Oxidative stress, caspase-3 activation and cleavage of ROCK-1 play an essential role in MeHg-induced cell death in primary astroglial cells

Alessandra Antunes dos Santos, Caridad López-Granero, Marcelo Farina, João B.T. Rocha, Aaron B. Bowman, Michael Aschner

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Methylmercury is a toxic environmental contaminant that elicits significant toxicity in humans. The central nervous system is the primary target of toxicity, and is particularly vulnerable during development. Rho-associated protein kinase 1 (ROCK-1) is a major downstream effector of the small GTPase RhoA and a direct substrate of caspase-3. The activation of ROCK-1 is necessary for membrane blebbing during apoptosis. In this work, we examined whether MeHg could affect the RhoA/ROCK-1 signaling pathway in primary cultures of mouse astrocytes. Exposure of cells with 10 μM MeHg decreased cellular viability after 24 h of incubation. This reduction in viability was preceded by a significant increase in intracellular and mitochondrial reactive oxygen species levels, as well as a reduced NAD+/NADH ratio. MeHg also induced an increase in mitochondrial-dependent caspase-9 and caspase-3, while the levels of RhoA protein expression were reduced or unchanged. We further found that MeHg induced ROCK-1 cleavage/activation and promoted LIMK1 and MYPT1 phosphorylation, both of which are the best characterized ROCK-1 downstream targets. Inhibiting ROCK-1 and caspases activation attenuated the MeHg-induced cell death. Collectively, these findings are the first to show that astrocytes exposed to MeHg showed increased cleavage/activation of ROCK-1, which was independent of the small GTPase RhoA.

Original languageEnglish (US)
Pages (from-to)328-336
Number of pages9
JournalFood and Chemical Toxicology
Volume113
DOIs
StatePublished - Mar 1 2018

Keywords

  • Caspase-3
  • Methylmercury
  • Oxidative stress
  • Primary astroglial cells
  • ROCK-1

ASJC Scopus subject areas

  • Food Science
  • Toxicology

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