Minimal Role of Enhanced Cell Proliferation in Skin Tumor Promotion by Mirex: A Nonphorbol Ester-Type Promoter

Abstract

Mirex, a chlorinated hydrocarbon previously used as a systemic insecticide and flame retardant, is a nongenotoxic hepatocarcinogen in both rats and mice. In liver, mirex induced biochemical responses and hyperplasia characteristic of increased cell proliferation, which is consistent with its role as a liver tumor promoter. We have recently shown that mirex is a potent nonphorbol ester-type skin tumor promoter in 7, 12-dimethylbenz[a]anthracene (DMBA)-initiated mice. However, unlike its effect in liver, a single topical application of mirex to skin does not induce the acute biochemical responses, such as increased epidermal DNA synthesis and ornithine decarboxylase activity, indicative of increased cell proliferation. Multiple topical applications of mirex over a 1 month period induced only a minimal increase in the number of epidermal nucleated cell layers, which contrasts with definitive hyperplasia induced by a comparable tumor-promoting dose of 12-0-tetradecanoylphorbol-13-acetate (TPA). Collectively, these data indicated that mirex is promoting through a novel mechanism. Further evidence that mirex promotes tumors through a mechanism distinct from that of the prototypical skin tumor promoter, TPA, was obtained by examining the effect of their simultaneous co-treatment. The co-application of mirex and TPA yielded a tumor multiplicity greater than the sum of the responses of each promoter individually. In summary, our results demonstrate that mirex, a carcinogenic and hyperplastic agent in liver, is also a very effective tumor promoter in mouse skin, but suggest that mirex operates via a novel mechanism in skin that may involve only a minimal role for enhanced cell proliferation.

A Preliminary Operational Classification System for Nonmutagenic Modes of Action for Carcinogenesis

“…By contrast, when promotion was started with TPA and switched at an analogous time point to BzPo, no additional papillomas were induced, indicating that some of the initiating mutations that are promotable by TPA are not promotable by BzPo (Mancuso et al, 2004). By contrast, administration of mirex and TPA to DMBA initiated animals yielded a tumor multiplicity greater than the sum of each agent separately (Meyer et al, 1993). This suggests that these agents act at different steps in the carcinogenic process leading to the same tumors.…”

Mouse Skin Models for Carcinogenic Hazard Identification: Utilities and Challenges

“…These early changes are relevant for human carcinogenesis as well, since many human carcinogens; including ultraviolet irradiation, components of tobacco smoke, and contact sensitizers; have tumor-promoting ability. Tumor promoters almost without exception (Moser et al, 1992; Meyer et al, 1993), increase cell proliferation, induce inflammation, and cause hyperplasia. Inflammation, irritation, and hyperplasia are frequently associated with, and predictive of, tumor promoting activity in mouse models including the Tg.AC mouse (Slaga et al, 1996; Hanausek et al, 2004; Humble et al, 2005).…”