Acute PFOS exposure consistently dysregulates glucose-stimulated insulin secretion across model systems
Bibliographic record
Abstract
ABSTRACT Aims/hypothesis Poly- and perfluoroalkyl substances (PFAS) are fluorinated chemicals widely used in consumer and industrial products. Serum PFAS concentrations have been linked to increased type 2 diabetes risk, but whether this is caused by direct effects of PFAS on the endocrine pancreas remains unclear. This study expands on previous biodistribution data to better characterize PFAS accumulation in human pancreas. We also assessed the effects of perfluorooctane sulfonic acid (PFOS) on pancreatic beta cell function using various model systems. Methods We measured concentrations of three legacy PFAS (PFOS, PFOA, PFHxS) in plasma and pancreas from 88 human donors. We also modeled PFOS and PFOA exposure in mice to confirm our human biodistribution data. We next exposed immortalized INS-1 cells, primary human donor islets, and primary mouse islets to DMSO (vehicle) or PFOS (1, 10 or 100 μM) either acutely during a glucose-stimulated insulin secretion (GSIS) assay or for 48h (prolonged) and GSIS was subsequently measured. We also assessed whether the acute effects of PFOS on GSIS in mouse islets were mediated by G-protein coupled receptor-40 (GPR40) and/or glucagon-like peptide-1 receptor (GLP-1R). Lastly, we exposed female mice to DMSO or 10 mg/kg PFOS with or without a 2 g/kg glucose bolus to assess the acute effects of PFOS on glucose homeostasis in vivo . Results PFOS was detected at higher concentrations in both plasma and pancreas compared to PFOA and PFHxS in our human donor population. Similarly, PFOS accumulated in pancreas at concentrations 2x higher than PFOA in our mouse model. We provide compelling evidence that PFOS exposure dysregulates insulin secretion in various model systems. Prolonged PFOS exposure suppressed GSIS in INS-1 832/3 cells and mouse islets, whereas acute PFOS exposure stimulated GSIS in mouse islets and in a subset of our human donor islets. We also show that the acute effects of PFOS on GSIS in mouse islets were partly mediated by GLP-1R. Importantly, acute PFOS exposure increased plasma insulin levels in female mice in vivo , but only when PFOS exposure was concurrent with a glucose bolus. Conclusions Legacy PFAS chemicals are consistently detected in human pancreas tissue. We clearly show that PFOS exposure dysregulates insulin secretion in various model systems, although effects varied based on the model and duration of exposure. Collectively, our findings support emerging evidence that PFOS contribute to beta cell dysfunction and points to the importance of model selection when assessing toxicological effects of PFAS on islet function.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".