Liver tumour promoting activity of 3,4,5,3',4'-pentachlorobiphenyl and its interaction with 2,3,7,8-tetrachlorodibenzo-p-dioxin (original) (raw)
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Promotion of Enzyme Altered Foci in Female Rat Livers by 2,3,3′,4,4′,5-Hexachlorobiphenyl
Toxicology and Applied Pharmacology, 1997
PCBs constitute a group of 209 different congeners and The tumor promoting activity of 2,3,3,4,4,5-hexachlorobiphenyl the numbers and sites of chlorine substitution determine the (PCB 156) was studied in an initiation/promotion bioassay in female chemical and biological characteristics of a specific conge-Sprague-Dawley rats initiated with N-nitrosodiethylamine after parner. The most toxic PCBs are those substituted in both para tial hepatectomy. PCB 156 (50, 300, 1500, or 7500 mg/kg body weight/ and at least two meta positions (Fig. 1). If these toxic congeweek) was administered by once-weekly subcutaneous injections for ners lack chlorine substituents in the ortho positions they 20 weeks. Some high dose animals were left without treatment for can assume a coplanar conformation and are thereby approxan additional 20 weeks to study posttreatment effects. The volume imate stereoisomers of 2,3,7,8-tetrachlorodibenzo-p-dioxin fraction of the liver occupied by glutathione S-transferase P-positive (TCDD) (Bandiera et al., 1982; Safe et al., 1985a). These foci was significantly increased to 2.9, 3.3, and 12% at 300, 1500, coplanar PCB congeners also cause biological effects resemand 7500 mg/kg body weight/week, respectively, compared to 1.2% bling those reported for TCDD, including the induction of in the controls. The volume fraction was 43% in the high dose group 20 weeks after treatment was stopped, probably reflecting the slow the monooxygenase enzymes cytochrome P450 1A1 body clearance of PCB 156 as indicated by the sustained liver and (CYP1A1) and CYP1A2, skin lesions, thymus atrophy, liver adipose tissue concentrations. Treatment with PCB 156 following damage, and a wasting syndrome (reviewed by Safe, 1990). initiation caused decreased body weight gain, thymic atrophy, liver If one or more chlorine substituents are introduced in an enlargement, induction of hepatic cytochrome P450 1A1/2 (CYP1A1/ ortho position, a decreased degree of coplanarity between 2) and CYP2B1/2 activities, histopathological effects, and increased the two phenyl rings will occur due to steric interactions. activities of aspartate aminotransferase and g-glutamyltransferase in Mono-ortho-chloro PCBs induce toxic effects that qualitaplasma. These results show that PCB 156 can enhance the growth tively resemble the toxicity of TCDD, but in addition to of altered foci in rat liver and probably act as a tumor promoter of the monooxygenases induced by TCDD, the mono-orthohepatocarcinogenesis. Based on promotional activity a relative posubstituted PCBs also induce CYP2B1 and/or CYP2B2 (Safe tency of PCB 156 to 2,3,7,8-tetrachlorodibenzo-p-dioxin of 0.0001-0.001 is proposed.
Toxicology and applied …, 1998
Interactive effects between the non-ortho-substituted 3,3, 4,4,5-pentachlorobiphenyl (PCB126), the mono-ortho-substituted 2,3,3,4,4-pentachlorobiphenyl (PCB105), and the diortho-substituted 2,2,4,4,5,5-hexachlorobiphenyl (PCB153) were studied in an initiation/promotion bioassay. Female Sprague-Dawley rats were injected with 30 mg/kg ip of N-nitrosodiethylamine 24 h after partial hepatectomy. Five weeks later, weekly sc administrations of the three PCBs in 15 systematically selected dose combinations started. After 20 weeks of administration, the animals were killed and the livers were analyzed for areas expressing placental glutathione-S-transferase as a marker of preneoplastic foci. In addition, concentration of liver and kidney retinoids and plasma retinol was analyzed, as well as body and organ weights, plasma transaminases, and induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities. Data were analyzed with a multivariate method. At the doses applied in this study, weak antagonism was observed between PCB126 and PCB153 for effects on volume fraction of foci, number of foci/cm 3 , concentration of plasma retinol and liver retinoids, relative liver weight, and induction of CYP2B1/2 activity. Weak antagonism was also observed between PCB126 and PCB105 for effects on volume fraction of foci, number of foci/cm 3 , and plasma retinol concentration. No interactions other than pure additivity were observed between PCB105 and PCB153. Synergism was not observed within the dose ranges investigated in this study. Knowledge of interactive effects is important for risk assessment of environmental mixtures of dioxin-like compounds. Antagonism between congeners generally results in risk assessments that overestimate human risk. The significance to human risk assessment of the relatively weak antagonism observed in this study is however unclear, considering many other uncertainties involved in the toxic equivalency factor (TEF) concept. A change of the TEF concept for risk assessments of dioxin-like substances is not motivated based on the results of this study.
Pharmacology & Toxicology, 1995
This study was undertaken to investigate tumour promoting interactions of 2,4,5,2',4',5'-hexachlorobiphenyl (PCB 153) and 3,4,5,3',4'-pentachlorobiphenyl (PCB 126) in female Sprague-Dawley rats. Five weeks before the promotion treatment, the rats were partially hepatectomized and initiated with nitrosodiethylamine. The test substances were administered by weekly, subcutaneous injections for 20 weeks. The results from this study suggest that treatment with a combination of these two congeners causes a more than additive effect on the formation of y-glutamyltranspeptidasepositive hepatic foci. Co-exposure to PCB 126 and PCB 153 caused a dose-dependent reduction of the PCB 153-induced CYP2BI/BZactivity in these livers.
Cancer research, 2000
Risk assessment of dioxins is currently based on induction of liver tumors in rats. The toxicity of dioxins is characterized by large sensitivity differences among animal species and even strains of the same species, which complicates the risk assessment. The significance of these differences in dioxin-induced carcinogenicity is not known. We therefore studied the liver tumor-promoting activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the sensitive Long-Evans (L-E) and the resistant Han/Wistar (H/W) rats differing >1000-fold in their sensitivity to the acute lethaity of TCDD. Female rats were partially hepatectomized, initiated with nitrosodiethylamine, and treated with TCDD for 20 weeks. Altered hepatic foci (AHF) were stereologically quantitated using glutathione S-transferase P as a marker. AHF were significantly (P < 0.001) and dose dependently increased in L-E rats at 10 and 100 ng/kg/day, but in H/W rats only at 1000 ng/kg/day and above, indicating a remarkable (...
Toxicology and applied pharmacology, 1998
Interactive effects between the non-ortho-substituted 3,3', 4,4', 5-pentachlorobiphenyl (PCB126), the mono-ortho-substituted 2,3,3',4, 4'-pentachlorobiphenyl (PCB105), and the di-ortho-substituted 2,2',4, 4',5,5'-hexachlorobiphenyl (PCB153) were studied in an initiation/promotion bioassay. Female Sprague-Dawley rats were injected with 30 mg/kg ip of N-nitrosodiethylamine 24 h after partial hepatectomy. Five weeks later, weekly sc administrations of the three PCBs in 15 systematically selected dose combinations started. After 20 weeks of administration, the animals were killed and the livers were analyzed for areas expressing placental glutathione-S-transferase as a marker of preneoplastic foci. In addition, concentration of liver and kidney retinoids and plasma retinol was analyzed, as well as body and organ weights, plasma transaminases, and induction of hepatic cytochrome P450 1A1/2 (CYP1A1/2) and CYP2B1/2 activities. Data were analyzed with a multivari...
Relative tumour promoting activity of three polychlorinated biphenyls in rat liver
European Journal of Pharmacology: Environmental Toxicology and Pharmacology, 1993
The relative tumour promoting activity of three structurally and toxicologically diverse polychlorinated biphenyls (3,4,5,3',4'penta-,2,3,4,3',4'-penta-and 2,4,5,2',4',5'-hexachlorobiphenyl) was measured in an initiation/promotion assay in nitrosodiethylamine-initiated female Sprague-Dawley rats. The congeners under study were administered by once-weekly subcutaneous injections for 20 weeks. Evaluation of the development of 7-glutamyl transpeptidase (GGT)-and glutation transferase P (GST-P)-positive hepatic foci showed that all congeners promoted altered hepatic loci, although 3,4,5,3',4'-pentachlorobiphenyl was far more potent. The volume fraction of the liver occupied by GGT-positive tissue in the 3,4,5,3',4'-pentachlorobiphenyltreated animals (100 /~g7kg per week) was 23%, while the volume fractions of altered liver tissue in the rats treated with 2,3,4,3',4'-pentachlorobiphenyl (5000 /~g/kg per week) and 2,4,5,2 ',4',5 '-hexaCB (20,000 /~g/kg per week) were 1.2 and 2.3, respectively. The enhancement of GGT-and GST-P-positive foci was accompanied by an increased incidence of histological changes in the livers.
Toxicological Sciences, 2002
This study evaluates and quantifies the interactive hepatic tumor promoting effects of two PCBs, the Ah receptor agonist PCB 126 (3,3,4,4,5-pentachlorobiphenyl) and the constitutive androstane receptor (CAR) agonist PCB 153 (2,2,4,4,5,5-hexachlorobiphenyl). Promotion of altered hepatic foci was evaluated utilizing a medium-term 8-week bioassay for promoters of hepatocarcinogenesis. The assay employs placental glutathione-Stransferase positive (GST-P؉) liver cell foci as markers of preneoplasia in female Fischer 344 rats treated with the known initiator diethylnitrosamine followed by partial hepatectomy and by gavage exposure to test chemicals. GST-P؉ foci were quantified by histomorphometry and were reported as areas and numbers of GST-P؉ foci within the area of liver examined. For PCB 126, the doses were 0.1, 1.0, and 10 g/kg body weight. For PCB 153, the doses were 10, 100, 1000, 5000, and 10,000 g/kg body weight. Combined PCB 126 and 153 exposures were 0.1 ؉ 10, 1 ؉ 100, 10 ؉ 1000, 10 ؉ 5000, and 10 ؉ 10,000 g/kg, respectively. Individual PCB treatment resulted in dose dependent increases in liver and adipose concentrations. Hepatic PCB 153 levels were significantly increased ( p < 0.01) after combined exposure. Treatment with PCB 126 or PCB 153 alone resulted in a significant ( p < 0.01) dose dependent increase in GST-P؉ foci area and number compared with controls. Treatment with the mixture of PCB 126 and 153 resulted in antagonistic GST-P؉ focus formation ( p < 0.001) for both foci area and number. The less than additive effect was present at all 5 PCB 126/PCB 153 dose combinations, including the low doses of PCB 126 and 153 that did not show significant promotional activity alone.
Initiating Activity of 4-Chlorobiphenyl Metabolites in the Resistant Hepatocyte Model
Toxicological Sciences, 2004
We recently reported that several mono-to tetrachlorinated biphenyls have initiating activity in the livers of Fischer 344 rats. In the present study, we investigated the metabolic activation of one of those compounds, 4-chlorobiphenyl (PCB 3). Monohydroxy (400 mol/kg), dihydroxy (200 mol/kg), and quinone (100 mol/ kg) metabolites of PCB 3 were evaluated for their initiating activity. Fischer 344 male rats were fasted for 4 days; 24 h after feeding again, they were injected (ip) with metabolites, vehicle, or diethylnitrosamine (DEN, 20 or 40 mg/kg). All animals were treated with selection agents as follows: three daily p.o. doses of 2-acetylaminofluorene (2-AAF, 30 mg/kg), followed by a single p.o. dose of carbon tetrachloride (2 ml/kg) and three additional daily treatments of 2-AAF. Rats were killed 2 weeks after the last 2-AAF intubation. Livers were evaluated for changes in morphology, and the number and volume of ␥-glutamyl transpeptidasepositive foci were measured. Of the metabolites tested, only one monohydroxy and one quinoid metabolite showed initiating activity. The metabolic activation of PCB 3, therefore, proceeds via parahydroxylation and oxidation to the ortho 3,4-quinone, the ultimate carcinogen. This is the first report to demonstrate that specific PCB metabolites possess initiating activity in the rodent liver in vivo. The results support the conclusion that 4-OH PCB 3 and 3,4-BQ PCB 3 act as proximate and ultimate carcinogenic metabolites resulting from the bioactivation of PCB 3 in rat liver.
Mechanism of 1,3-Dichloropropene-Induced Rat Liver Carcinogenesis
Toxicological Sciences, 2014
1,3-Dichloropropene (1,3-D) is a soil fumigant used primarily for preplanting control of parasitic nematodes. In a previous chronic dietary exposure study, 1,3-D induced an increased incidence of hepatocellular adenomas in male rats at a dose of 25 mg/kg/day. Although the mechanism for tumor induction in the rat liver by 1,3-D has not been specifically elucidated, available data suggested that the observed liver tumorigenesis was through a nongenotoxic mode of action at the tumor promotion stage. Fischer 344 rats containing preneoplastic lesions were treated (via gavage) with 25 mg/kg/day 1,3-D or 80 mg/kg/day phenobarbital (PB) for 30 days and 60 days, or for 30 days followed by a 30-day recovery period (no compound exposure). Following treatment, placental form glutathione S-transferase (GSTP) positive and GSTP-negative liver focal lesions were quantitated as to size and number. 1,3-D treatment had no effect on GSTP-positive foci number or relative size but significantly increased the number, labeling index, and relative size of GSTP-negative focal lesions (identified by H and E staining) after 30 and 60 days of treatment. Following the 30-day recovery period, the number, labeling index, and relative size of the GSTP-negative lesions in 1,3-D-treated animals returned to control levels. As expected, PB treatment produced an increase in number and relative size of the GSTP-positive lesions. The results of this study are consistent with 1,3-D inducing liver carcinogenesis through a nongenotoxic mode of action by functioning as a tumor promoter specifically through induction of a non-GSTP staining focal hepatocyte population.
Food and Chemical Toxicology, 2008
Polychlorinated biphenyls (PCBs) have promoting activity in the liver, which may be brought about in part by the induction of oxidative stress. In this study we examined the effects of several antioxidant phytochemicals on the tumor promoting activity of 3,3′,4′4-tetrachlorobiphenyl (PCB-77). Female Sprague Dawley rats were first injected with diethylnitrosamine (DEN, 150 mg/kg) and one week later the rats were fed an AIN-93 based purified diet or the same diet containing ellagic acid (0.4%), β-carotene (0.5%), curcumin (0.5%), N-acetyl cysteine (NAC, 1.0%), co-enzyme CoQ 10 (CoQ 10 , 0.4%), resveratrol (0.005%), lycopene (10% as LycoVit (Sweeny et al.), which contains 10% lycopene), or a tea extract (1%, containing 16.5% epigallocatechin-3-gallate [EGCG] and 33.4% total catechins). Rats were fed the diets for the remainder of the study. After 3 weeks, 2/3 of the control rats and all of the antioxidant diet-fed rats were injected i.p. with PCB-77 (300 μmol/kg) every other week for four injections. All rats were euthanized 10 days after the last PCB injection. The rats that received PCB-77 alone showed an increase in the number and size of placental glutathione S-transferase (PGST)-positive foci in the liver. Lycopene significantly decreased the number of foci, while curcumin and CoQ 10 decreased the size of the foci. In contrast ellagic acid increased the number but decreased the size of the foci. All of the other phytochemicals showed only slight or no effects. Compared with the PCB-77 group, CoQ10 increased cell proliferation in normal hepatocytes, whereas the other antioxidants had no effect in either normal or PGST-positive hepatocytes. These findings show that none of the antioxidant phytochemicals produced a clear decrease in the promoting activity of PCB-77.