3266

Background: Perfluoroalkyl substances (PFAS) are persistent environmental pollutants that may induce metabolic perturbations in humans. However, underlying molecular mechanisms are still unknown and both direct and inverse associations of PFAS exposures with T2D have been reported. Thus, in this exploratory study, we investigated PFAS-related plasma metabolites for their associations with type 2 diabetes (T2D) to gain insight in these PFAS-induced alterations.
Methods: We used data from plasma measurements of PFAS exposures and untargeted LC-MS metabolomics in a case-control study on T2D (n=187 matched pairs) nested within the Västerbotten Intervention Programme cohort in northern Sweden. Principal component analysis (PCA) showed that six PFAS appeared in two groups: 1) longer-chain PFAS (perfluorononanoic acid, perfluorodecanoic acid and perfluoroundecanoic acid) and 2) shorter-chain PFAS (perfluorohexane sulfonic acid, perfluorooctane sulfonic acid and perfluorooctanoic acid). A random forest algorithm was used to find metabolite features associated with PFAS exposure patterns, which were then investigated for their prospective associations with T2D using conditional logistic regression.
Results: Out of 171 PFAS-related metabolite features (0.16 ≤ |r| ≤ 0.37), 35 also associated with T2D (p<0.05). PCA of the 35 PFAS- and T2D-related metabolites revealed two metabolite patterns, dominated by glycerophospholipids and diacylglycerols. Both metabolite patterns correlated positively with the longer-chain PFAS. The glycerophospholipid pattern associated with decreased T2D risk (OR = 0.2 per standard deviation (sd) increase in metabolite pattern score; 95% CI = 0.1-0.4), whereas the diacylglycerol pattern associated with increased T2D risk (OR = 1.9 per sd; 95% CI = 1.3-2.7).
Conclusions: Our results suggest that longer-chain PFAS associate with two metabolite patterns with opposite relations to T2D risk. The occurrence of these two metabolite patterns may imply co-occurring metabolic regulations, which could facilitate understanding of the conflicting results in the literature for PFAS and T2D associations.