{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T19:45:48Z","timestamp":1792784748751,"version":"4.5.0"},"reference-count":49,"publisher":"American Chemical Society (ACS)","issue":"6","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"publisher","award":["2023AFA007"],"award-info":[{"award-number":["2023AFA007"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018537","name":"National Science and Technology Major Project","doi-asserted-by":"publisher","award":["2024ZD0531600"],"award-info":[{"award-number":["2024ZD0531600"]}],"id":[{"id":"10.13039\/501100018537","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Natural Science Foundation of China (NSFC)","award":["82273717"],"award-info":[{"award-number":["82273717"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>To elucidate the sex-specific associations of per- and polyfluoroalkyl substances (PFASs) on type 2 diabetes (T2D) risk and to explore whether genetic susceptibility and baseline lipid profiles may help explain these associations. A nested case-control study including 985 matched case-control pairs from the Dongfeng-Tongji Cohort was conducted. Serum PFAS concentrations, T2D-related pathway polygenic risk scores (PRSs), blood lipid profiles, and plasma lipidomes were integrated. Conditional logistic regression, weighted quantile sum (WQS) regression, mediation analysis, and gene-environment interaction analysis were used to explore the associations and mechanisms. Sex-specific associations were observed between PFAS exposure and incident T2D, with PFOA and PFNA being associated with higher T2D risk in females. Liver-lipid pathway PRS strengthened these sex-specific associations. PFAS exposure was associated with triglyceride-related lipid profiles in females. Exploratory analyses suggested that the lipid score statistically accounted for part of the selected PFAS-T2D associations. CYP19A1-rs2414098 modified the association in females, with 50% mediation by the lipid score in the CC genotype (higher estrone). Baseline lipid profiles may partly account for the observed sex-specific associations between PFAS exposure and incident T2D. The observed effect modification by CYP19A1 rs2414098 suggests that hormonal pathways may contribute to the sex-specific associations, although this hypothesis requires confirmation in studies with direct hormone measurements and experimental validation.<\/jats:p>","DOI":"10.1021\/ehp.6c00071","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:02:34Z","timestamp":1785934954000},"page":"688-698","source":"Crossref","is-referenced-by-count":0,"title":["Sex-Specific Associations\nBetween Per- and Polyfluoroalkyl\nSubstances and the Risk of Type 2 Diabetes: The Role of Genetic Susceptibility\nand Lipid Metabolism"],"prefix":"10.1021","volume":"134","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4426-6527","authenticated-orcid":true,"given":"Xu","family":"Cheng","sequence":"first","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Gao","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Guo","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaokun","family":"Qiu","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2096-921X","authenticated-orcid":true,"given":"Meian","family":"He","sequence":"additional","affiliation":[{"name":"Huazhong University of Science and Technology , , , ,","place":["Wuhan, China, 430030"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026101215564212400_cit1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes\nAtlas: Global, regional and country-level diabetes prevalence\nestimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. 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Epidemiol"},{"key":"2026101215564212400_cit33","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1021\/acs.est.3c06561","article-title":"Elucidating Key Characteristics\nof PFAS Binding to Human Peroxisome\nProliferator-Activated Receptor Alpha: An Explainable Machine Learning\nApproach","volume":"58","author":"Maeda","year":"2024","journal-title":"Environ. Sci. Technol."},{"key":"2026101215564212400_cit34","doi-asserted-by":"publisher","first-page":"e148798","DOI":"10.1172\/JCI148798","article-title":"Inhibition\nof phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome\nin mice","volume":"131","author":"Mishra","year":"2021","journal-title":"J. Clin Invest"},{"key":"2026101215564212400_cit35","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1016\/j.ijheh.2018.07.007","article-title":"Nonlinear associations between dietary exposures to perfluorooctanoic\nacid (PFOA) or perfluorooctane sulfonate (PFOS) and type 2 diabetes\nrisk in women: Findings from the E3N cohort study","volume":"221","author":"Mancini","year":"2018","journal-title":"Int. J. Hyg Environ. Health"},{"key":"2026101215564212400_cit36","doi-asserted-by":"publisher","first-page":"14817","DOI":"10.1021\/acs.est.3c02765","article-title":"Paired Liver:Plasma\nPFAS Concentration Ratios from Adolescents in\nthe Teen-LABS Study and Derivation of Empirical and Mass Balance Models\nto Predict and Explain Liver PFAS Accumulation","volume":"57","author":"Baumert","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"2026101215564212400_cit37","doi-asserted-by":"publisher","DOI":"10.1289\/EHP10092","article-title":"Exposure to per- and Polyfluoroalkyl Substances and Markers of Liver\nInjury: A Systematic Review and Meta-Analysis","volume":"130","author":"Costello","year":"2022","journal-title":"Environ. Health Perspect"},{"key":"2026101215564212400_cit38","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1007\/s10654-025-01271-4","article-title":"The relationship between PFAS exposure and dyslipidemia: an updated\nreview, meta-analysis, and evaluation of bias","volume":"40","author":"Hussey","year":"2025","journal-title":"Eur. J. Epidemiol"},{"key":"2026101215564212400_cit39","doi-asserted-by":"publisher","first-page":"113680","DOI":"10.1016\/j.ijheh.2020.113680","article-title":"Per- and\npolyfluoroalkyl substance plasma concentrations and metabolomic markers\nof type 2 diabetes in the Diabetes Prevention Program trial","volume":"232","author":"Mitro","year":"2021","journal-title":"International Journal of Hygiene and Environmental Health"},{"key":"2026101215564212400_cit40","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2022.116136","article-title":"In vitro activity of\na panel of per- and polyfluoroalkyl substances\n(PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated\nreceptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays","volume":"449","author":"Evans","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"2026101215564212400_cit41","doi-asserted-by":"publisher","first-page":"809","DOI":"10.1038\/s41569-021-00569-6","article-title":"PPAR control of metabolism and cardiovascular\nfunctions","volume":"18","author":"Montaigne","year":"2021","journal-title":"Nat. Rev. Cardiol"},{"key":"2026101215564212400_cit42","doi-asserted-by":"publisher","first-page":"1563","DOI":"10.1056\/NEJMoa1001282","article-title":"Effects of combination\nlipid therapy in type 2 diabetes mellitus","volume":"362","author":"Accord Study Group","year":"2010","journal-title":"N\nEngl J. Med."},{"key":"2026101215564212400_cit43","doi-asserted-by":"publisher","first-page":"481","DOI":"10.1038\/emm.2002.67","article-title":"Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism","volume":"34","author":"Yoon","year":"2002","journal-title":"Exp Mol. Med."},{"key":"2026101215564212400_cit44","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2021.152845","article-title":"Why is elevation of serum cholesterol associated with exposure to\nperfluoroalkyl substances (PFAS) in humans? A workshop report on potential\nmechanisms","volume":"459","author":"Andersen","year":"2021","journal-title":"Toxicology"},{"key":"2026101215564212400_cit45","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2023.107951","article-title":"Insight into the binding\nmodel of per- and polyfluoroalkyl substances\nto proteins and membranes","volume":"175","author":"Zhao","year":"2023","journal-title":"Environ. Int."},{"key":"2026101215564212400_cit46","doi-asserted-by":"publisher","first-page":"12291","DOI":"10.1021\/acs.est.1c01200","article-title":"Rapid Characterization\nof Human Serum Albumin Binding for Per- and Polyfluoroalkyl Substances\nUsing Differential Scanning Fluorimetry","volume":"55","author":"Jackson","year":"2021","journal-title":"Environ.\nSci. Technol."},{"key":"2026101215564212400_cit47","doi-asserted-by":"publisher","DOI":"10.1289\/EHP11885","article-title":"A State-of-the-Science\nReview of Interactions of Per- and Polyfluoroalkyl\nSubstances (PFAS) with Renal Transporters in Health and Disease: Implications\nfor Population Variability in PFAS Toxicokinetics","volume":"131","author":"Niu","year":"2023","journal-title":"Environ. Health Perspect"},{"key":"2026101215564212400_cit48","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1007\/s12403-025-00743-y","article-title":"Associations Between\nSeafood Consumption and Serum PFAS Levels Among\nAsian\/Pacific Islanders in the San Francisco Bay Area, California","volume":"18","author":"Chen","year":"2026","journal-title":"Expo Health"},{"key":"2026101215564212400_cit49","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2026.110251","article-title":"Diet, lifestyle, and\nsociodemographic influences on serum concentration\nof PFASs: Insights from human biomonitoring in Switzerland","volume":"211","author":"Riou","year":"2026","journal-title":"Environ. Int."}],"container-title":["Environmental Health Perspectives"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/EHP.6c00071","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/134\/6\/688\/66378763\/ehp.6c00071.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article-pdf\/134\/6\/688\/66378763\/ehp.6c00071.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T20:09:12Z","timestamp":1791835752000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/evhpaz\/article\/134\/6\/688\/5242159\/Sex-Specific-Associations-Between-Per-and"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,4]]},"references-count":49,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,8,4]]},"published-print":{"date-parts":[[2026,10,6]]}},"URL":"https:\/\/doi.org\/10.1021\/ehp.6c00071","relation":{},"ISSN":["1552-9924"],"issn-type":[{"value":"1552-9924","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,4]]}}}