INDUCTION OF CYTO-TOXICITY, MUTATION, CYTOGENETIC CHANGES, AND NEOPLASTIC TRANSFORMATION BY BENZO(A)PYRENE AND DERIVATIVES IN C3H/1OT1/2 CLONE 8 MOUSE FIBROBLASTS

Abstract

Benzo(a)pyrene (BaP), a series of its metabolic derivatives, and benzo(e)pyrene, a very weakly carcinogenic isomer, were tested for their biological effects on transformable C3H/10T1/2 cells. These cells were used as targets in a series of assays designed to measure oncogenic transformation, mutation to ouabain resistance, cytotoxicity and induction of cytogenetic changes, as evidenced by chromosomal aberrations and sister chromatid exchange. Only the parent hydrocarbon, BaP, and (.+-.)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene were significantly active in production transformation and cytogenetic alterations. BaP, (.+-.)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, and (.+-.)-7.alpha., 8.beta.-dihydroxy-9.beta.,10.beta.-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene, however, were all effective inducers of mutation in C3H/10T1/2 cells. (.+-.)-7.alpha., 8.beta.-Dihydroxy-9.beta.,10.beta.-epoxy-7,8,-9,10-tetrahydrobenzo(a)pyrene was the most potent agent in tests for cytotoxicity. Benzo(e)pyrene was inactive in all assays examined. Among the compounds tested, there was a correlation between the ability to induce cytogenetic changes and the ability to produce mutation and transformation. These results support the demonstrated role of (.+-.)-trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene as a proximal carcinogenic form of BaP and illustrate the utility of the C3H/10T1/2 cell system as an important tool for the detection of genotoxic damage by carcinogenic chemicals.