Polychlorinated Biphenyls-Modulated Tumorigenesis in Sprague-Dawley Rats: Correlation with Mixed Function Oxidase Activities and Superoxide (O sub(2) super( times -)) Formation Potentials and Implied Mode of Action

Parallel, chronic (24 months) multidose bioassays of the PCB (polychlorinated biphenyls) 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 months and screened for correlation with late life hepatotumorigenesis (HT; mostly adenomas). Consistently correlated with HT were (1) tissue accumulations of capital sigma PCBs (correlated in both sexes) and of dioxin equivalents (toxic equivalency [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 (O sub(2) super( times -)) 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. The new findings, along with other recently reported relationships, were indicative of a MOA consisting of (1) capital sigma PCB/TEQ accumulation in rat tissues; (2) capital sigma PCB/TEQ repression of constitutive MFOs; (3) capital sigma PCB/TEQ induction of other MFOs; (4) MFO-mediated formation of RCQs; (5) RCQ-mediated formation of O sub(2) super( times -); (6) O sub(2) super( times -) dismutation to H sub(2)O sub(2); and (7) H sub(2)O sub(2)-mediated mitotic signaling, resulting in the proliferation of spontaneously or otherwise initiated cells to form hepatic tumors, as in tumor promotion.