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.
Highlights
Pentachlorophenol (PCP) and its salt are used extensively as biocides and wood preservatives [1,2,3]
The results of the analyses of the cleaved caspase-3 and PARP degradation with western blots and the assessment of caspase-3 activity by a fluorogenic assay further confirmed the inhibition of apoptosis in the splenocytes treated with the higher doses of TCHQ (Fig. 3A, 3B and 3C), implying that a cell death type other than apoptosis could be induced by TCHQ
The results suggest that PCP and lower doses of TCHQ induced apoptosis in splenocytes, but higher doses of TCHQ induced cell death more characteristic of necrosis than apoptosis
Summary
Pentachlorophenol (PCP) and its salt are used extensively as biocides and wood preservatives [1,2,3]. It has been indicated that PCP is persistent with a half-life of up to 200 days in water systems [7]. The half-life of PCP ranges from 33 hours to 16 days in humans [8]. Malignant lymphoma and leukemia have been associated with occupational exposure to PCP [12]. Tetrachlorohydroquinone (TCHQ) is a major toxic metabolite of PCP. In the presence of oxygen, TCHQ can lead to production of superoxide radicals through a cycle of autoxidation and reduction between TCHQ and its corresponding semiquinone radical under certain physiological conditions [13]. Reactive oxygen species (ROS) are believed to be involved in the toxic effects of TCHQ
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