Polyfluoroalkyl substances (PFAS) are widely used industrial compounds that have been identified as contaminants in almost every component of the global ecosystem, and in human studies, higher levels of PFAS have been correlated with increased incidence of multiple diseases. Based on the results of human and laboratory animal studies, we hypothesize that the orphan nuclear receptor 4A1 (NR4A1) may be a critical target for some PFAS such as the legacy linear polyfluorooctanesulfonate (PFOS) and other sulfonates. We show that PFOS and related compounds bound the ligand binding domain (LBD) of NR4A1 and induced the growth of several cancer cell lines and enhanced tumor growth in an athymic nude mouse model. Using NR4A1-responsive rhabdomyosarcoma Rh30 cells as a model, PFOS induced NR4A1-dependent cell proliferation and Rh30 cell migration and invasion. Moreover, in Rh30 cells, PFOS also induces several NR4A1-regulated genes including the PAX3-FOXO1 oncogene and downstream gene products, and in a chromatin immunoprecipitation assay, PFOS does not decrease NR4A1 binding to the promoter. These results demonstrate that PFOS is an NR4A1 ligand and enhances tumorigenesis through the activation of this receptor.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.chemrestox.4c00528 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Perfluorooctane Sulfonate (PFOS) and Related Compounds Induce Nuclear Receptor 4A1 (NR4A1)-Dependent Carcinogenesis.
Chem Res Toxicol
March 2025
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas 77843 , United States.
Polyfluoroalkyl substances (PFAS) are widely used industrial compounds that have been identified as contaminants in almost every component of the global ecosystem, and in human studies, higher levels of PFAS have been correlated with increased incidence of multiple diseases. Based on the results of human and laboratory animal studies, we hypothesize that the orphan nuclear receptor 4A1 (NR4A1) may be a critical target for some PFAS such as the legacy linear polyfluorooctanesulfonate (PFOS) and other sulfonates. We show that PFOS and related compounds bound the ligand binding domain (LBD) of NR4A1 and induced the growth of several cancer cell lines and enhanced tumor growth in an athymic nude mouse model.
View Article and Find Full Text PDFNAM-based analysis of contaminant short-term organ toxicity in HepaRG and RPTEC/TERT1 cells.
Toxicology
March 2025
German Federal Institute for Risk Assessment, Department of Pesticides Safety, Berlin, Germany. Electronic address:
New Approach Methodologies (NAMs), including cell culture and multi-level omics analyses, are promising alternatives to animal testing. To become useable for risk assessment purposes they have to be applicable for different substance groups. One important group of substances is food contaminants, including synthetic chemicals, such as perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), and natural compounds, such as mycotoxins and pyrrolizidine alkaloids.
View Article and Find Full Text PDFEcosurveillance reveals subtle metabolic effects on the non-native cane toad (Rhinella marina) from low levels of accumulated environmental per- and polyfluoroalkyl substances.
Environ Pollut
March 2025
Environment Research Unit, CSIRO, Ecosciences Precinct, Dutton Park Qld, 4102, Australia.
Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment, bioaccumulate, and may have toxic effects. This study used non-native cane toads (Rhinella marina) to examine PFAS and metal accumulation and impacts in large terrestrial amphibians from urban and peri-urban areas. We quantified 38 PFAS compounds and 36 environmental and legacy metal(loid)s in 52 adult cane toad livers collected from six locations around Southeast Queensland, Australia, along a known PFAS gradient.
View Article and Find Full Text PDFDeciphering PFAS Mode of Action: Comparative Gene Expression Analysis in Human Liver Spheroids.
Toxicol Sci
March 2025
Environmental Health Science and Research Bureau, Health Canada.
Understanding the mechanisms by which environmental chemicals cause toxicity is necessary for effective human health risk assessment. High-Throughput Transcriptomics (HTTr) can be used to inform risk assessment on toxicological mechanisms, hazards, and potencies. We applied HTTr to elucidate the molecular mechanisms by which Per- and Polyfluoroalkyl Substances (PFAS) cause liver perturbations.
View Article and Find Full Text PDFPer- and polyfluoroalkyl substances: toxicokinetics, exposure and health risks.
J Toxicol Sci
March 2025
Department of Health and Environmental Science, Kyoto University Graduate School of Medicine.
Per- and polyfluoroalkyl substances (PFAS) are a group of chemicals containing stable per- or polyfluoroalkyl groups. Recent epidemiological studies have shown that PFAS cause health risks even at low concentrations. This review outlines the toxicokinetics, exposure and health risks of PFAS, with a focus on perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and long-chain perfluoroalkyl carboxylic acids (LC-PFCAs).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!