Perfluorooctanoic acid: a potential environmental modulator of susceptibility to gestational diabetes mellitus - PROJECT SUMMARY 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 developing 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 influencing maternal vitamin B6 levels can alter islet serotonin levels and beta cell proliferation, inducing hyperglycemia and glucose intolerance in pregnant mice deficient in vitamin B6. The proposed research aims to identify environmental and genetic modulators of maternal vitamin B6 to help identify risk factors associated with the development of GDM. Specifically, the proposed studies will 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 across the globe. Preliminary findings from our lab indicate that gestational exposure to PFOA reduces levels of islet vitamin B6 and serotonin. The proposed studies will test the overarching 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. Elucidating the mechanisms by which gene- environment interactions alter maternal vitamin B6 levels is pertinent to understanding the disparate risks for GDM among individuals and populations. These studies will provide new insights that will benefit maternal and child health outcomes.
