Dose‐dependent Induction of 8‐Hydroxyguanine and Preneoplastic Foci in Rat Liver by a Food‐derived Carcinogen, 2‐Amino‐3,8‐dimethylimidazo[4,5‐<i>f</i>]quinoxaline, at Low Dose Levels

Katô, Toshio; Hasegawa, Ryohei; Nakae, Dai; Hirose, Masao; Yaono, Makoto; Chen, Lin; Kobayashi, Yozo; Konishi, Yoichi; Ito, Nobuyuki; Shirai, Tomoyuki

doi:10.1111/j.1349-7006.1996.tb03149.x

Cited by 37 publications

(18 citation statements)

References 41 publications

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“…56 The fact that the level of 8-OHdG formation showed a statistical significant decrease at a dose of 0.005 ppm DDT compared to the concurrent control group in our study, thus provides further evidence in favour of a role for change in CYP3A2 protein expression. Although we also examined OGG1 mRNA expression, this proved to be unchanged.…”

Section: Discussionsupporting

confidence: 62%

Detailed low‐dose study of 1,1‐b™IS(p‐chlorophenyl)‐2,2,2‐ trichloroethane carcinogenesis suggests the possibility of a hormetic effect

Sukata

Uwagawa

Ozaki

et al. 2002

Intl Journal of Cancer

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To obtain information on the effects of nongenotoxic carcinogens at low doses for human cancer risk assessment, the carcinogenic potential of the organochlorine insecticide, 1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane (DDT), in the liver was assessed in F344 rats. In experiment 1, 240 male animals, 21 days old, were administered 0, 0.5, 1.0, 2.0, 5.0, 20, 100 and 500 ppm DDT in the diet for 16 weeks. Experiment 2 was conducted to elucidate the carcinogenic potential of DDT at lower levels using 180 rats given doses of 0, 0.005, 0.01, 0.1, 0.2 and 0.5 ppm. The livers of all animals were immunohistochemically examined for expression of glutathione S-transferase placental form (GST-P), putative preneoplastic lesions. Quantitative values for GST-P-positive foci in the liver were increased dose-dependently in rats given 20 ppm DDT and above with statistical significance as compared with the concurrent control value. In contrast, doses of 0.005 and 0.01 ppm were associated with a tendency for decrease below the control value, although not significantly. Western blotting analysis show that cytochrome P-450 3A2 (CYP3A2) protein expression tended to decrease at 0.005 and 0.01 ppm, a good correlation being observed with the change in the number of GST-P-positive foci. These findings suggest that a DDT hepatocarcinogenicity may show nonlinear response, that is, hormetic response at low doses. Furthermore, since CYP3A2 protein expression appears to be important for the effects of phenobarbital and the ␣-isomer of benzene hexachloride, mRNAs for IL-1 receptor type 1 (IL-1R1) and TNF-␣ receptor type 1 (TNFR1) whose ligands have roles not only in downregulating CYP3A2 expression but also in inducing antiproliferative effect or apoptosis in hepatocyte were examined. Increase was observed at low doses of DDT. Oxidative stress in liver DNA, assessed in terms of 8-hydroxydeoxyguanosine as a marker, was also decreased. These findings suggest that the possible hormetic effect that was observed in our detailed low-dose study of DDT carcinogenesis, although not statistically significant, may be linked to levels of oxidative stress and proinflammatory cytokines.

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Section: Discussionsupporting

confidence: 62%

Detailed low‐dose study of 1,1‐b™IS(p‐chlorophenyl)‐2,2,2‐ trichloroethane carcinogenesis suggests the possibility of a hormetic effect

Sukata

Uwagawa

Ozaki

et al. 2002

Intl Journal of Cancer

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“…G3 T transversions are the most commonly observed mutations, but other point mutations have been documented. Increases in 8-OH-Gua levels have also been correlated with carcinogenesis in numerous studies [Nakae et al, 1997;Yamaguchi et al, 1996;Asami et al, 1996;Kato et al, 1996;Floyd, 1990]. Therefore, the 3(Ϯ1)-fold dose-dependent increase of 8-OH-Gua levels observed in type II cells exposed to H 2 O 2 suggests that they have been predisposed to mutagenesis.…”

Section: Discussionmentioning

confidence: 81%

Hydrogen peroxide induces oxidative DNA damage in rat type II pulmonary epithelial cells

Meehan

Spencer

Rannels

et al. 1999

Environ. Mol. Mutagen.

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“…However, clear dose-dependence was not observed, and reversible alteration of liver DNA after administration of genotoxic carcinogens has been demonstrated. 19,32,33) In one study, 8-OHdG levels assessed after 1 week of dietary MeIQx administration were dose-dependently increased, but this was not the case at the end of the treatment period, especially with the higher-dose groups.…”

Section: Meiqx Treatmentmentioning

confidence: 99%

“…8,10,35) Recently, quantitative data for GST-P-positive foci comprising very small numbers of hepatocytes have been used for detection of liver carcinogens and assessment of hepatocarcinogenic risk. 11,17,32,36) It has been demonstrated that levels of MeIQx-DNA adducts linearly increase from very low doses, but this is not the case for GST-P-positive foci development. 11,17) Our present data also demonstrated that maternal exposure to MeIQx during the period of pregnancy and lactation did not increase the number of GST-P-positive foci in the liver despite causing genetic damage.…”

Section: Meiqx Treatmentmentioning

confidence: 99%

Induction of DNA‐adducts and increase of 8‐hydroxy‐2‐deoxyguanosine, but no development of preneoplastic lesions in offspring liver with transplacental and trans‐breast milk exposure to 2‐amino‐3,8‐dimethylimidazo [4,5‐f]quinoxaline (MelQx) in rats

et al. 2004

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Humans may be exposed to 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) at low doses during the period of gestation and lactation, and thereafter throughout life. The current study was designed to examine the possibility that early exposure may increase the risk of liver tumor development and related genetic changes. Male and female F344 rats were therefore administered MeIQx in diet (1, 10 and 100 ppm) for 4 weeks before mating and also during gestation and lactation. We also examined the carcinogenic risk of low-dose maternal and postweaning exposure (MeIQx at doses of 1 and 10 ppm). Surviving male F1 rats were sacrificed under ether anesthesia at 19 weeks of age for analyses of glutathione S-transferase placental formpositive foci in the liver and aberrant crypt foci in the colon, as putative preneoplastic lesions. Transplacental and trans-breast milk exposure to MeIQx did not enhance development of the lesions, and levels of cell proliferation in the liver also did not differ from control values. However, excretion of MeIQx into breast milk and transfer to the fetus and offspring were observed with resultant hepatic MeIQx-DNA adducts and 8-hydroxy-2′ ′ ′ ′-deoxyguanosine formation. Thus, our data suggest that maternal exposure to MeIQx during the period of pregnancy and lactation may not increase the risk of hepatocarcinogenesis in male offspring, despite causing genetic damage. If this result can be extrapolated to humans, exposure to MeIQx may not increase carcinogenic risk in offspring at usual human exposure levels.

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Dose‐dependent Induction of 8‐Hydroxyguanine and Preneoplastic Foci in Rat Liver by a Food‐derived Carcinogen, 2‐Amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline, at Low Dose Levels

Cited by 37 publications

References 41 publications

Detailed low‐dose study of 1,1‐b™IS(p‐chlorophenyl)‐2,2,2‐ trichloroethane carcinogenesis suggests the possibility of a hormetic effect

Detailed low‐dose study of 1,1‐b™IS(p‐chlorophenyl)‐2,2,2‐ trichloroethane carcinogenesis suggests the possibility of a hormetic effect

Hydrogen peroxide induces oxidative DNA damage in rat type II pulmonary epithelial cells

Induction of DNA‐adducts and increase of 8‐hydroxy‐2‐deoxyguanosine, but no development of preneoplastic lesions in offspring liver with transplacental and trans‐breast milk exposure to 2‐amino‐3,8‐dimethylimidazo [4,5‐f]quinoxaline (MelQx) in rats

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