(106) Perfluorooctanoic acid: an environmental modulator of susceptibility to gestational diabetes

Knickole L. Bergman¹,Mary Jerred, Madeline O’Connell, Ashley Fields, Philip Spinelli, Clementina Mesaros, Martha Susiarjo

¹Department of Environmental Medicine, School of Medicine & Dentistry, University of Rochester Medical Center (URMC), Rochester, NY (USA); ²Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania (UPenn), Philadelphia, PA (USA)


Abstract Text:

Gestational diabetes mellitus (GDM) is a form of diabetes that manifests during pregnancy and is characterized by hyperglycemia and glucose intolerance due to pregnancy-driven insulin resistance and inadequate pancreatic beta cell adaptation. GDM has a worldwide prevalence of 1.1-31.5 % and is influenced by race, ethnicity, age, body composition, and screening and diagnostic criteria. The rate of GDM in the US has increased by 30% from 2016 to 2020 and is expected to continue to increase in subsequent years. Women with GDM have an increased risk for pregnancy complications and adverse health conditions following pregnancy, while their fetuses face risks such as premature birth and metabolic disease later in life. Published studies have demonstrated that pancreatic beta cell proliferation is critical for maintaining healthy maternal glucose levels during pregnancy. One mechanism regulating beta cell proliferation is serotonin-dependent activation of the G1 cyclins for the cell cycle by the binding of serotonin to the HTR2B receptor. This mechanism is driven by pregnancy-induced activation of the tryptophan hydroxylase 1 gene (Tph1) and local islet serotonin production, a vitamin B6-dependent process. Previous work from our lab has shown that nutritional and genetic factors reducing maternal vitamin B6 levels can lower islet serotonin levels and beta cell proliferation, inducing hyperglycemia and glucose intolerance in pregnant mice.

The proposed research aims to investigate the effects of perfluorooctanoic acid (PFOA) on maternal pancreatic beta cell proliferation. PFOA is a synthetic and ubiquitous endocrine disrupting chemical (EDC) that has been detected in blood of humans and wildlife, soil, water, and household products. Epidemiologic studies have shown that gestational PFOA exposure is significantly associated with higher GDM risk. Preliminary studies using liquid chromatography high resolution mass spectrometry (LC-HRMS) show that gestational PFOA exposures lower islet vitamin B6 and serotonin levels in pregnant mice in a dose-dependent manner. Ongoing studies are performed to characterize the effects of gestational exposure to PFOA on pancreatic serotonin signaling, beta cell proliferation, and metabolic health, as well as genetic factors that may alter susceptibility to PFOA-induced GDM-like phenotypes. The proposed studies will test the overall hypothesis that PFOA exposure at an environmentally relevant dose alters glucose homeostasis regulation and GDM susceptibility in pregnant mice through mechanisms that are dependent on serotonin-driven beta cell proliferation. To test this hypothesis, C57BL6/J female mice are exposed to control or PFOA (0 or 8 µg PFOA/kg body weight/day, respectively) for two weeks prior to mating and throughout gestation (GD12.5 or 16.5). To assess the metabolic phenotype of these mice, mice undergo glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) testing. Another subset of these mice is used for histological analyses, utilizing immunohistochemistry (IHC) immunofluorescence (IF) and hematoxylin and eosin (H&E) staining to measure for islet serotonin abundance, beta cell proliferation, and islet morphology. Preliminary data suggest that PFOA exposure significantly decreases islet serotonin abundance, beta cell proliferation, and beta cell mass in GD12.5 pregnant mice without significantly altering islet morphology. Furthermore, PFOA-exposed GD16.5 pregnant mice have worse glucose tolerance relative to controls, consistent with a GDM-like phenotype. Future studies aim to whether the PFOA-induced effects are directly associated with reduced islet serotonin function by testing whether an HTR2B agonist administration restores the glucose intolerance phenotype. Together these studies can reveal areas for clinical intervention to help prevent and reduce GDM.