The tumor promoter TPA enhances benzo[a]pyrene and benzo[a]pyrene diolepoxide mutagenesis in Big Blue� mouse skin

Miller, Marian L.; Vasunia, Kersi; Talaska, Glenn; Andringa, Anastasia; Boer, J. de; Dixon, Kathleen

doi:10.1002/1098-2280(2000)35:4<319::aid-em6>3.0.co;2-h

Cited by 17 publications

(9 citation statements)

References 32 publications

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“…The magnitude of the induction of mutant frequencies observed here using embryos exposed to BaP dosed sediments is somewhat lower than that reported for adult medaka exposed to 50 lg/L BaP in water for 5 days, 13.1 · 10 À5 (Winn and Norris, 2005), but nevertheless demonstrates BaP from sediments can cross the chorion and interact with embryonic DNA sufficiently to produce a measurable increase in mutations in adult fish. The increased mutations at G:C base pairs observed here is consistent with known mechanisms of BaP-induced mutagenesis demonstrated in both rodent and fish models (Jiang et al, 2001;Miller et al, 2000;and Winn and Norris, 2005).…”

Section: A Benzo[α]pyrene Concentrationsupporting

confidence: 92%

Uptake, metabolism, mutant frequencies and mutational spectra in λ transgenic medaka embryos exposed to benzo[α]pyrene dosed sediments

McElroy

Bogler

Weisbaum

et al. 2006

Marine Environmental Research

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Section: A Benzo[α]pyrene Concentrationsupporting

confidence: 92%

Uptake, metabolism, mutant frequencies and mutational spectra in λ transgenic medaka embryos exposed to benzo[α]pyrene dosed sediments

McElroy

Bogler

Weisbaum

et al. 2006

Marine Environmental Research

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“…In addition, the modest elevation in the MF in carcinogen-treated Big Blue mice additionally treated with TPA (64%) (37) is comparable to the HBx-associated 23%-increased MF found in DEN-treated mice in the present study. Finally, neither TPA nor HBx alone has any affect on the MF (35,37); their effect is apparent only in the presence of DNA damage. Thus, the influence of HBx measured in the present study is very similar to that measured for the well-known tumor promoter TPA.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis B Virus X Protein Acts as a Tumor Promoter in Development of Diethylnitrosamine-Induced Preneoplastic Lesions

Madden

Finegold

Slagle³

2001

J Virol

116

107

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Chronic infection with hepatitis B virus (HBV) is one of the major etiological factors in the development of human hepatocellular carcinoma. Transgenic mice that express the HBV X protein (HBx) have previously been shown to be more sensitive to the effects of hepatocarcinogens. Although the mechanism for this cofactor role remains unknown, the ability of HBx to inhibit DNA repair and to influence cell cycle progression suggests two possible pathways. To investigate these possibilities in vivo, we treated double-transgenic mice that both express HBx (ATX mice) and possess a bacteriophage lambda transgene with the hepatocarcinogen diethylnitrosamine (DEN). Histological examination of liver tissue confirmed that DEN-treated ATX mice developed approximately twice as many focal lesions of basophilic hepatocytes as treated wild-type littermates. Treatment of mice with DEN resulted in a six-to eightfold increase in the mutation frequency (MF), as measured by a functional analysis of the lambda transgene. HBx expression was confirmed by immunoprecipitation and Western blotting and was associated with a modest 23% increase in the MF. Importantly, the extent of hepatocellular proliferation in 14-day-old mice, as measured by the detection of proliferating cell nuclear antigen and by the incorporation of 5-bromo-2-deoxyuridine, was determined to be approximately twofold higher in ATX livers than in wild-type livers. These results are consistent with a model in which HBx expression contributes to the development of DEN-mediated carcinogenesis by promoting the proliferation of altered hepatocytes rather than by directly interfering with the repair of DNA lesions.Liver cancer is the fourth-leading cause of cancer mortality worldwide and results in more than 400,000 deaths annually (41). One of the primary risk factors for the development of hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV) (1, 53). For individuals chronically infected with HBV, concurrent exposure to dietary aflatoxin increases the probability of developing HCC by at least threefold (57). The synergistic contributions of these two factors to the development of HCC has led to speculation that chronic HBV infection predisposes an individual to the detrimental effects of hepatocarcinogens.Several studies using transgenic mouse lines provide experimental evidence to support the hypothesis that chronic HBV infection acts synergistically with environmental carcinogens. The increased sensitivity to aflatoxin B1 of mice that overexpress the HBV surface antigen (18) is believed to be due in part to elevated levels of cytochrome P450 isoenzymes (27) that metabolize aflatoxin B1 into a mutagenic epoxide. Transgenic mice that express the HBV (54) or woodchuck hepatitis virus (13) X proteins (HBx or WHx, respectively) are also more sensitive to the effects of the hepatocarcinogen diethylnitrosamine (DEN). However, the levels of carcinogen-metabolizing enzymes do not appear to be elevated in mice expressing HBx (12). Therefore, the mechanism b...

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“…Indeed, a mild effect of HBx on hepatocellular proliferation has been measured in these ATX mice and is thought to be responsible for the increased MF in DEN-treated ATX mice (33). This modest effect of HBx on proliferation is similar to that previously reported for the tumor-promoting agent 12-myristate-13-acetate (TPA) (36). This would also explain the altered DNA MF found in ATX mice.…”

mentioning

confidence: 87%

Altered DNA Mutation Spectrum in Aflatoxin B1-Treated Transgenic Mice That Express the Hepatitis B Virus X Protein

Madden¹,

Finegold

Slagle³

2002

J Virol

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Humans chronically infected with hepatitis B virus (HBV) are at further risk of liver cancer upon exposure to dietary aflatoxin B1 (AFB1), a carcinogenic product of the mold Aspergillus flavus. For the present study, we utilized double-transgenic mice (ATX mice) that express the HBV X protein (HBx) and possess a bacteriophage lambda transgene to evaluate the in vivo effect of HBx expression on AFB1-induced DNA mutations. The expression of HBx correlated with a 24% increase in mutation frequency overall and an approximately twofold increase in the incidence of G/C-to-T/A transversion mutations following AFB1 exposure. These results are consistent with a model in which expression of HBx during chronic HBV infection may contribute to the development of hepatocellular carcinoma following exposure to environmental carcinogens.Chronic infection with hepatitis B virus (HBV) is a primary risk factor for the development of hepatocellular carcinoma (HCC) (2, 49). Additional risk factors include chemical agents, such as aflatoxin and ethanol, which can result in liver damage upon repeated exposure (7,56,58). Epidemiological data, as well as experimental studies utilizing transgenic animals, have indicated that chronic HBV infection and exposure to hepatocarcinogens act synergistically in the development of HCC (10,14,31,33,46,50,53,57). However, the mechanism by which chronic HBV infection sensitizes an individual to carcinogeninduced liver cancer remains unknown.The 17-kDa HBV X protein (HBx) is a nonstructural protein necessary for the establishment of hepadnaviral infection in woodchucks and presumably in all mammals (8, 59). Depending upon experimental conditions, HBx is reported to inhibit nucleotide excision repair (NER) (3,17,21,32,41), to influence apoptosis (11,23,39,40,52,54,55), and to induce cell cycle progression (4,26,27). By affecting these pathways, HBx could facilitate the mutagenic effects of hepatocarcinogens or promote the survival and proliferation of hepatocytes altered after exposure. Although transgenic mice that express HBx are more sensitive to the carcinogenic effects of the hepatocarcinogen diethylnitrosamine (DEN [10,33,50]), they do not demonstrate significant increases in overall mutation accumulation (32, 33). These results suggest that HBx contributes to DEN-mediated carcinogenesis by a mechanism that does not involve a dramatic inhibition of DNA repair. Recently, a study demonstrated that expression of HBx increased mutagenesis in a human liver cell line treated with aflatoxin B1 (AFB1) (17). The effect of HBx on AFB1-induced damage in vivo has not been examined.Aflatoxins are a family of potent hepatocarcinogens produced by the mold Aspergillus flavus. A common dietary contaminant in many parts of the world, aflatoxins are metabolized in vivo by cytochrome P450 isoenzymes to form mutagenic epoxides (13). The induction of P450 enzyme levels may explain the increased AFB1 sensitivity of mice that overexpress the hepatitis B surface antigen (24). However, the levels of carcinogen-metabolizin...

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The tumor promoter TPA enhances benzo[a]pyrene and benzo[a]pyrene diolepoxide mutagenesis in Big Blue� mouse skin

Cited by 17 publications

References 32 publications

Uptake, metabolism, mutant frequencies and mutational spectra in λ transgenic medaka embryos exposed to benzo[α]pyrene dosed sediments

Uptake, metabolism, mutant frequencies and mutational spectra in λ transgenic medaka embryos exposed to benzo[α]pyrene dosed sediments

Hepatitis B Virus X Protein Acts as a Tumor Promoter in Development of Diethylnitrosamine-Induced Preneoplastic Lesions

Altered DNA Mutation Spectrum in Aflatoxin B1-Treated Transgenic Mice That Express the Hepatitis B Virus X Protein

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