Methylmercury exposure induces ROS/Akt inactivation-triggered endoplasmic reticulum stress-regulated neuronal cell apoptosis. (1st September 2019)

• Record Type: Journal Article
• Authors: Chung, Yao-Pang; Yen, Cheng-Chieh; Tang, Feng-Cheng; Lee, Kuan-I; Liu, Shing-Hwa; Wu, Chin-Ching; Hsieh, Shang-Shu; Su, Chin-Chuan; Kuo, Chun-Ying; Chen, Ya-Wen
• Is Part Of: Toxicology. Volume 425(2019)
• Publication Date: 2019-09-01
• Subjects: MeHg methylmercury -- ND neurodegenerative diseases -- CNS central nervous system -- PS phosphatidylserine -- ER endoplasmic reticulum -- PARP poly (ADP-ribose) polymerase -- GRP glucose-regulated protein -- CHOP C/EBP homologous protein -- XBP-1 X-box binding protein-1 -- PERK protein kinase R-like ER kinase -- eIF2α eukaryotic initiation factor 2α -- ERE-1 inositol-requiring enzyme-1 -- ATF activation transcription factor -- siRNA small interfering RNA -- NAC N-acetylcysteine -- ROS reactive oxygen species -- myr-Akt1 myristoylated-Akt1; Methylmercury -- Neurotoxicity -- Apoptosis -- Endoplasmic reticulum stress -- Akt -- Reactive oxygen species; Toxicology -- Periodicals; Chemicals -- Physiological effect -- Periodicals; 615.9005
• DOI: 10.1016/j.tox.2019.152245
• Languages: English
• ISSNs: 0300-483X

Abstract

Graphical abstract: Highlights: Methylmercury (MeHg) induced neuronal cell death underwent apoptosis. MeHg triggered endoplasmic reticulum stress-regulated neuronal cell apoptosis. ROS-mediated Akt inactivation signals involved in MeHg-induced neurotoxicity. Abstract: Epidemiological studies have positively linked mercury exposure and neurodegenerative diseases (ND). Methylmercury (MeHg), an organic form of mercury, is a ubiquitous and potent environmental neurotoxicant that easily crosses the blood-brain barrier and causes irreversible injury to the central nervous system (CNS). However, the molecular mechanisms underlying MeHg-induced neurotoxicity remain unclear. Here, the present study found that Neuro-2a cells underwent apoptosis in response to MeHg (1–5 μM), which was accompanied by increased phosphatidylserine (PS) exposure on the outer cellular membrane leaflets, caspase-3 activity, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Exposure of Neuro-2a cells to MeHg also triggered endoplasmic reticulum (ER) stress, which was identified via several key molecules (including: glucose-regulated protein (GRP)78, GRP94, C/EBP homologous protein (CHOP) X-box binding protein(XBP)-1, protein kinase R-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme(IRE)-1, activation transcription factor(AFT)4, and ATF6. Transfection with GRP78-, GRP94-, CHOP-, and XBP-1-specific small interfering (si)RNA significantly suppressed the expression of these proteins, and attenuated cytotoxicity and caspase-12, -7, and -3 activation in MeHg-exposed cells. Furthermore, MeHg dramatically decreased Akt phosphorylation, and the overexpression of activation of Akt1 (myr-Akt1) could significantly prevent MeHg-induced Akt inactivation, as well as apoptotic and ER stress-related signals. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively prevented MeHg-induced neuronal cell reactive oxygen species (ROS) generation, apoptotic and ER stress-related signals, and Akt inactivation. Collectively, these results indicate that MeHg exerts its cytotoxicity in neurons by inducing ROS-mediated Akt inactivation up-regulated ER stress, which induces apoptosis and ultimately leads to cell death.