Midya Vishal, Yao Meizhen, Colicino Elena, Barupal Dinesh, Lin Xiangping, Gennings Chris, Chatzi Leda, Setiawan Veronica Wendy, Loos Ruth J F, Walker Ryan W, Walker Douglas I, Valvi Damaskini
Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Environmental Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
EBioMedicine. 2025 Aug;118:105838. doi: 10.1016/j.ebiom.2025.105838. Epub 2025 Jul 21.
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.
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.
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.
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.
National Institutes of Health (R01ES033688, P30ES023515, R21ES035148, R35ES030435, R01ES032242, R01ES034521, R01ES029944, R01ES030364, U01HG013288, R21ES037112 and P30ES007048).
越来越多的证据表明，接触全氟和多氟烷基物质（PFAS）与2型糖尿病（T2D）风险增加有关；然而，PFAS混合物的影响及其潜在机制尚未完全明确。我们研究了接触PFAS混合物与后续T2D诊断以及潜在代谢失调之间的关联。
我们在BioMe中进行了一项巢式病例对照研究，BioMe是一个与电子健康记录相关联的生物样本库，自2007年以来，有超过65000名患者在纽约西奈山医院寻求初级医疗服务。在排除基线时的T2D现患病例后，我们选择了180例T2D新发病例（33%为非裔美国人，33%为西班牙裔，33%为白人）以及180名年龄、性别和血统匹配的无T2D对照。在基线时（诊断前约6年）采集的诊断前血浆中，我们对7种PFAS和非靶向代谢组学谱进行了定量分析。我们使用加权分位数和回归来评估PFAS混合物与T2D发病几率之间的关联。我们分别使用分层贝叶斯加权分位数和逻辑回归分析了约650种注释代谢物与PFAS混合物或T2D发病几率之间的关联，并对匹配因素和其他混杂因素进行了调整。使用Mummichog进行通路富集分析。
PFAS混合物每增加一个三分位数与T2D发病几率升高相关（OR[95%CI]=1.31[1.01,1.70]），其中全氟辛烷磺酸（PFOS）对这种关联的贡献最大。与PFAS混合物和T2D发病几率均相关的代谢物有5-羟色氨酸、葡庚糖和磺化石胆酰甘氨酸；与磺化石胆酰甘氨酸的关联在多次检验校正后仍然显著。与PFAS混合物和T2D均相关的通路有谷氨酸代谢、精氨酸和脯氨酸代谢以及药物代谢-细胞色素P450。
在多民族人群中，接触PFAS混合物可能通过氨基酸和药物代谢失调而增加T2D发病几率。需要在多民族人群中进行更大规模的研究，以阐明PFAS对代谢改变和T2D风险的潜在影响。
美国国立卫生研究院（R01ES033688、P30ES023515、R21ES035148、R35ES030435、R01ES032242、R01ES034521、R01ES029944、R01ES030364、U01HG0!3288、R21ES037112和P30ES007048）。
