tool; Atmosphere; 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 Pollutants; 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; Immunotoxicology; Impairment; In Vitro; Individual; Industrial Product; Industrialization; Infection; Information Protection; Innate Immune System; Knowledge; Macrophage; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Mus; Natural Immunity; North Carolina; Organism; Outcome; Phagocytes; Phagocytosis; Plasma Cells; Poly-fluoroalkyl substances; Production; Proliferating; Public Health; Reactive Oxygen Species; Research; Research Project Grants; Resistance; Respiration; Risk; Risk Assessment; Risk Marker; Sampling; Serum; Signal Pathway; Signaling Protein; Site; Source; Stains; Superfund; T-Lymphocyte; Testing; Toxic effect; United States; Universities; Water; Work; Zebrafish; adaptive immunity; animal model selection; 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; manufacture; metabolome; metabolomics; migration; mouse model; neutrophil; novel; perfluorooctane sulfonate; programs; rapid technique; reproductive toxicity; response; transcriptome; vaccine response

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