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Flurochloridone Induced Cell Apoptosis via ER Stress and eIF2α-ATF4/ATF6-CHOP-Bim/Bax Signaling Pathways in Mouse TM4 Sertoli Cells

Author

Listed:
  • Fen Zhang

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

  • Zhijing Ni

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

  • Shuqi Zhao

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

  • Yanna Wang

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

  • Xiuli Chang

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

  • Zhijun Zhou

    (School of Public Health, MOE Key Laboratory for Public Health Safety/NHC Key Lab of Health Technology Assessment, Fudan University, Shanghai 200032, China)

Abstract

Flurochloridone (FLC), as a novel herbicide, has been widely used in many countries since 1980s. Current studies have shown that FLC has toxic effects on male reproduction and its target organ is testis, while the underlying mechanism is still unknown. Mouse testis Sertoli cell line TM4 cells were used as an in vitro model and treated with FLC at different doses (40, 80, 160 μM) for different times (6, 12, 24 h). Cell viability, cytotoxicity and apoptotic cells were detected by CCK-8 assay, LDH leakage assay and flow cytometry. The protein levels of GRP78, phosphorylated-eIF2α, ATF4, ATF6, CHOP, Bim and Bax were observed by Western Blot and Immunofluorescence staining. FLC inhibited cell viability and induced cytotoxicity in dose-dependent way in TM4 cells. The percentage of apoptotic cells were 6.2% ± 0.6%, 7.3% ± 0.3%, 9.8% ± 0.4%, 13.2% ± 0.2%, respectively. The expression levels of ER stress and UPR related proteins were activated over dose. Meanwhile, the pro-apoptotic proteins (Bim and Bax) were also up-regulated in dose-dependent. After pretreated with ISRIB, the inhibitor of eIF2α phosphorylation, the elevated expression of GRP78, phosphorylated-eIF2α, ATF4, ATF6, CHOP and Bim was down to normal level accordingly. In conclusion, FLC induced apoptosis in TM4 cells mediated by UPR signaling pathways.

Suggested Citation

  • Fen Zhang & Zhijing Ni & Shuqi Zhao & Yanna Wang & Xiuli Chang & Zhijun Zhou, 2022. "Flurochloridone Induced Cell Apoptosis via ER Stress and eIF2α-ATF4/ATF6-CHOP-Bim/Bax Signaling Pathways in Mouse TM4 Sertoli Cells," IJERPH, MDPI, vol. 19(8), pages 1-12, April.
    • Handle: RePEc:gam:jijerp:v:19:y:2022:i:8:p:4564-:d:790851
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    References listed on IDEAS

    as
    1. Hongyan Zhu & Rui Li & Su Zhou & Suhui Zhang & Yu Wang & Shihong Liu & Qingwen Song & Xiuli Chang & Yubin Zhang & Luqing Liu & Liming Tang & Zhijun Zhou, 2019. "The Oral NOAEL of Flurochloridone in Male Wistar Rats in Ninety-Day Subchronic Toxicity Test Was 3mg/kg/day," IJERPH, MDPI, vol. 16(4), pages 1-7, February.
    2. Suhui Zhang & Xiaoqin Cheng & Yu Wang & Junpei Fan & Rui Li & Su Zhou & Shihong Liu & Jingmin Shi & Jie Sun & Yue Hu & Chaojin Xu & Chunhua Wu & Xiuli Chang & Liming Tang & Zhijun Zhou, 2015. "Ninety Day Toxicity and Toxicokinetics of Fluorochloridone after Oral Administration in Rats," IJERPH, MDPI, vol. 12(5), pages 1-25, May.
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