Existence of a Threshold for Induction of Aberrant Crypt Foci in the Rat Colon with Low Doses of 2-Amino-1-methyl-6-phenolimidazo[4,5-b]pyridine

Fukushima, Shoji; Wanibuchi, Hideki; Morimura, Keiichirou; Iwai, Shuji; Nakae, Dai; Kishida, Hideki; Tsuda, Hiroyuki; Uehara, Nobuaki; Imaida, Katsumi; Shirai, Tomoyuki; Tatematsu, Masae; Tsukamoto, Tetsuya; Hirose, Masao; Furukawa, Fumio

doi:10.1093/toxsci/kfh104

Cited by 42 publications

(37 citation statements)

References 24 publications

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“…However, based on the present animal examination, the 10 ppm dose can be proposed as a no-observed effect level of PhIP on rat large intestinal carcinogenesis. A similar conclusion has been proposed by Fukushima et al 31 on the basis of data from a large number of rats (a total of 1,835 F344 males) with examination of formation of colon ACF, 1%) than that of the control group (20%). The proportion in the distal segment of the 50 ppm group (31%) was significantly lower than that of the 0.001-10 ppm subgroup (47.3%).…”

Section: Discussionsupporting

confidence: 83%

“…PhIP is known to induce ACF in different strains of rats in a dosedependent manner, 28 but to a much lower degree than azoxymethane (AOM) 29 or dimethylhydrazine (DMH). 30 Furthermore, lowdose potential of PhIP on the induction of ACF has already been described by Fukushima et al 31 In the present study, the particular focus was on the pathologic examination of practical effects of PhIP at low doses mimicking human exposure levels. For this purpose, we adopted a 2-stage carcinogenesis model featuring initiation with AOM to gain an appreciable tumor yield in the large intestine for quantitative analysis using tumors as endpoints.…”

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confidence: 59%

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

Doi

Wanibuchi

Salim

et al. 2005

Intl Journal of Cancer

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2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), an abundant food-derived heterocyclic amine (HCA), has attracted particular attention as a human colon carcinogen. Humans are in fact exposed to continuous low doses of HCAs during lifetime. Therefore, we focused on rat large intestinal carcinogenicity of PhIP at levels that mimic practical human exposure. A total of 192 6-weekold male F344 rats were subcutaneously injected twice with 15 mg/ kg body weight azoxymethane (AOM), then continuously fed various doses (0, 0.001, 0.01, 0.1, 1, 10, 50 and 200 ppm) of PhIP in the diet. At week 16, aberrant crypt foci (ACF) were quantitatively analyzed. At week 36, tumor occurrence was pathologically analyzed. Then immunohistochemical examinations were performed. PhIP was found to enhance strongly AOM-initiated rat large intestinal tumorigenesis at high doses (50 and 200 ppm), while lower doses (0.001-10 ppm) had no apparent effects. High doses also caused variation in tumor histologic types and their distribution throughout the large intestinal segments. Frequencies of ACF/cm 2 did not meaningfully vary between the groups. Cellular proliferation activity in normal-appearing colonic mucosa was significantly increased at high doses. These novel findings may provide evidence of a low-dose potential for PhIP, with a no-observed effect level speculated to be 10 ppm in the present initiation-promotion experimental model. ' 2005 Wiley-Liss, Inc.Key words: rat; large intestine; carcinogenesis; PhIP; azoxymethane; no-observed effect level Carcinogenesis is widely accepted to be a multistep process caused by a series of genetic and/or subsequent epigenetic alterations that are indispensable to the different stages from initiation to promotion and progression of cancer development. 1,2 Humans are consistently exposed to very many naturally occurring or synthetic chemical carcinogens at quite low-dose levels in the environment, 3 although concomitantly they may consume mixtures of naturally occurring anticarcinogenic compounds in their daily diets. 4 One focus of attention has been food-derived heterocyclic amines (HCAs) generated in cooking processes that have proved to be carcinogenic in rodent species. 5,6 HCAs are highly mutagenic 6 and genotoxic carcinogens that are generally thought to have no threshold in exerting their carcinogenic potential, which was postulated to exhibit dose dependence in vivo. 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. 10 In practice, the many factors active in vivo, from intake of carcinogens through to lesion development, mean that the processes are highly complicated, so that if the DNA-damaging pote...

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Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 59%

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

Doi

Wanibuchi

Salim

et al. 2005

Intl Journal of Cancer

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“…In our laboratory, different rat models of colon carcinogenesis have been employed, and PhIP-dose-dependent variation in the yield of aberrant crypt foci (ACF) and colon tumors has been well documented [17, 18]. ACF have been accepted as putative precursor lesions of colorectal neoplasms, both in humans and rodents, and have been frequently used in colon carcinogenesis models [19].…”

Section: Introductionmentioning

confidence: 99%

“…ACF have been accepted as putative precursor lesions of colorectal neoplasms, both in humans and rodents, and have been frequently used in colon carcinogenesis models [19]. Although PhIP can induce preneoplastic ACF in the colon in a dose-dependent fashion, their numbers are very small and lesion increment is limited to high-dose levels (≥50 ppm) [17]. On the other hand, DMH or azoxymethane (AOM), well-known genotoxic initiators of rodent colon carcinogenesis, induce large numbers of ACF.…”

Section: Introductionmentioning

confidence: 99%

“…1 Description of PhIP-enhanced colon carcinogenesis initiated with AOM in rats. Our concept is based on our previous and other experimental data [8, 9, 17, 18]: when high-dose PhIP alone is chronically administered to rats ( a ), the yields of colon preneoplastic lesions (such as ACF) and neoplasms are relatively low; if AOM alone is injected to rats during the initial few weeks ( b ), much higher numbers of preneoplastic lesions (such as ACF) are noted, but tumor yields remain relatively low similar to the high-dose PhIP alone case; if high-dose PhIP is continuously administered to rats after initial AOM exposure ( c ), the preneoplastic lesion yield is almost equal to that in the AOM-alone group, but final tumor incidence and multiplicity can reach extremely high levels, and this may be linked to alterations in oncogenes and related mechanisms. …”

Section: Introductionmentioning

confidence: 99%

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Altered Gene Expression in Rat Colonic Adenocarcinomas Induced in an Azoxymethane plus 2-Amino-1-Methyl-6-Phenylimidazo[4,5-<i>b</i>]- Pyridine Initiation-Promotion Model

Doi

Hagihara²,

Wei³

et al. 2007

Oncology

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2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), the most abundant food-derived mutagenic/carcinogenic heterocyclic amine (HCA), has attracted particular attention as a probable human colon carcinogen. Some studies have shown that PhIP administered in the post-initiation phase is able to enhance rat colon carcinogenesis remarkably. To determine whether this genotoxicant leaves a DNA footprint in colon carcinogenesis, 6-week-old male F344 rats were first subcutaneously injected with azoxymethane (AOM) and then continuously treated with various doses (0–200 ppm) of PhIP added to their diet. Animals were killed at week 36 for histopathological examination, and colonic adenocarcinomas derived from animals receiving 0, 50 and 200 ppm PhIP were subjected to a novel three-dimensional (3D)-microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. A total of five candidate genes were identified in adenocarcinomas following 200 ppm of PhIP and AOM initiation, with a dose-dependent increment. Among them, Stat1 (signal transducer and activator of transcription 1) and VEGFc (vascular endothelial growth factor c) demonstrated statistically significant upregulation by real-time RT-PCR. In addition, HSP90 (heat shock protein 90) and VEGFa showed a non-significant tendency to increase. In summary, overexpression of Stat1, VEGF and other genes could be involved in PhIP-enhanced colon tumorigenesis in the post-initiation phase.

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Thresholds for Genotoxic Carcinogens: Evidence from Mechanism‐Based Carcinogenicity Studies

Fukushima

Wei

Kakehashi

et al. 2010

Cancer Risk Assessment

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Existence of a Threshold for Induction of Aberrant Crypt Foci in the Rat Colon with Low Doses of 2-Amino-1-methyl-6-phenolimidazo[4,5-b]pyridine

Cited by 42 publications

References 24 publications

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

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

Altered Gene Expression in Rat Colonic Adenocarcinomas Induced in an Azoxymethane plus 2-Amino-1-Methyl-6-Phenylimidazo[4,5-<i>b</i>]- Pyridine Initiation-Promotion Model

Thresholds for Genotoxic Carcinogens: Evidence from Mechanism‐Based Carcinogenicity Studies

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