Tumorigenicity in newborn mice of fjord region and other sterically hindered diol epoxides of benzo[g]chrysene, dibenzo[a, l]pyrene (dibenzo[def, p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene
Diol epoxides of benzo[g]chrysene, dibenzo[a, l]pyrene (dibenzo[def, p]chrysene), 4H-cyclopenta[def]chrysene and fluoranthene were tested for tumorigenicity in newborn mice. The compounds tested were racemic trans-11, 12-dihydroxy-anti-13,14-epoxy-11,12,13,14-tetrahydrobenzo[g]-chrysene (BgCDE), trans-11, 12-dihydroxy-anti-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a, l]pyrene (DB[a, l]PDE),trans-1,2-dihydroxy-anti-3,3a-epoxy-1,2,3,3a-tetrahydro-4H-cyclopenta[def]chrysene (C[def]C-1-3a-DE), trans-6,7-dihydroxy-anti-8,9-epoxy-6,7,8,9-tetrahydro-4H-cyclopenta-[def]chrysene (C[def]C-6-9-DE) and trans-2,3-dihydroxy-anti-1,10b-epoxy-10b,1,2,3-tetrahydrofluoranthene (FDE). BgCDE and DB[a,l]PDE are fjord region diol epoxides and their tumorigenic activities were compared to those of trans-3,4-dihydroxy-anti-1,2-epoxy-1,2,3, 4-tetrahydrobenzo-[c]phenanthrene (BcPDE), a fjord region diol epoxide with known high tumorigenicity and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene (BPDE), a highly tumorigenic bay region diol epoxide. The protocol called for testing of each compound at a total dose of 25 nmol per mouse, administered on days 1, 7 and 15 of life, with killing at age 35 weeks. BgCDE had similar activity as BcPDE for induction of lung tumors and was more active than BcPDE for induction of liver tumors in male mice. Both compounds were significantly more tumorigenic than BPDE. DB[a,l]PDE was highly toxic. All mice died within 1 week of the first dose. It was then tested in a second study using total doses of 5 and 1 nmol per mouse. Only the first dose of the intended 5 nmol total dose was given due to toxicity. The full course of doses with a total of 1 nmol per mouse was administered; DB[a,l]PDE induced a significant incidence and multiplicity of lung tumors and, in male mice, liver tumors at both doses. These results demonstrate that fjord region diol epoxides are highly active tumorigens in newborn mice, with activity greater than that of the most active unsubstituted bay region diol epoxide, BPDE. C[def]C-1-3a-DE and C[def]-6-9-DE were compared to trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydrochrysene (CDE), at a total dose of 500 nmol per mouse. FDE was also tested at this dose. The most active compound among the chrysene derivatives was C[def]C-1-3a-DE, followed by C[def]C-6-9-DE and CDE. C[def]C-1-3a-DE has a sterically constrained bay region, in which the benzylic carbon of the tri-substituted epoxide ring is part of a fused ring system. This feature is also present in FDE, which had considerable tumorigenic activity, greater than that of CDE in lung and greater than any of the chrysene derivatives in liver. These results demonstrate that the tumorigenicity of diol epoxides in newborn mice is enhanced by steric constraints present when the epoxide ring is part of a fjord region or is attached to a fused ring system. The tumorigenic activity of FDE may be relevant to human risk since it is a stable metabolite of the widely distributed environmental pollutant fluoranthene.