The pentachlorophenol metabolite tetrachlorohydroquinone induces massive ROS and prolonged p-ERK expression in splenocytes, leading to inhibition of apoptosis and necrotic cell death

PLoS One. 2014 Feb 26;9(2):e89483. doi: 10.1371/journal.pone.0089483. eCollection 2014.

Abstract

Pentachlorophenol (PCP) has been used extensively as a biocide and a wood preservative and has been reported to be immunosuppressive in rodents and humans. Tetrachlorohydroquinone (TCHQ) is a major metabolite of PCP. TCHQ has been identified as the main cause of PCP-induced genotoxicity due to reactive oxidant stress (ROS). However, the precise mechanisms associated with the immunotoxic effects of PCP and TCHQ remain unclear. The aim of this study was to examine the effects of PCP and TCHQ on the induction of ROS and injury to primary mouse splenocytes. Our results shown that TCHQ was more toxic than PCP and that a high dose of TCHQ led to necrotic cell death of the splenocytes through induction of massive and sudden ROS and prolonged ROS-triggered ERK activation. Inhibition of ROS production by N-acetyl-cysteine (NAC) partially restored the mitochondrial membrane potential, inhibited ERK activity, elevated caspase-3 activity and PARP cleavage, and, eventually, switched the TCHQ-induced necrosis to apoptosis. We suggest that prolonged ERK activation is essential for TCHQ-induced necrosis, and that ROS play a pivotal role in the different TCHQ-induced cell death mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Death / drug effects*
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Flow Cytometry
  • Hydroquinones / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Necrosis
  • Pentachlorophenol / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Spleen / cytology
  • Spleen / drug effects*
  • Spleen / enzymology
  • Spleen / metabolism

Substances

  • Hydroquinones
  • Reactive Oxygen Species
  • 2,3,5,6-tetrachlorohydroquinone
  • Pentachlorophenol
  • Extracellular Signal-Regulated MAP Kinases

Grants and funding

This study was supported by the National Science Council, Taiwan (NSC 102-2314-B-006-034). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.