Nonlinearities in 2-Acetylaminofluorene Exposure Responses for Genotoxic and Epigenetic Effects Leading to Initiation of Carcinogenesis in Rat Liver

Abstract

R. (1998). Toxicol. Sci. 45,[152][153][154][155][156][157][158][159][160][161] The dose responses for several effects of low-level limited exposures to 2-acetylaminofluorene (AAF) in the livers of male Fischer 344 rats were measured and a subsequent phenobarbital tumor promotion regimen was used to manifest initiation of carcinogenesis. Three doses over a 10-fold range yielding cumulative total exposures of 0.126,0.42, and 1.26 mmol AAF/kg body weight were achieved by daily intragastric instillation for up to 12 weeks with interim terminations. This was followed by 24 weeks administration of 500 ppm phenobarbital (PB) in the diet to promote liver tumor development. At 12 weeks at the end of AAF administration, all exposures produced adducts in liver DNA, measured by 32 P postlabeling, and the level of adducts increased with exposure, except that the high exposure did not produce a dose proportional increase. Measurement of arylsutfotransferase activity, a key enzyme in the metabolic activation of AAF, revealed that in livers from the high exposure animals, the enzyme was inhibited. To assess for toxicity, the centrilobular zone of glutamine synthetasepositive hepatocytes was quantified immunohistochemically at 12 weeks. The area of the zone was reduced in the high exposure group and there was a trend to reduction in relationship to exposure. The two lower exposures to AAF produced no increase in cell proliferation, whereas the high exposure resulted in a marked increase, about 8-fold over controls. Initiation was assessed by induction of hepatocellular altered foci (HAF) that expressed the placental form of glutathione 5-transferase. AAF induced HAF in the high exposure group, 9-fold at 8 weeks and 170-fold at 12 weeks compared to controls. In rats maintained on PB for 24 weeks after exposure, the multiplicity of HAF increased in controls and comparably in the low and mid exposure groups, but remained at the about the same high level in the high exposure group. The high exposure produced a substantial incidence of benign neoplasms by 12 weeks, and with promotion by 36 weeks, all rats developed hepatocellular neoplasia. In the mid exposure

Alteration of Liver Cell Function and Proliferation: Differentiation Between Adaptation and Toxicity

“…The exposures studied ranged from those producing toxicity and promotable neoplastic initiation ( > 395 mg/kg cumulative exposure) to those producing minimal effects and no measurable initiation (40 mg/kg cumulative exposure); the latter exposure is more than 10 times lower than those exposures previously studied by others. In this study (132), at 4 weeks, at the low dose with a cumulative exposure of 13 mg/kg, increases were found in LBR and DNA adduct formation, which persisted for 4 additional weeks with a cumulative exposure of 26 mg/kg. By week 12, with a cumulative exposure of 40 mg/kg, the LBR remained increased and the magnitude of DNA adduct formation was 29% of that of the high cumulative exposure of 395 mg/kg, at which formation of adducts had plateaued.…”

“…AAF is one of those hepatocarcinogens whose effects are diminished by pretreatment with enzyme inducers (97). This laboratory has been conducting studies of the dose-response of a variety of hepatocellular effects of AAF in male F344 rats (123,131,132), which are highly susceptible to AAF hepatocarcinogenicity (124). The exposures studied ranged from those producing toxicity and promotable neoplastic initiation ( > 395 mg/kg cumulative exposure) to those producing minimal effects and no measurable initiation (40 mg/kg cumulative exposure); the latter exposure is more than 10 times lower than those exposures previously studied by others.…”

Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

“…At the end of the PS, no hepatocellular neoplasm was found in controls or in the LE group. In the MLE group, which was the previously studied LE, only 1 adenoma was found, whereas the incidence of liver neoplasms was 32% in the MHE and 80% in the HE, increases that were dispropor- In a follow-up study (50). the exposure responses for several effects of low-level exposures to AAF were mea- (Table 6).…”

Lack of large intestinal carcinogenicity of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5‐b]pyridine at low doses in rats initiated with azoxymethane

“…3 However, in practice, low-dose administration has not necessarily led to cancer development in the rat liver. 7 Thereby, in our laboratory, the nonthreshold theory for hepatocarcinogenesis of one HCA, 2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline (MeIQx), has been challenged, since in vivo dose-response curves do not show linearity at low-dose levels. 8,9 Moreover, thresholds for chemical carcinogenesis were concluded in a recent article.…”