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Activation of PCBs to Genotoxins in Vivo


Commercial PCB mixtures induce hepatocellular carcinomas in rats and mice, but the mechanisms by which they do so have not been determined. We hypothesize that the lower halogenated biphenyls are activated by hepatic enzymes to oxygenated species that are electrophilic and bind to DNA.</p>
Employing the Solt-Farber protocol, we identified 4- cholorbiphenyl as an initiator of hepatocarcinogenesis in the rat. We propose to extend our studies to: <ol>
<li> identify the metabolic activation pathway of 4-chlorobiphenyl with cell culture and in vivo methods,</li>
<li> determine the primary sequence changes in oncogenes/tumor suppressor genes, and/or karyotic changes during foci/nodule formation and carcinogenesis in rats,</li>
<li> employ shuttle vector, recombinant cells, and recombinant rat methods to identify the genotoxic profiles of the metabolites and to find appropriate short term tests, </li>
<li> determine the changes in DNA arising from oxidative stress during PCB toxicity, and </li>
<li> identify biomarkers of exposure/susceptibility/toxicity in a highly- exposed North American In. </li> </ol></p>

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Jointly these studies may explain why some PCBs are activated to genotoxins, while others are not, which target genes are involved, the nature of the DNA lesions, and the mutations that ensure, organs and human populations at risk, and finally whether these lesions are evident in an exposed population. </P>
These data may also provide clues about whether nutritional or other interventions are warranted to protect highly-exposed humans. These mechanistic and biomonitoring issues will form a basis for the quantitative human health risk assessment for these important Superfund Chemicals.</p>

Robertson, Larry
University of Kentucky
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