Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice
Objective: Perfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic eff...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001715 |
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| author | Brecht Attema Aafke W.F. Janssen Deborah Rijkers Evert M. van Schothorst Guido J.E.J. Hooiveld Sander Kersten |
| author_facet | Brecht Attema Aafke W.F. Janssen Deborah Rijkers Evert M. van Schothorst Guido J.E.J. Hooiveld Sander Kersten |
| author_sort | Brecht Attema |
| collection | DOAJ |
| description | Objective: Perfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We examined whether exposure to low-dose PFOA and GenX induces metabolic disturbances in mice, including NAFLD, dyslipidemia, and glucose tolerance, and studied the involvement of PPARα. Methods: Male C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg body weight/day PFOA, or 0.3 mg/kg body weight/day GenX while being fed a high-fat diet for 20 weeks. Glucose and insulin tolerance tests were performed after 18 and 19 weeks. Plasma metabolite levels were measured next to a detailed assessment of the liver phenotype, including lipid content and RNA sequencing. Results: Exposure to high-dose PFOA decreased body weight and increased liver weight in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides was dependent on PPARα. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. RNA sequencing showed that the effects of GenX on hepatic gene expression were entirely dependent on PPARα, while the effects of PFOA were mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR and CAR became more prominent. Conclusion: Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts hepatic lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, the effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver. |
| first_indexed | 2024-04-11T06:05:39Z |
| format | Article |
| id | doaj.art-ce47522f87b34db69f0c886bfcd2d363 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T06:05:39Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-ce47522f87b34db69f0c886bfcd2d3632022-12-22T04:41:31ZengElsevierMolecular Metabolism2212-87782022-12-0166101602Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in miceBrecht Attema0Aafke W.F. Janssen1Deborah Rijkers2Evert M. van Schothorst3Guido J.E.J. Hooiveld4Sander Kersten5Nutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, the NetherlandsWageningen Food Safety Research (WFSR), Wageningen, the NetherlandsWageningen Food Safety Research (WFSR), Wageningen, the NetherlandsHuman and Animal Physiology, Wageningen University, the NetherlandsNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, the NetherlandsNutrition, Metabolism and Genomics Group, Division of Human Nutrition and Health, Wageningen University, the Netherlands; Corresponding author. Division of Human Nutrition and Health, Wageningen University, Stippeneng 4, 6708 WE Wageningen, Netherlands.Objective: Perfluoroalkyl substances (PFAS) are man-made chemicals with demonstrated endocrine-disrupting properties. Exposure to perfluorooctanoic acid (PFOA) has been linked to disturbed metabolism via the liver, although the exact mechanism is not clear. Moreover, information on the metabolic effects of the new PFAS alternative GenX is limited. We examined whether exposure to low-dose PFOA and GenX induces metabolic disturbances in mice, including NAFLD, dyslipidemia, and glucose tolerance, and studied the involvement of PPARα. Methods: Male C57BL/6J wildtype and PPARα−/− mice were given 0.05 or 0.3 mg/kg body weight/day PFOA, or 0.3 mg/kg body weight/day GenX while being fed a high-fat diet for 20 weeks. Glucose and insulin tolerance tests were performed after 18 and 19 weeks. Plasma metabolite levels were measured next to a detailed assessment of the liver phenotype, including lipid content and RNA sequencing. Results: Exposure to high-dose PFOA decreased body weight and increased liver weight in wildtype and PPARα−/− mice. High-dose but not low-dose PFOA reduced plasma triglycerides and cholesterol, which for triglycerides was dependent on PPARα. PFOA and GenX increased hepatic triglycerides in a PPARα-dependent manner. RNA sequencing showed that the effects of GenX on hepatic gene expression were entirely dependent on PPARα, while the effects of PFOA were mostly dependent on PPARα. In the absence of PPARα, the involvement of PXR and CAR became more prominent. Conclusion: Overall, we show that long-term and low-dose exposure to PFOA and GenX disrupts hepatic lipid metabolism in mice. Whereas the effects of PFOA are mediated by multiple nuclear receptors, the effects of GenX are entirely mediated by PPARα. Our data underscore the potential of PFAS to disrupt metabolism by altering signaling pathways in the liver.http://www.sciencedirect.com/science/article/pii/S2212877822001715PFOAGenXPPARαLipid metabolismDyslipidemiaNAFLD |
| spellingShingle | Brecht Attema Aafke W.F. Janssen Deborah Rijkers Evert M. van Schothorst Guido J.E.J. Hooiveld Sander Kersten Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice Molecular Metabolism PFOA GenX PPARα Lipid metabolism Dyslipidemia NAFLD |
| title | Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| title_full | Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| title_fullStr | Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| title_full_unstemmed | Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| title_short | Exposure to low-dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| title_sort | exposure to low dose perfluorooctanoic acid promotes hepatic steatosis and disrupts the hepatic transcriptome in mice |
| topic | PFOA GenX PPARα Lipid metabolism Dyslipidemia NAFLD |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001715 |
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