Identification of Sulfated Metabolites of 4-chlorobiphenyl (PCB3) in the Serum and Urine of Male Rats

Overview

Journal Chem Res Toxicol

Publisher American Chemical Society

Specialty Toxicology

Date 2012 Nov 10

PMID 23137097

Citations 42

Authors

Kiran Dhakal

Xianran He

Hans-Joachim Lehmler

Lynn M Teesch

Michael W Duffel

Larry W Robertson

Affiliations

Soon will be listed here.

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 μmol/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 β-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 μg/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.

Citing Articles

Elucidating the Metabolism of Chiral PCB95 in Wildtype and Transgenic Mouse Models with Altered Cytochrome P450 Enzymes Using Intestinal Content Screening.

Li X, Bullert A, Gautam B, Han W, Yang W, Zhang Q Chem Res Toxicol. 2024; 37(12):1989-2002.

PMID: 39561283 PMC: 11653397. DOI: 10.1021/acs.chemrestox.4c00350.

Significant metabolic alterations in mouse dams exposed to an environmental mixture of polychlorinated biphenyls (PCBs) during gestation and lactation: Insights into PCB and metabolite profiles.

Li X, Suh Y, Wilson R, Lein P, Cui J, Lehmler H Environ Toxicol Pharmacol. 2024; 111:104567.

PMID: 39305941 PMC: 11499005. DOI: 10.1016/j.etap.2024.104567.

New Perspectives on the Risks of Hydroxylated Polychlorinated Biphenyl (OH-PCB) Exposure: Intestinal Flora α-Glucosidase Inhibition.

Qin G, Jia R, Xue J, Chen L, Li Y, Luo W Toxics. 2024; 12(4).

PMID: 38668460 PMC: 11053903. DOI: 10.3390/toxics12040237.

Distribution of 2,2',5,5'-Tetrachlorobiphenyl (PCB52) Metabolites in Adolescent Rats after Acute Nose-Only Inhalation Exposure.

Bullert A, Li X, Gautam B, Wang H, Adamcakova-Dodd A, Wang K Environ Sci Technol. 2024; 58(14):6105-6116.

PMID: 38547313 PMC: 11008251. DOI: 10.1021/acs.est.3c09527.

Complex roles for sulfation in the toxicities of polychlorinated biphenyls.

Duffel M, Lehmler H Crit Rev Toxicol. 2024; 54(2):92-122.

PMID: 38363552 PMC: 11067068. DOI: 10.1080/10408444.2024.2311270.

References

Berger I, Guttman C, Amar D, Zarivach R, Aharoni A . The molecular basis for the broad substrate specificity of human sulfotransferase 1A1. PLoS One. 2011; 6(11):e26794. PMC: 3206062. DOI: 10.1371/journal.pone.0026794. View

Jones K, de Voogt P . Persistent organic pollutants (POPs): state of the science. Environ Pollut. 2004; 100(1-3):209-21. DOI: 10.1016/s0269-7491(99)00098-6. View

Bender R, Lehmler H, Robertson L, Ludewig G, Osheroff N . Polychlorinated biphenyl quinone metabolites poison human topoisomerase IIalpha: altering enzyme function by blocking the N-terminal protein gate. Biochemistry. 2006; 45(33):10140-52. DOI: 10.1021/bi0524666. View

Amaro A, Oakley G, Bauer U, Spielmann H, Robertson L . Metabolic activation of PCBs to quinones: reactivity toward nitrogen and sulfur nucleophiles and influence of superoxide dismutase. Chem Res Toxicol. 1996; 9(3):623-9. DOI: 10.1021/tx950117e. View

Liu Y, Apak T, Lehmler H, Robertson L, Duffel M . Hydroxylated polychlorinated biphenyls are substrates and inhibitors of human hydroxysteroid sulfotransferase SULT2A1. Chem Res Toxicol. 2006; 19(11):1420-5. DOI: 10.1021/tx060160+. View

van t Erve T, Rautiainen R, Robertson L, Luthe G . Trimethylsilyldiazomethane: a safe non-explosive, cost effective and less-toxic reagent for phenol derivatization in GC applications. Environ Int. 2010; 36(8):835-42. PMC: 4090112. DOI: 10.1016/j.envint.2010.02.011. View

Chaudhuri L, Sarsour E, Goswami P . 2-(4-Chlorophenyl)benzo-1,4-quinone induced ROS-signaling inhibits proliferation in human non-malignant prostate epithelial cells. Environ Int. 2010; 36(8):924-30. PMC: 2888671. DOI: 10.1016/j.envint.2010.01.001. View

Volp R . Glucuronidation in 4-chlorobiphenyl metabolism by rat and human liver microsomes. Drug Metab Dispos. 1988; 16(4):650-2. View

Dirtu A, Jaspers V, Cernat R, Neels H, Covaci A . Distribution of PCBs, their hydroxylated metabolites, and other phenolic contaminants in human serum from two European countries. Environ Sci Technol. 2010; 44(8):2876-83. DOI: 10.1021/es902149b. View

10.

Persoon C, Peters T, Kumar N, Hornbuckle K . Spatial distribution of airborne polychlorinated biphenyls in Cleveland, Ohio and Chicago, Illinois. Environ Sci Technol. 2010; 44(8):2797-802. PMC: 2855146. DOI: 10.1021/es901691s. View

11.

Daidoji T, Gozu K, Iwano H, Inoue H, Yokota H . UDP-glucuronosyltransferase isoforms catalyzing glucuronidation of hydroxy-polychlorinated biphenyls in rat. Drug Metab Dispos. 2005; 33(10):1466-76. DOI: 10.1124/dmd.105.004416. View

12.

Iwata H, Tanabe S, Sakai N, Nishimura A, Tatsukawa R . Geographical distribution of persistent organochlorines in air, water and sediments from Asia and Oceania, and their implications for global redistribution from lower latitudes. Environ Pollut. 1994; 85(1):15-33. DOI: 10.1016/0269-7491(94)90234-8. View

13.

BAKKE J, Bergman A, Larsen G . Metabolism of 2,4',5-trichlorobiphenyl by the mercapturic acid pathway. Science. 1982; 217(4560):645-7. DOI: 10.1126/science.6806905. View

14.

Gustafsson J, Rafter J, BAKKE J, GUSTAFSSON B . The effect of intestinal microflora on the enterohepatic circulation of mercapturic acid pathway metabolites. Nutr Cancer. 1981; 2(4):224-31. DOI: 10.1080/01635588109513687. View

15.

Klaassen C, Liu L, Dunn 2nd R . Regulation of sulfotransferase mRNA expression in male and female rats of various ages. Chem Biol Interact. 1998; 109(1-3):299-313. DOI: 10.1016/s0009-2797(97)00141-5. View

16.

Arellano L, Fernandez P, Tatosova J, Stuchlik E, Grimalt J . Long-range transported atmospheric pollutants in snowpacks accumulated at different altitudes in the Tatra Mountains (Slovakia). Environ Sci Technol. 2011; 45(21):9268-75. DOI: 10.1021/es202111n. View

17.

Wangpradit O, Teesch L, Mariappan S, Duffel M, Norstrom K, Robertson L . Oxidation of 4-chlorobiphenyl metabolites to electrophilic species by prostaglandin H synthase. Chem Res Toxicol. 2008; 22(1):64-71. PMC: 2637223. DOI: 10.1021/tx800300t. View

18.

Flor S, Ludewig G . Polyploidy-induction by dihydroxylated monochlorobiphenyls: structure-activity-relationships. Environ Int. 2010; 36(8):962-9. PMC: 2949501. DOI: 10.1016/j.envint.2010.03.012. View

19.

Joshi S, Vyas S, Duffel M, Parkin S, Lehmler H . Synthesis of Sterically Hindered Polychlorinated Biphenyl Derivatives. Synthesis (Stuttg). 2011; 7:1045-1054. PMC: 3080045. DOI: 10.1055/s-0030-1258454. View

20.

Hempel N, Gamage N, Martin J, McManus M . Human cytosolic sulfotransferase SULT1A1. Int J Biochem Cell Biol. 2006; 39(4):685-9. DOI: 10.1016/j.biocel.2006.10.002. View