High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis
Perfluoroalkyl substances (PFAS) have been associated with cancer, but the potential underlying mechanisms need to be further elucidated and include studies of PFAS mixtures. This mechanistic study revealed that very low concentrations (500 pM) of the binary PFOS and PFOA mixture induced synergistic...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Environment International |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0160412023000193 |
| _version_ | 1797903505255563264 |
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| author | Paula Pierozan Marissa Kosnik Oskar Karlsson |
| author_facet | Paula Pierozan Marissa Kosnik Oskar Karlsson |
| author_sort | Paula Pierozan |
| collection | DOAJ |
| description | Perfluoroalkyl substances (PFAS) have been associated with cancer, but the potential underlying mechanisms need to be further elucidated and include studies of PFAS mixtures. This mechanistic study revealed that very low concentrations (500 pM) of the binary PFOS and PFOA mixture induced synergistic effects on human epithelial breast cell (MCF-10A) proliferation. The cell proliferation was mediated by pregnane X receptor (PXR) activation, an increase in cyclin D1 and CDK6/4 levels, decrease in p21 and p53 levels, and by regulation of phosphor-Akt and β-catenin. The PFAS mixture also altered histone modifications, epigenetic mechanisms implicated in tumorigenesis, and promoted cell migration and invasion by reducing the levels of occludin. High-content screening using the cell painting assay, revealed that hundreds of cell features were affected by the PFAS mixture even at the lowest concentration tested (100 pM). The detailed phenotype profiling further demonstrated that the PFAS mixture altered cell morphology, mostly in parameters related to intensity and texture associated with mitochondria, endoplasmic reticulum, and nucleoli. Exposure to higher concentrations (≥50 µM) of the PFOS and PFOA mixture caused cell death through synergistic interactions that induced oxidative stress, DNA/RNA damage, and lipid peroxidation, illustrating the complexity of mixture toxicology. Increased knowledge about mixture-induced effects is important for better understanding of PFAS’ possible role in cancer etiology, and may impact the risk assessment of these and other compounds. This study shows the potential of image-based multiplexed fluorescence assays and high-content screening for development of new approach methodologies in toxicology. |
| first_indexed | 2024-04-10T09:35:11Z |
| format | Article |
| id | doaj.art-4118647b8a68447382e692f1d1285fb0 |
| institution | Directory Open Access Journal |
| issn | 0160-4120 |
| language | English |
| last_indexed | 2024-04-10T09:35:11Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Environment International |
| spelling | doaj.art-4118647b8a68447382e692f1d1285fb02023-02-18T04:16:13ZengElsevierEnvironment International0160-41202023-02-01172107746High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesisPaula Pierozan0Marissa Kosnik1Oskar Karlsson2Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, SwedenScience for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, SwedenCorresponding author.; Science for Life Laboratory, Department of Environmental Science, Stockholm University, Stockholm 114 18, SwedenPerfluoroalkyl substances (PFAS) have been associated with cancer, but the potential underlying mechanisms need to be further elucidated and include studies of PFAS mixtures. This mechanistic study revealed that very low concentrations (500 pM) of the binary PFOS and PFOA mixture induced synergistic effects on human epithelial breast cell (MCF-10A) proliferation. The cell proliferation was mediated by pregnane X receptor (PXR) activation, an increase in cyclin D1 and CDK6/4 levels, decrease in p21 and p53 levels, and by regulation of phosphor-Akt and β-catenin. The PFAS mixture also altered histone modifications, epigenetic mechanisms implicated in tumorigenesis, and promoted cell migration and invasion by reducing the levels of occludin. High-content screening using the cell painting assay, revealed that hundreds of cell features were affected by the PFAS mixture even at the lowest concentration tested (100 pM). The detailed phenotype profiling further demonstrated that the PFAS mixture altered cell morphology, mostly in parameters related to intensity and texture associated with mitochondria, endoplasmic reticulum, and nucleoli. Exposure to higher concentrations (≥50 µM) of the PFOS and PFOA mixture caused cell death through synergistic interactions that induced oxidative stress, DNA/RNA damage, and lipid peroxidation, illustrating the complexity of mixture toxicology. Increased knowledge about mixture-induced effects is important for better understanding of PFAS’ possible role in cancer etiology, and may impact the risk assessment of these and other compounds. This study shows the potential of image-based multiplexed fluorescence assays and high-content screening for development of new approach methodologies in toxicology.http://www.sciencedirect.com/science/article/pii/S0160412023000193Breast cancerCell invasionCell paintingChemical mixtureCocktail effectEpigenetics |
| spellingShingle | Paula Pierozan Marissa Kosnik Oskar Karlsson High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis Environment International Breast cancer Cell invasion Cell painting Chemical mixture Cocktail effect Epigenetics |
| title | High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis |
| title_full | High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis |
| title_fullStr | High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis |
| title_full_unstemmed | High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis |
| title_short | High-content analysis shows synergistic effects of low perfluorooctanoic acid (PFOS) and perfluorooctane sulfonic acid (PFOA) mixture concentrations on human breast epithelial cell carcinogenesis |
| title_sort | high content analysis shows synergistic effects of low perfluorooctanoic acid pfos and perfluorooctane sulfonic acid pfoa mixture concentrations on human breast epithelial cell carcinogenesis |
| topic | Breast cancer Cell invasion Cell painting Chemical mixture Cocktail effect Epigenetics |
| url | http://www.sciencedirect.com/science/article/pii/S0160412023000193 |
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