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

Chen HM, Zhu BZ, Chen RJ, Wang BJ, Wang YJ - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.

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.

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The probable cell death pathways mediated by high doses of TCHQ in splenocytes.
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pone-0089483-g007: The probable cell death pathways mediated by high doses of TCHQ in splenocytes.

Mentions: Our results indicate that high doses of TCHQ led to necrosis of splenocytes through induction of massive and sudden ROS and ROS-triggered prolonged ERK activation. The inhibition of ROS production by NAC can partially prevent the changes in mitochondrial membrane potential, inhibit ERK activity, elevate caspase-3 activity and PARP cleavage, and, eventually switch the TCHQ-induced cell death from necrosis to apoptosis. Similar to the effects of NAC, U0126 can also lead to the cleavage of caspase-3 and PARP by in habiting ERK activity. We suggested that prolonged ERK activation is essential for TCHQ-induced necrosis (Fig. 7).


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

Chen HM, Zhu BZ, Chen RJ, Wang BJ, Wang YJ - PLoS ONE (2014)

The probable cell death pathways mediated by high doses of TCHQ in splenocytes.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935892&req=5

pone-0089483-g007: The probable cell death pathways mediated by high doses of TCHQ in splenocytes.
Mentions: Our results indicate that high doses of TCHQ led to necrosis of splenocytes through induction of massive and sudden ROS and ROS-triggered prolonged ERK activation. The inhibition of ROS production by NAC can partially prevent the changes in mitochondrial membrane potential, inhibit ERK activity, elevate caspase-3 activity and PARP cleavage, and, eventually switch the TCHQ-induced cell death from necrosis to apoptosis. Similar to the effects of NAC, U0126 can also lead to the cleavage of caspase-3 and PARP by in habiting ERK activity. We suggested that prolonged ERK activation is essential for TCHQ-induced necrosis (Fig. 7).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental and Occupational Health, National Cheng Kung University, Medical College, Tainan, Taiwan.

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.

Show MeSH
Related in: MedlinePlus