Mechanisms of SEPA 0009-Induced Tumorigenesis in v-ras^Ha Transgenic Tg.AC Mice

Abstract

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-ras Ha transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.

Report on Carcinogens Monograph on Haloacetic Acids Found as Water Disinfection By-Products

“…The p53 haploinsufficient transgenic mice may not be able to detect non-genotoxic carcinogens (Gulezian et al 2000;Spalding et al 2000;Tennant and Spalding 1996). Concerns for the Tg.AC hemizygous mice include production of false positive results from vehicle controls (Jacobs and Hatfield 2013), or minor skin abrasions (Fuhrman et al 2005), and its inability to distinguish between promotion and de novo carcinogenicity (Jacobs and Hatfield 2013;Luijten et al 2016). The use of the Tg.AC hemizygous mouse is no longer recommended by the FDA (Luijten et al 2016).…”

Report on Carcinogens Monograph on Pentachlorophenol and By-products of Its Synthesis

“…This transgenic mouse model is more sensitive to tumor induction than conventional cancer bioassays, as it has an oncogenic mutation. However, this model has been questioned as neoplasms can be induced by non-carcinogenic treatments, such as skin irritation and wounding (Fuhrman et al 2005).…”

“…No 2-year dietary cancer studies were available using 99% pure pentachlorophenol in mice; however, a 6-month cancer study in TgAC mice (dermal application) was positive for papillomas and gave a positive effect of dose on tumor multiplicity, lending support to the hypothesis that pure pentachlorophenol has a role in the pathogenesis of cancer in the mouse. However, this model has been questioned as neoplasms can be induced by non-carcinogenic treatments, such as skin irritation and wounding (Fuhrman et al 2005). It would also appear that dioxin-like components contributed as well since the less pure technical grade pentachlorophenol had more liver tumors at the same exposure concentration (200 ppm) than the Dowicide EC-7 that was of higher purity.…”

“…The positive response only in the TgAC model is consistent with a nongenotoxic mechanism. However, the appropriateness of this model has been questioned, as neoplasms can be induced by non-carcinogenic treatments, such as skin irritation and wounding (Fuhrman et al 2005). Other studies provided evidence that pentachlorophenol could enhance or inhibit the carcinogenicity of other compounds by inhibiting various enzymes involved in oxidation, epoxidation, sulfation of phenols, and acetylation (Arrhenius et al 1977;Goodman 2001;Meerman et al 1983;Moorthy and Randerath 1996).…”