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

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Abstract

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.

AbstractSection 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.

AbstractSection Graphical abstract

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (81770773 to W. T.; 81870531 and 82070843 to Y-X. Z.), the Natural Science Foundation of Jiangsu Province (BK20171499), the Science and Technology Development Fund of Nanjing Medical University (NMUB2018172), and the Scientific Research Project of Jiangsu Health Vocational College (JKFY201809).

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Author notes

  1. Xiaowei He and Dan Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Islet Cell Senescence and Function Research Laboratory, Nanjing Medical University Affiliated Geriatric Hospital/Jiangsu Province Geriatric Hospital, 30 Luojia Road, Nanjing, 210024, Jiangsu, China

    Xiaowei He, Dan Wu & Wei Tang

  2. Department of Endocrinology, The Second Affiliated Hospital of Nanjing Medical University, 121 Jiangjia Yuan, Nanjing, 210011, Jiangsu, China

    Yanan Xu

  3. Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China

    Yaqin Zhang, Yue Sun, Xiaoai Chang & Yunxia Zhu

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  1. Xiaowei He
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  2. Dan Wu
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  3. Yanan Xu
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  8. Wei Tang
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Contributions

X. H., investigation and writing — original draft. D. W., data curation and formal analysis. Y. X., validation. Y. Z., investigation. Y. S., methodology. X. C., resources. Y. Z., visualization and writing — reviewing and editing. W. T., conceptualization and project administration.

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Correspondence to Wei Tang.

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The animal experiments were approved by the Institutional Animal Care and Use Committee at Nanjing Medical University.

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He, X., Wu, D., Xu, Y. et al. Perfluorooctanoic acid promotes pancreatic β cell dysfunction and apoptosis through ER stress and the ATF4/CHOP/TRIB3 pathway. Environ Sci Pollut Res 29, 84532–84545 (2022). https://doi.org/10.1007/s11356-022-21188-9

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