期刊
TOXICOLOGY IN VITRO
卷 65, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tiv.2020.104795
关键词
Hexavalent chromium (Cr(VI)); Neurotoxicity; Apoptosis; Reactive oxygen species; Akt; ERK1/2; AMPK alpha
类别
资金
- Ministry of Science and Technology, Taiwan [MOST 105-2320-B-039-023]
- Changhua Christian Hospital, Changhua, Taiwan [104-CCH-IRP-066]
- Taichung Tzuchi Hospital
- Buddhist Tzuchi Medical Foundation, Taiwan [TTCRD 104-16]
- Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan [10712, 10814]
- China Medical University, Taichung, Taiwan [CMU108-MF-76]
Hexavalent chromium (Cr(VI)), a well-known toxic industrial and environmental pollutant, has been shown to cause serious toxic and health effects. However, limited information is available on Cr(VI)-induced neurotoxic potential, with the underlying toxicological mechanisms remain mostly unclear. The present study demonstrated that the mitochondria-dependent apoptosis pathway was involved in Cr(VI)-induced SH-SY5Y cell (the human neuroblastoma cell line) death, which was accompanied by the appearance of cell shrinkage, increased mitochondrial membrane potential (MMP) depolarization and cytochrome c release, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Cr(VI) treatment also increased the generation of intracellular reactive oxygen species (ROS). Pretreatment of SH-SY5Y cells with antioxidant N-acetylcysteine (NAC) effectively attenuated ROS production and reversed these Cr(VI)-induced cytotoxicity and apoptotic responses. Furthermore, exposure to Cr(VI) significantly increased the phosphorylation levels of Akt, extracellular regulated kinase (ERK)1/2, and AMP-activated protein kinase (AMPK)alpha. NAC and the pharmacological inhibitor of Akt (LY294002), ERK1/2 (PD980590), and AMPK alpha (Compound C) markedly abrogated the Cr(VI)-induced activation of Akt, ERK1/2, and AMPK alpha signal, respectively, with the concomitant inhibition of mitochondrial dysfunction and caspase activation. Additionally, all these inhibitors suppressed Cr(VI)-induced phosphorylation of Akt, ERK1/2, and AMPK alpha and of each other. Collectively, these results suggest that Cr(VI) exerts its cytotoxicity on neuronal cells by inducing mitochondria-dependent apoptosis through the interdependent activation of Akt, ERK1/2, and AMPK alpha, which are mainly mediated by ROS generation.
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