Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context
Summary: Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) are linked to an increased risk of type 2 diabetes (T2D); however, the effect of PFAS mixtures and underlying mechanisms are not well understood. We examined the associations between exposure...
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Elsevier
2025-08-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396425002828 |
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| author | Vishal Midya Meizhen Yao Elena Colicino Dinesh Barupal Xiangping Lin Chris Gennings Leda Chatzi Veronica Wendy Setiawan Ruth J.F. Loos Ryan W. Walker Douglas I. Walker Damaskini Valvi |
| author_facet | Vishal Midya Meizhen Yao Elena Colicino Dinesh Barupal Xiangping Lin Chris Gennings Leda Chatzi Veronica Wendy Setiawan Ruth J.F. Loos Ryan W. Walker Douglas I. Walker Damaskini Valvi |
| author_sort | Vishal Midya |
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| description | Summary: Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) are linked to an increased risk of type 2 diabetes (T2D); however, the effect of PFAS mixtures and underlying mechanisms are not well understood. We examined the associations between exposure to PFAS mixture with later T2D diagnosis and underlying metabolic dysregulations. Methods: We conducted a nested case–control study within BioMe, an electronic health record-linked biobank of >65,000 patients seeking primary care at Mount Sinai Hospital, New York, since 2007. After excluding prevalent T2D cases at baseline, we selected 180 incident T2D cases (33% African Americans, 33% Hispanics, 33% Whites) and 180 age, sex, and ancestry-matched T2D-free controls. In prediagnostic plasma collected at baseline (∼6 years before diagnosis), we quantified seven PFAS and untargeted metabolomic profiles. We used Weighted Quantile Sum regression to evaluate the PFAS mixture association with the odds for incident T2D. We analysed the associations between ∼650 annotated metabolites and the PFAS mixture or T2D odds using Hierarchical Bayesian Weighted Quantile Sum and logistic regression, respectively, adjusting for matching factors and other confounders. Pathway enrichment analyses were performed using Mummichog. Findings: Each tertile increase in the PFAS mixture was associated with higher odds of incident T2D (OR [95% CI] = 1.31 [1.01, 1.70]), with Perfluorooctane Sulfonate (PFOS) having the highest contribution to this association. Metabolites associated with both the PFAS mixture and T2D odds were 5-hydroxytryptophan, glucoheptulose, and sulfolithocholylglycine; the associations with sulfolithocholylglycine survived multiple testing corrections. Pathways associated with both the PFAS mixture and T2D were glutamate metabolism, arginine and proline metabolism, and drug metabolism—cytochrome p450. Interpretation: Exposure to PFAS mixtures may be associated with increased odds for T2D in multiethnic populations via dysregulations in amino acid and drug metabolism. Larger investigations in multiethnic populations are required to elucidate the potential PFAS contribution to metabolic alterations and T2D risk. Funding: National Institutes of Health (R01ES033688, P30ES023515, R21ES035148, R35ES030435, R01ES032242, R01ES034521, R01ES029944, R01ES030364, U01HG013288, R21ES037112 and P30ES007048). |
| format | Article |
| id | doaj-art-d79fe7f4dff943cc9ad238e11415bf7a |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
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| spelling | doaj-art-d79fe7f4dff943cc9ad238e11415bf7a2025-08-20T03:38:26ZengElsevierEBioMedicine2352-39642025-08-0111810583810.1016/j.ebiom.2025.105838Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in contextVishal Midya0Meizhen Yao1Elena Colicino2Dinesh Barupal3Xiangping Lin4Chris Gennings5Leda Chatzi6Veronica Wendy Setiawan7Ruth J.F. Loos8Ryan W. Walker9Douglas I. Walker10Damaskini Valvi11Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Corresponding author.Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Genetics, Stanford University School of Medicine, Palo Alto, CA, USADepartment of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USADepartment of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USAThe Charles Bronfman Institutes for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DenmarkDepartment of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USAGangarosa Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, GA, USADepartment of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USASummary: Background: Growing evidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) are linked to an increased risk of type 2 diabetes (T2D); however, the effect of PFAS mixtures and underlying mechanisms are not well understood. We examined the associations between exposure to PFAS mixture with later T2D diagnosis and underlying metabolic dysregulations. Methods: We conducted a nested case–control study within BioMe, an electronic health record-linked biobank of >65,000 patients seeking primary care at Mount Sinai Hospital, New York, since 2007. After excluding prevalent T2D cases at baseline, we selected 180 incident T2D cases (33% African Americans, 33% Hispanics, 33% Whites) and 180 age, sex, and ancestry-matched T2D-free controls. In prediagnostic plasma collected at baseline (∼6 years before diagnosis), we quantified seven PFAS and untargeted metabolomic profiles. We used Weighted Quantile Sum regression to evaluate the PFAS mixture association with the odds for incident T2D. We analysed the associations between ∼650 annotated metabolites and the PFAS mixture or T2D odds using Hierarchical Bayesian Weighted Quantile Sum and logistic regression, respectively, adjusting for matching factors and other confounders. Pathway enrichment analyses were performed using Mummichog. Findings: Each tertile increase in the PFAS mixture was associated with higher odds of incident T2D (OR [95% CI] = 1.31 [1.01, 1.70]), with Perfluorooctane Sulfonate (PFOS) having the highest contribution to this association. Metabolites associated with both the PFAS mixture and T2D odds were 5-hydroxytryptophan, glucoheptulose, and sulfolithocholylglycine; the associations with sulfolithocholylglycine survived multiple testing corrections. Pathways associated with both the PFAS mixture and T2D were glutamate metabolism, arginine and proline metabolism, and drug metabolism—cytochrome p450. Interpretation: Exposure to PFAS mixtures may be associated with increased odds for T2D in multiethnic populations via dysregulations in amino acid and drug metabolism. Larger investigations in multiethnic populations are required to elucidate the potential PFAS contribution to metabolic alterations and T2D risk. Funding: National Institutes of Health (R01ES033688, P30ES023515, R21ES035148, R35ES030435, R01ES032242, R01ES034521, R01ES029944, R01ES030364, U01HG013288, R21ES037112 and P30ES007048).http://www.sciencedirect.com/science/article/pii/S2352396425002828ExposomicsType 2 diabetesPer-and polyfluoroalkyl substancesMetabolomicsExposure mixture |
| spellingShingle | Vishal Midya Meizhen Yao Elena Colicino Dinesh Barupal Xiangping Lin Chris Gennings Leda Chatzi Veronica Wendy Setiawan Ruth J.F. Loos Ryan W. Walker Douglas I. Walker Damaskini Valvi Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context EBioMedicine Exposomics Type 2 diabetes Per-and polyfluoroalkyl substances Metabolomics Exposure mixture |
| title | Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context |
| title_full | Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context |
| title_fullStr | Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context |
| title_full_unstemmed | Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context |
| title_short | Exposure to per- and poly-fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic US populationResearch in context |
| title_sort | exposure to per and poly fluoroalkyl substances in association to later occurrence of type 2 diabetes and metabolic pathway dysregulation in a multiethnic us populationresearch in context |
| topic | Exposomics Type 2 diabetes Per-and polyfluoroalkyl substances Metabolomics Exposure mixture |
| url | http://www.sciencedirect.com/science/article/pii/S2352396425002828 |
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