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ToxSci Advance Access published online on May 16, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm122
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

PCB-Modulated Tumorigenesis in Sprague-Dawley rats: Correlation with Mixed Function oxidase (MFO) Activities and Superoxide (OFormula) Formation Potentials and Implied Mode of Action

John F. Brown, Jr.*,{dagger},1, Brian A. Mayes{dagger}, Jay B. Silkworth{dagger} and Stephen B. Hamilton*

* General Electric Company, Fairfield, Connecticut 06431 {dagger} General Electric Company, Global Research Center, One Research Circle, Niskayuna, New York, 12309

1 To whom the correspondence should be addressed at 1479 Dean St., Niskayuna, NY 12309-5235, E-mail john.brown{at}ge.com.

Received December 19, 2006; revision received May 4, 2007; accepted May 8, 2007


  Abstract

Parallel, chronic (24 mo.) multidose bioassays of the PCB Aroclors 1016, 1242, 1254, and 1260 in male and female Sprague-Dawley rats showed sex/Aroclor-dependent increases in hepatic tumors and decreases in extrahepatic tumors. To elucidate the PCB mode of action (MOA) involved, levels of a number of hypothesized mediators were measured in liver specimens collected at 3, 6, 12,18 and 24 mo. and screened for correlation with late life hepatotumorigenesis (HT; mostly adenomas). Consistently correlated with HT were: (1) tissue accumulations of {Sigma}PCBs (correlated in both sexes) and of dioxin equivalents (TEQ; correlated in females only); (2) net activities of six groups of mixed function oxidases (MFOs), some PCB-induced, some PCB-repressed, as determined by differential metabolism of PCB congeners; (3) activities of deproteinated, reoxidized hepatic cytosols as catalysts for superoxide (OFormula) production, such activity having the chemical characteristics of redox-cycling quinones (RCQs), e.g., those derived from the glutathionylated estrogen catechols that were identified in the female rat livers, and (4) increased expression of the indicator of cell proliferation, proliferating cell nuclear antigen (PCNA). The new findings, along with other recently reported relationships, were indicative of a MOA consisting of: (1) {Sigma}PCB/TEQ accumulation in rat tissues; (2) {Sigma}PCB/TEQ repression of constitutive MFOs; (3) {Sigma}PCB/TEQ induction of other MFOs; (4) MFO-mediated formation of RCQs; (5) RCQ-mediated formation of OFormula; (6) OFormula dismutation to H2O2; and (7) H2O2-mediated mitotic signaling, resulting in the proliferation of spontaneously or otherwise initiated cells to form hepatic tumors, as in tumor promotion.


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[Abstract] [Full Text] [PDF]


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