Dataset Information

Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats.

ABSTRACT: Polychlorinated biphenyls (PCBs) are legacy pollutants that exert toxicities through various mechanisms. In recent years exposure to PCBs via inhalation has been recognized as a hazard. Those PCBs with lower numbers of chlorine atoms (LC-PCBs) are semivolatile and have been reported in urban air, as well as in the indoor air of older buildings. LC-PCBs are bioactivated to phenols and further to quinone electrophiles with genotoxic/carcinogenic potential. We hypothesized that phenolic LC-PCBs are subject to conjugation and excretion in the urine. PCB3, often present in high concentrations in air, is a prototypical congener for the study of the metabolism and toxicity of LC-PCBs. Our objective was to identify metabolites of PCB3 in urine that could be potentially employed in the estimation of exposure to LC-PCBs. Male Sprague-Dawley rats (150-175 g) were housed in metabolism cages and received a single intraperitoneal injection of 600 ?mol/kg body weight of PCB3. Urine was collected every 4 h; rats were euthanized at 36 h; and serum was collected. LC/MS analysis of urine before and after incubation with ?-glucuronidase and sulfatase showed that sulfate conjugates were in higher concentrations than glucuronide conjugates and free phenolic forms. At least two major metabolites and two minor metabolites were identified in urine that could be attributed to mercapturic acid metabolites of PCB3. Quantitation by authentic standards confirmed that approximately 3% of the dose was excreted in the urine as sulfates over 36 h, with peak excretion occurring at 10-20 h after exposure. The major metabolites were 4'PCB3sulfate, 3'PCB3 sulfate, 2'PCB3 sulfate, and presumably a catechol sulfate. The serum concentration of 4'PCB3 sulfate was 6.18 ± 2.16 ?g/mL. This is the first report that sulfated metabolites of PCBs are formed in vivo. These findings suggest a prospective approach for exposure assessment of LC-PCBs by analysis of phase II metabolites in urine.

SUBMITTER: Dhakal K

PROVIDER: S-EPMC3524396 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats.

Dhakal Kiran K He Xianran X Lehmler Hans-Joachim HJ Teesch Lynn M LM Duffel Michael W MW Robertson Larry W LW

Chemical research in toxicology 20121116 12

Polychlorinated biphenyls (PCBs) are legacy pollutants that exert toxicities through various mechanisms. In recent years exposure to PCBs via inhalation has been recognized as a hazard. Those PCBs with lower numbers of chlorine atoms (LC-PCBs) are semivolatile and have been reported in urban air, as well as in the indoor air of older buildings. LC-PCBs are bioactivated to phenols and further to quinone electrophiles with genotoxic/carcinogenic potential. We hypothesized that phenolic LC-PCBs are ...[more]

PMID: 23137097

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Project description:PCBs, such as PCB3, are air contaminants in buildings and outdoors. Metabolites of PCB3 are potential endocrine disrupting chemicals and genotoxic agents. We studied the disposition of phenolic and sulfated metabolites after acute nose-only inhalation exposure to airborne PCB3 for 2 h in female rats. Inhalation exposure was carried out in three groups. In the first group, rats exposed to an estimated dose of 26 μg/rat were euthanized at 0, 1, 2, and 4 h after exposure. Highest concentrations of phenols and sulfates were observed at 0 h, and the values were 7 ± 1 and 560 ± 60 ng/mL in serum, 213 ± 120 and 842 ± 80 ng/g in liver, 31 ± 27 and 22 ± 7 ng/g in lung, and 27 ± 6 and 3 ± 0 ng/g in brain, respectively. First-order serum clearance half-lives of 0.5 h for phenols and 1 h for sulfates were estimated. In the second group, rats exposed to an estimated dose of 35 μg/rat were transferred to metabolism cages immediately after exposure for the collection of urine and feces over 24 h. Approximately 45 ± 5% of the dose was recovered from urine and consisted mostly of sulfates; the 18 ± 5% of the dose recovered from feces was exclusively phenols. Unchanged PCB3 was detected in both urine and feces but accounted for only 5 ± 3% of the dose. Peak excretion of metabolites in both urine and feces occurred within 18 h postexposure. In the third group, three bile-cannulated rats exposed to an estimated dose of 277 μg/rat were used for bile collection. Bile was collected for 4 h immediately after 2 h exposure. Biliary metabolites consisted mostly of sulfates, some glucuronides, and lower amounts of the free phenols. Control rats in each group were exposed to clean air. Clinical serum chemistry values, serum T4 level, and urinary 8-hydroxy-2'-deoxyguanosine were similar in treated and control rats. These data show that PCB3 is rapidly metabolized to phenols and conjugated to sulfates after inhalation and that both of these metabolites are distributed to liver, lungs, and brain. The sulfates elaborated into bile are either reabsorbed or hydrolyzed in the intestine and excreted in the feces as phenols.

Project description:Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants with myriad biological effects, including carcinogenicity. We present data showing gender-specific genotoxicity in Fischer 344 transgenic BigBlue rodents exposed to 4-chlorobiphenyl (PCB3), a hydroxylated metabolite, and the positive control 3-methylcholanthrene (3-MC) where female rats are more resistant to the genotoxic effects of the test compounds compared to their male counterparts. This difference is further highlighted through our examination of gene expression, organ-specific weight changes, and tissue morphology. The purpose of the present study was to explore the complex and multifaceted issues of lower molecular weight PCBs as initiators of carcinogenesis, by examining the mutagenicity of PCB3, a hydroxylated metabolite (4'-OH-PCB3), and 3-methylcholanthrene (3-MC, positive control) in a transgenic rodent model. Previous findings indicated that PCB3 is mutagenic in the liver of male BigBlue transgenic rats under identical exposure conditions. We expected that female rats would be equally, if not more sensitive than male rats, since a 2-year carcinogenesis bioassay with Sprague-Dawley rats and commercial PCB mixtures reported much higher liver cancer rates in female than in male rats. The current study, however, revealed a similar trend in the mutation frequencies across all four treatment groups in females as reported previously in males, but increased variability among animals within each group and a lower overall effect, led to non significant differences in mutation frequencies. A closer analysis of the possible reasons for this negative result using microarray, organ weight and histology data comparisons shows that female Fischer 344 rats 1) had a higher baseline mutation frequency in the corn oil control group and greater variability than male rats; 2) responded with robust gene expression changes, which may also play a role in our observation of 3) highly increased liver, spleen, and lung weight in 3-MC and PCB3-treated female rats and thus changed distribution and kinetics of the test compounds. Our analysis indicates that female transgenic BigBlue Fischer 344 rats are more resistant to PCB3 and 3-MC genotoxicity compared to their male counterparts.

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Dataset Information

Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats.

Publications

Identification of sulfated metabolites of 4-chlorobiphenyl (PCB3) in the serum and urine of male rats.

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