Development of in vitro test methods in a model of human pancreatic β-cells to identify metabolism disrupting chemicals with diabetogenic activity

Abstract

There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-{beta}H1 {beta}-cell line, the rat {beta}-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 M). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as "unknowns". Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPAR{gamma}, respectively. ROS production was a consistent key event in BPA- and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a "new" diabetogenic agent. Our results indicate that the EndoC-{beta}H1 cell line is a suitable human {beta}-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into tier protocols for the identification of MDCs.