Environmental origins of gestational diabetes: PFAS-induced mitochondrial dysfunction in pancreatic beta cells
Active Project Grant Awarded Last action
- Award ID
- F31ES038000
- Recipient
-
University Of Wisconsin System UEI LCLSJAGTNZQ7
- Awarding agency
-
National Institute of Environmental Health Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $74,930
Award facts
- Assistance listing
- 93.113 Environmental Health
- Completion date 0% complete
- Originally
- Place of performance
- Madison, WI 53715, USA
Award details come from USAspending.gov.
Description
- Abstract
- Pregnancy-induced pancreatic beta cell expansion and adequate release of insulin are essential for supporting metabolic and nutritional demands of the mother and fetus. Disruption of these processes leads to gestational diabetes mellitus (GDM), a frequent complication affecting 18% of pregnancies. The cause of GDM is not known, but the environmental exposure to per- and poly-fluoroalkyl substances (PFAS) and its bioaccumulation in the pancreas may hold important keys to understanding the origins of the disease and the underlying causes of maternal organ dysfunction. Perfluorooctane sulfonate (pfos), a legacy PFAS, is the most produced and representative of PFAS. Elevated maternal pfos is shown to be associated with GDM in humans. Whether this increase in pfos is directly involved in pancreatic dysfunction and manifestations of GDM is unknown. Our pilot studies show that pfos exposure in pregnant rats leads to glucose intolerance, blunts insulin secretion, and decreases ATP production. Pretreatment with mitoq, a mitochondrial-targeted antioxidant, effectively restored ATP production and insulin secretion. Based on these findings, we hypothesize that pfos decreases maternal pancreatic beta cell function by disrupting mitochondria-related insulin secretion mechanisms, leading to glucose intolerance. We will examine this premise with 2 aims, employing in vivo animal studies, EX vivo tissue-level functional analysis, and in vitro molecular analyses. Aim 1 will first establish the functional effects of pfos on glucose intolerance and insulin secretion and if the effects of pfos are exacerbated during pregnancy. To test the direct effects of pfos on pancreatic islets, EX vivo glucose- stimulated insulin secretion (gsis) assays on isolated islets will be performed. Also, the pfos effects on beta cell expansion will be assessed. Aim 2 will examine pfos-mediated beta cell mechanisms: intracellular calcium, camp, ATP, mitochondrial oxphos complexes, biogenesis, fission, and fusion pathways will be determined. Also, the expression of key signaling components of beta cell function will be measured. The role of mitoq, a mitochondrial-targeted antioxidant, in rescuing the effects of pfos on insulin secretion will provide further evidence for the role of mitochondrial dysfunction in pfos-induced beta cell impairment. Then, translational studies will test whether pfos affects the beta pathways and mechanisms by examining the effects in isolated human islets. These results are expected to have an important impact because they will contribute substantively to a mechanism-based understanding of pfos's role in pregnancy complications and alert environmental agencies to devise policies to curtail pfos exposure in reproductive-age women.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $37,465 | |
| Amendment | $0 | |
| Original award | $37,465 |
Quick answers
Who received award F31ES038000?
F31ES038000 was awarded to University Of Wisconsin System by National Institute of Environmental Health Sciences (National Institutes of Health) on November 21, 2026.
How much is award F31ES038000 worth?
$74,930 has been obligated on F31ES038000.
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