Trichloroethylene (TCE) is widely used as a metal degreaser in industrial processes. The present study reports on the effects of TCE exposure on workers employed in the lock industries. To ensure exposure of the workers to TCE, its toxic metabolites, trichloroacetic acid (TCA), dichloroacetic acid (DCA) and trichloroethanol (TCEOH) were detected in the plasma of the subjects through solid phase microextraction-gas chromatography-electron capture detection. TCA, DCA and TCEOH were detected in the range of 0.004–2.494 μg/mL, 0.01–3.612 μg/mL and 0.002–0.617 μg/mL, respectively. Quantitative reverse transcription polymerase chain reaction analysis revealed up-regulated expression of p53 (2.4-fold; p < 0.05), p21 (2-fold; p < 0.01), bax (2.9-fold; p < 0.01) mRNAs and down-regulated expression of bcl-2 (67%; p < 0.05) mRNAs, indicating DNA damaging potential of these metabolites. No effects were observed on the levels of p16 and c-myc mRNAs. Further, as TCA and DCA, the ligand of peroxisome proliferator activated receptor alpha (PPARA), are involved in the process of hepatocarcinogenesis in rodents, we examined expression of PPARA mRNA and let-7c miRNA in the workers. No statistically significant differences in expression of PPARA mRNA and let-7c miRNA in patients were observed as compared to values in controls. Dehydroepiandosterone sulfate (DHEAS) is a reported endogenous ligand of PPARA so its competitive role was also studied. We observed decreased levels of DHEAS hormone in the subjects. Hence, its involvement in mediation of the observed changes in the levels of various mRNAs analyzed in this study appears unlikely.
Trichloroacetic acid (TCA), a common water disinfection byproduct and a persistent metabolite of trichloroethylene (TCE), has been examined for its genotoxic potential in human lymphocytes. Chromosomal aberration (CA) and cytokinesis-block micronucleus (CBMN) assay were employed to assess the toxicity of TCA. Lymphocytes obtained from three healthy donors were exposed to 25, 50, and 100 μg/ml concentration of TCA separately. TCA exposure resulted in chromosomal anomalies and the formation of micronuclei in lymphocytes. Chromosome analysis revealed the dose-dependent and significant induction of CA. Chromatid break/chromosome break, fragments, and chromatid exchanges were commonly observed. Exposure of higher concentration (50 and 100 μg/ml) significantly inhibited mitotic index. Data obtained with CBMN assay indicated that the induction of micronucleus (MN) formation was greater than that of CA. At 25 μg/ml, TCA induced significant frequencies of MN as compared to control cells. Significant induction of MN at the lowest concentration indicates TCA may also interact with mitotic spindles. Lower percentage of CA and MN at 100 μg/ml as compared to 50 μg/ml indicates occurrence of severe cytotoxicity on exposure of 100 μg/ml TCA in lymphocytes. Collectively, results of both cytogenetic assays indicate that exposure of TCA can induce significant genotoxic and cytotoxic effects.
Swiss albino mice were exposed to formulated cypermethrin (CMR) and/or or chlorpyrifos (CPF) through oral gavages for 60 days. Test doses of CMR (0.69, 1.38 or 2.76mg/kg/day) or CPF (0.5, 1.0 or 2.0mg/kg/day) or CMR + CPF (0.69 + 0.5, 1.38 + 1.0 or 2.76 + 2.0mg/kg/day) were based on the acute oral median lethal doses of CMR or CPF. Chromosome aberrations (CA), micronucleus (MN) induction, cell cycle perturbations, apoptosis and reactive oxygen species (ROS) generation were analysed in bone marrow cells. To explore the involvement of ROS induction, HaCat cells were exposed in vitro to arbitrary concentrations of CMR and/or CPF. Exposure of CMR (2.76mg/kg/day) induced significant inhibition of mitotic index. Significant (P < 0.01) frequencies of CA and MN were observed with the CMR at 1.38mg/kg/day, whereas CPF or its mixture CMR + CPF showed at highest doses. Chromosome/chromatid breaks and fragments were found to be major aberrations in all the treatment groups. Highest doses of CMR or CMR + CPF revealed significant (P < 0.01 or 0.001) elevation of G/G peak, while CPF-exposed cells revealed significant (P < 0.01) declined in G phase. Decline in S phase was observed with highest dose of CMR only. Apoptosis induction measured by gating cell population beside G peak showed 3- to 4-fold increase in apoptotic cells in CPF-exposed mice as compared to control or CMR or CMR + CPF-treated mice. Further, all the treatment groups in vivo as well as in vitro revealed significant generation of ROS in comparison with the control group. Present results, together with the earlier reports, which substantiate ROS generation may be major cause of genotoxicity, cell cycle perturbations and apoptosis, nonetheless co-exposure of low doses of CMR and CPF mixture does not potentiate genotoxicity.
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