Perfluorooctanoic acid promotes pancreatic β cell dysfunction and apoptosis through ER stress and the ATF4/CHOP/TRIB3 pathway

• Published in: Environmental science and pollution research international 2022-12, Vol.29 (56), p.84532-84545
• Main Authors: He, Xiaowei, Wu, Dan, Xu, Yanan, Zhang, Yaqin, Sun, Yue, Chang, Xiaoai, Zhu, Yunxia, Tang, Wei
• Format: Article
• Language: English
• Subjects: Annexin V; Apoptosis; Aquatic Pollution; Atmospheric Protection/Air Quality Control/Air Pollution; Beta cells; Biosynthesis; Cell survival; Cell viability; Cholecystokinin; Defects; Diabetes mellitus (non-insulin dependent); Earth and Environmental Science; Ecotoxicology; Endoplasmic reticulum; Environment; Environmental Chemistry; Environmental Health; Environmental science; Gene expression; Gene sequencing; Genes; Glucose; Insulin; Insulin secretion; Pancreas; Pathogenesis; Perfluoroalkyl & polyfluoroalkyl substances; Perfluorooctanoic acid; Research Article; Secretion; Transcription activation; Waste Water Technology; Water Management; Water Pollution Control
• ISSN: 0944-1344; 1614-7499
• DOI: 10.1007/s11356-022-21188-9

Perfluorooctanoic acid (PFOA), a widely used chemical substance, causes an increased risk of human type 2 diabetes (T2D), but its underlying mechanism is not well elucidated. The aim of the present study was to investigate whether PFOA regulates the functions of pancreatic β cells, which are specialized for the biosynthesis and secretion of insulin. The treatment of the mouse pancreatic β cell line (MIN6 cells) with PFOA caused a time- and dose-dependent inhibition of cell viability in CCK-8 assays. Annexin V/PI and TUNEL staining results confirmed that exposure to a high PFOA dose (500 μM) promoted apoptosis of β cells, while a low dose (300 μM) had no effects on β cell survival. PFOA treatment, even at a low dose, diminished glucose-stimulated insulin secretion (GSIS) in both primary islet perfusion and MIN6 cell experiments. RNA-sequencing data showed significantly increased expression of endoplasmic reticulum (ER) stress-associated genes, with tribbles homolog 3 ( Trib3 ) ranking first among the altered genes. The activation of ER stress pathways was verified by qRT-PCR assays, and the ATF4/CHOP/TRIB3 pathway contributed to PFOA-induced β cell damage. The inhibition of TRIB3 expression significantly protected MIN6 cells from PFOA-induced GSIS defects and apoptosis by ameliorating ER stress. These findings reveal a link between ER stress and PFOA-induced β cell defects, opening up a new set of questions about the pathogenesis of T2D due to environmental chemicals. Highlights PFOA exposure results in pancreatic β cell apoptosis. PFOA treatment diminishes glucose-stimulated insulin secretion in β cells. PFOA activates endoplasmic reticulum stress and increases TRIB3 expression. Inhibition of TRIB3 expression ameliorates PFOA-caused β cell dysfunction and apoptosis. Graphical abstract