Dose-specific production of chlorinated quinone and semiquinone adducts in rodent livers following administration of pentachlorophenol.
Production of chlorinated quinoid metabolites was investigated in the livers of Sprague-Dawley rats and B6C3F1 mice following single oral administration of pentachlorophenol (PCP) (0-40 mg/kg body weight) and in male Fischer 344 rats, following chronic ingestion of PCP at 1,000 ppm in the diet for 6 months (equivalent to 60 mg PCP/kg body weight/day). Analyses of the rates of adduction in the livers of Sprague-Dawley rats and B6C3F1 mice suggested that the production of tetrachloro-1,2-benzosemiquinone (Cl4-1,2-SQ) adducts was proportionally greater at low doses of PCP (less than 4-10 mg/kg body weight) and was 40-fold greater in rats than in mice. Production of tetrachloro-1,4-benzoquinone (Cl4-1,4-BQ) adducts, on the other hand, was proportionally greater at high doses of PCP [greater than 60-230 mg/kg body weight] and was 2- to 11-fold greater in mice than in rats over the entire range of dosages. A mathematical model employed these data to predict the rates of daily adduct production and steady state levels of PCP-derived quinone and semiquinone adducts in rats and mice. To evaluate predictions of the model, levels of PCP-derived adducts at steady state were investigated in the livers of male Fischer 344 rats chronically ingesting 60 mg PCP/kg body weight/day. Levels of total Cl4-1,4-BQ-derived adducts in liver cytosolic proteins (Cp) (22.0 nmol/g) and in liver nuclear proteins (Np) (3.07 nmol/g) were comparable to those of model predictions (15.0 and 3.02 nmol/g for Cp and Np, respectively). Overall, these results suggest that species differences in the metabolism of PCP to semiquinones and quinones were, in part, responsible for the production of liver tumors in mice but not rats in chronic bioassays. (+info)
Toxicology and carcinogenesis studies of pentachlorophenol in rats.
Pentachlorophenol (PCP) has been used as an herbicide, algaecide, defoliant, wood preservative, germicide, fungicide, and molluscicide. A 28-day toxicity study of PCP in F344/N rats of both sexes was conducted to select dose levels for a carcinogenicity study. Groups of 10 male and 10 female rats were given 0, 200, 400, 800, 1600, or 3200 ppm PCP in feed for 28 days. The incidences of minimal to mild hepatocyte degeneration in males and females exposed to 400 ppm or greater and the incidences of centrilobular hepatocyte hypertrophy in the 3200-ppm groups were increased. For carcinogenicity studies, groups of 50 male and 50 female F344/N rats were fed diets containing 200, 400, or 600 PCP for 2 years. A stop-exposure group of 60 male and 60 female rats received 1000 ppm of PCP in feed for 52 weeks and control feed thereafter for the remainder of the 2-year studies; 10 male and 10 female rats were evaluated at 7 months. Survival of 600-ppm males was significantly greater than that of the controls; survival of all other exposed groups was similar to that of the control groups. Mean body weights of the 400- and 600-ppm groups were generally less than those of the controls throughout the studies. There was no evidence of carcinogenic activity of PCP in male or female rats fed diets containing 200, 400, or 600 ppm for 2 years. Stop-exposure study males and females regained a transitory body weight reduction by the end of the 2 year study, and males had better survival than the controls. At a 7-month interim evaluation, the incidences of centrilobular hypertrophy in stop-exposure males and females exceeded those in the controls. At 2 years, malignant mesothelioma originating from the tunica vaginalis was present in 9 1000-ppm males and 1 control male (p = 0.014). Nasal squamous cell carcinomas were present in five 1000-ppm males and 1 control male. This incidence was not significantly increased but exceeded the historical control range (0-4%). Based on the increased incidences of mesotheliomas and nasal tumors, there was some evidence of carcinogenic activity of PCP in male rats given a diet containing 1000 ppm for 1 year followed by control diet for 1 year. There was no evidence of PCP carcinogenic activity in stop-exposure female rats. (+info)
Pentachlorophenol (PCP) produces liver oxidative stress and promotes but does not initiate hepatocarcinogenesis in B6C3F1 mice.
To elucidate the mechanism of hepatocarcinogenesis of pentachlorophenol (PCP) in mice, critical effects related to carcinogenicity were studied in the livers of B6C3F1 male mice administered PCP at concentrations of 600 and 1200 p.p.m. in the diet for 8 weeks. Oxidative stress was assessed by measurements of 8-oxodeoxyguanosine (8-oxodG) in the liver nuclear DNA and hepatocyte cell proliferation was quantified by bromodeoxyuridine incorporation. Also, initiation and promotion were assessed in a two-stage hepatocarcinogenesis model in which one group of mice was given PCP at concentrations of 600 and 1200 p.p.m. as initiator for the first 13 weeks with subsequent administration of phenobarbital (PB) as promoter at a concentration of 500 p.p.m. in the drinking water for 29 weeks. A second group was initiated with diethylnitrosamine (DEN) at 20 p.p.m. in the drinking water for the first 13 weeks followed after a 4 week recovery interval by PCP at concentrations of 300 and 600 p.p.m. in the diet for 25 weeks. Significant elevations in 8-oxodG levels and cell proliferation were observed in a dose-dependent manner. Incidences and multiplicities of hepatocellular tumors in mice treated with PCP after DEN initiation were increased compared with those in mice given initiation only. In contrast, in mice given PCP as initiator followed by PB no enhancement of neoplastic lesions occurred. These findings are interpreted to demonstrate that PCP exerts a promoting action, but not an initiating effect on liver carcinogenesis and that the promoting action is related to oxidative stress and compensatory hepatocellular proliferation. (+info)
Reproductive and endocrine function in rams exposed to the organochlorine pesticides lindane and pentachlorophenol from conception.
There is controversy over the potential endocrine modulating influence of pesticides, particularly during sensitive phases of development. In this study, ram lambs were exposed to lindane and pentachlorophenol from conception to necropsy at 28 weeks of age. The rams (and their mothers) were given untreated feed (n = 7) or feed treated with 1 mg kg-1 body weight per day of lindane (n = 12) or pentachlorophenol (n = 5). Semen was collected from 19 weeks onwards and reproductive behaviour was tested at 26 weeks. Serum was collected every 2 weeks and at 27 weeks every 15 min for 6 h during both day and night, and for 1 h before and 5 h after stimulation with GnRH, adrenocorticotrophic hormone and thyroid-stimulating hormone. The pesticides did not affect body weight and ejaculate characteristics, or cause overt toxicity. In pentachlorophenol-treated rams, scrotal circumference was increased. However, seminiferous tubule atrophy was more severe and epididymal sperm density was reduced in comparison with untreated rams at necropsy (P < 0.05). Thyroxine concentrations were lower in pentachlorophenol-treated rams than in untreated rams (P < 0.05). However, after thyroid-stimulating hormone treatment, the thyroxine response was unaltered. Reproductive behaviour was reduced in lindane-treated rams compared with control rams (P < 0.05). Serum LH and oestradiol concentrations during reproductive development, LH pulse frequency at 27 weeks and testosterone secretion after GnRH treatment were lower in lindane-treated rams than in untreated rams (P < 0.05). In summary, the effects of pentachlorophenol on the testis may be linked to a decrease in thyroxine concentrations, and reduced reproductive behaviour in lindane-treated rams may be related to decreased LH, oestradiol and testosterone concentrations. (+info)
Biodegradation of pentachlorophenol in a continuous anaerobic reactor augmented with Desulfitobacterium frappieri PCP-1.
In this work, a strain of anaerobic pentachlorophenol (PCP) degrader, Desulfitobacterium frappieri PCP-1, was used to augment a mixed bacterial community of an anaerobic upflow sludge bed reactor degrading PCP. To estimate the efficiency of augmentation, the population of PCP-1 in the reactor was enumerated by a competitive PCR technique. The PCP-1 strain appeared to compete well with other microorganisms of the mixed bacterial community, with its population increasing from 10(6) to 10(10) cells/g of volatile suspended solids within a period of 70 days. Proliferation of strain PCP-1 allowed for a substantial increase of the volumetric PCP load from 5 to 80 mg/liter of reaction volume/day. A PCP removal efficiency of 99% and a dechlorination efficiency of not less than 90.5% were observed throughout the experiment, with 3-Cl-phenol and phenol being observable dechlorination intermediates. (+info)
PcpA, which is involved in the degradation of pentachlorophenol in Sphingomonas chlorophenolica ATCC39723, is a novel type of ring-cleavage dioxygenase.
The pentachlorophenol (PCP) mineralizing bacterium Sphingomonas chlorophenolica ATCC39723 degrades PCP via 2,6-dichlorohydroquinone (2,6-DCHQ). The pathway converting PCP to 2,6-DCHQ has been established previously; however, the pathway beyond 2,6-DCHQ is not clear, although it has been suggested that a PcpA plays a role in 2, 6-DCHQ conversion. In this study, PcpA expressed in Escherichia coli was purified to homogeneity and shown to have novel ring-cleavage dioxygenase activity in conjunction with hydroquinone derivatives, and converting 2,6-DCHQ to 2-chloromaleylacetate. (+info)
Inhibition of bacterial transport by uncouplers of oxidative phosphorylation. Effects of pentachlorophenol and analogues in Bacillus subtilis.
Analogues of the potent uncoupler of oxidative phosphorylation pentachlorophenol were tested as inhibitors of proline and glycine transport by Bacillus subtilis. These analogues included less highly substituted chlorophenols and pentachlorothiophenol. Like pentachlorophenol, they are non-competitive inhibitors of proline transport and uncompetitive inhibitors of glycine transport. However, the less highly substituted chlorophenols are weaker acids than pentachlorophenol and also weaker inhibitors. Analysis indicated that the anionic form of the uncouplers is the inhibiting species. Pentachlorothiophenol, a water-insoluble anion, is also a potent inhibitor. These results support previous studies that concluded that uncouplers of oxidative phosphorylation inhibit amino acid transport by binding at specific sites on proteins, the free energy of interaction stabilizing 'unproductive' conformations. Such specific interactions of uncoupler with protein are probably commonplace. (+info)
Degradation of pentachlorophenol by Phanerochaete chrysosporium: intermediates and reactions involved.
Under nitrogen-limiting, secondary metabolic conditions, the lignin-degrading basidiomycete Phanerochaete chrysosporium rapidly degrades pentachlorophenol. The pathway for the degradation of pentachlorophenol has been elucidated by the characterization of fungal metabolites and oxidation products generated by purified lignin peroxidase (LiP) and manganese peroxidase (MnP). The multi-step pathway is initiated by a LiP- or MnP-catalysed oxidative dechlorination reaction to produce tetrachloro-1,4-benzoquinone. Under primary or secondary metabolic conditions, the quinone is further degraded by two parallel pathways with cross-links. The quinone is reduced to tetrachlorodihydroxybenzene, which can undergo four successive reductive dechlorinations to produce 1,4-hydroquinone, and the latter is o-hydroxylated to form the final aromatic metabolite, 1,2,4-trihydroxybenzene. Alternatively, the tetrachloro-1,4-benzoquinone is converted, either enzymically or nonenzymically, to 2,3,5-trichlorotrihydroxybenzene, which undergoes successive reductive dechlorinations to produce 1,2,4-trihydroxybenzene. Finally, at several points, hydroxylation reactions convert chlorinated dihydroxybenzenes to chlorinated trihydroxybenzenes, linking the two pathways at each of these steps. Presumably, the 1,2,4-trihydroxybenzene produced in each pathway is ring-cleaved with subsequent degradation to CO2. In contrast to the oxidative dechlorination step, the reductive dechlorinations and hydroxylations occur during both primary and secondary metabolic growth. Apparently, all five chlorine atoms are removed from the substrate prior to ring cleavage. (+info)