The broad, long-term objective of this proposal is to better understand the cellular and molecular mechanisms through which the chlorinated pesticide, mirex functions as a potent tumor promoter. It is anticipated that this understanding will yield new insight into the fundamental mechanism utilized by nongenotoxic carcinogens and as a consequence, provide information pertinent to the identification and rational risk assessment of nongenotoxic carcinogens. Mirex and the phorbol ester, 12- O-tetradecanoylphorbol-13-acetate (TPA) are two very effective skin tumor promoters that vary dramatically in their structure. PTA as well as other structurally related and unrelated skin tumor promoters have the ability to induce certain biochemical changes and a sustained epidermal hyperplasia in mouse skin which are considered necessary but not sufficient for tumor promotion. Mirex does not appear to produce these changes, indicating that is may be functioning through a novel mechanism. However, mirex does appear, based on the A->T transversion in 61st codon of the Ha-ras gene, to clonally expand the same population of cells as TPA in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. These data suggest two major mechanistic possibilities: 1) that mirex and TPA converge on some common underlying mechanism that requires the function of a mutated Ha-ras gene, or 2) that mirex and TPA function through two distinct mechanisms that independently require a mutated Ha-ras gene. Co-treatment of DMBA-initiated mouse skin with mirex and TPA indicates that the promoting activities of TPA and mirex are additive and that mirex and TPA may be clonally expanding different populations of cells through independent mechanisms. Therefore, while mirex- and TPA-promoted tumors both contain a common mutated Ha-ras gene it is possible that there are other genetic alterations that are not common and that these are selected for by each promoter. Additional tumor experiments will be considered to thoroughly document the additive nature of the promoting effects of TPA and mirex and to conclude that TPA and mirex are operationally clonally expanding different populations of cells. Tumors from these experiments will be characterized with respect to the Ha-ras mutation. In order to begin to test the hypothesis that there are other genetic alterations that are not common and that these are selected for by each promoter, mirex- and TPA-promoted tumors will be characterized for their genetic diversity with respect to the mutational spectra of the tumor suppressor gene, p53. Since mirex appears to produce a selective mitogenesis of initiated cells without the concomitant mitogenesis of normal cells, mechanisms involving mitoinhibition and mitostimulation of normal and initiated cells with be investigated. Finally, in order to better understand the function of the mutated Ha-ras gene, and mechanisms that may be common to mirex- and TPA-promoted papillomas, defects in a growth factor pathway that may be associated with the mutated Ha-ras gene will be examined. It is anticipated that the results of these studies will yield important information regarding the mechanisms through which some nongenotoxic carcinogens function.
| Bain, L J; McLachlan, J B; LeBlanc, G A (1997) Structure-activity relationships for xenobiotic transport substrates and inhibitory ligands of P-glycoprotein. Environ Health Perspect 105:812-8 |
| LeBlanc, G A; Bain, L J; Wilson, V S (1997) Pesticides: multiple mechanisms of demasculinization. Mol Cell Endocrinol 126:1-5 |
