2. Academic Validation
  3. 1,2-Dichloroethane induces cerebellum granular cell apoptosis via mitochondrial pathway in vitro and in vivo

1,2-Dichloroethane induces cerebellum granular cell apoptosis via mitochondrial pathway in vitro and in vivo

  • Toxicol Lett. 2020 Apr 1;322:87-97. doi: 10.1016/j.toxlet.2020.01.004.
Manqi Huang 1,  Yizhou Zhong 2,  Li Lin 3,  Boxuan Liang 3,  Jun Liu 3,  Junying Jiang 4,  Manjiang Hu 3,  Yuji Huang 3,  Xi Lin 3,  Lvliang Lu 3,  Ziwei Bian 3,  Wenyu Zhong 3,  Jiejiao Wu 5,  Jiewei Zheng 2,  Weifeng Rong 2,  Yating Zhang 4,  Liang Jiang 5,  Jieling Wu 6,  Xin Zhang 7,  Xingfen Yang 3,  Qiansheng Hu 8,  Zhenlie Huang 9
Affiliations

Affiliations

  • 1 Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China; Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
  • 2 Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
  • 3 Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China.
  • 4 Faculty of Preventive Medicine, School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510006, China.
  • 5 Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
  • 6 Department of Healthcare, Guangdong Women and Children Hospital, Guangzhou 511442, China.
  • 7 Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
  • 8 Faculty of Preventive Medicine, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China. Electronic address: huqsh@mail.sysu.edu.cn.
  • 9 Guangdong Provincial Key Laboratory of Tropical Disease Research, Department of Toxicology, School of Public Health, Southern Medical University, Guangzhou 510515, China. Electronic address: huangzhenlie@126.com.
PMID: 31935479 DOI: 10.1016/j.toxlet.2020.01.004
Abstract

1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant, but little is known about the cerebellar dysfunction induced by excessive exposure to it. To uncover 1,2-DCE-induced neurotoxicity in cerebellar granular cells (CGCs), and to investigate the underlying mechanisms, we explored this, both in vitro and in vivo. Our findings showed significant cell viability inhibition in human CGCs (HCGCs) treated with 1,2-DCE. Flow cytometry and mitochondrial membrane potential analyses discovered an increase in apoptotic-mediated cell death in HCGCs after 1,2-DCE treatment. This HCGC Apoptosis was involved in the increases of protein expression in Cytochrome c, Caspase-3, Bad, Bim, transformation related protein 53, Caspase-8, tumor necrosis factor-α, and Survivin. Quantitative Real-Time PCR (qPCR) and western blot confirmed the increases in Cytochrome c, Caspase-3, cleaved Caspase-3, and Bad in HCGCs after 1,2-DCE treatment. Bax Inhibitor peptide V5 rescued 1,2-DCE-induced HCGC Apoptosis. Furthermore, 80 CD-1 male mice were exposed to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day for 4 weeks. An open field test found abnormal neurobehavioral changes in the mice exposed to 1,2-DCE. Histopathological examination showed significantly shrunken and hypereosinophilic cytoplasm with nuclear pyknosis in mouse CGCs from the 700 mg/m3 1,2-DCE group. TdT-mediated dUTP nick-end labeling assay verified significant increases in apoptotic positive cells in the mouse CGCs after 1,2-DCE exposure. We confirmed the increases in the expressions of Cytochrome c, Caspase-3, cleaved Caspase-3 and Bad in the mice exposed to 1,2-DCE. These findings suggest that 1,2-DCE exposure can induce CGC Apoptosis and cerebellar dysfunction, at least in part, through mitochondrial pathway.

Keywords

1,2-Dichloroethane; Apoptosis; Cerebellar dysfunction; Mitochondria; Neurotoxicity.

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