The genotoxic air pollutant 3-nitrobenzanthrone and its reactive metabolite N-hydroxy-3-aminobenzanthrone lack initiating and complete carcinogenic activity in NMRI mouse skin

Schmeiser, Heinz H.; Fürstenberger, Gerhard; Takamura-Enya, Takeji; Phillips, David H.; Arlt, Volker M.

doi:10.1016/j.canlet.2009.04.003

Cited by 8 publications

(8 citation statements)

References 53 publications

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“…Representative TLC autoradiographs are shown in Figure 5 a . The adduct pattern observed after oral administration of DMBA (in the presence or absence of TCDD) was similar to that found in mouse skin epidermis after topical application 41. It consisted of three major adduct spots, which have been shown to represent DMBA‐DNA adducts formed by bay‐region diol epoxides.…”

Section: Resultssupporting

confidence: 67%

“…Genomic DNA from homogenized mammary glands was isolated by a standard phenol–chloroform extraction method 40. DNA adducts were determined for each DNA sample using the nuclease P1 enrichment version of the 32 P‐postlabeling method as described previously 41, 42. Briefly, DNA samples (4 μg) were digested with micrococcal nuclease (120 mU) and calf spleen phosphodiesterase (40 mU), enriched and labeled as reported.…”

Section: Methodsmentioning

confidence: 99%

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Aryl hydrocarbon receptor activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA‐induced mammary tumors

Wang

Gavin

Arlt

et al. 2011

Intl Journal of Cancer

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TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), the prototypic ligand for the aryl hydrocarbon receptor (AhR), promotes tumor formation in some model systems. However with regard to breast cancer, epidemiological and animal studies are inconclusive as to whether exposure increases tumor incidence or may instead be protective. We have previously reported that mice exposed to TCDD during pregnancy have impaired differentiation of mammary tissue, including decreased branching and poor development of lobuloalveolar structures. Because normal pregnancy-induced mammary differentiation may protect against subsequent neoplastic transformation, we hypothesized that TCDD-treated mice would be more susceptible to chemical carcinogenesis after parturition. To test this, mice were treated with TCDD or vehicle during pregnancy. Four weeks later, DMBA (7,12-dimethylbenz[a]anthracene) was administered to induce mammary tumor formation. Contrary to our hypothesis, TCDD-exposed parous mice showed a four-week delay in tumor formation relative to controls, and had a lower tumor incidence throughout the 27-week time course. The same results were obtained in nulliparous mice given TCDD and DMBA on the same schedule. We next addressed whether the delayed tumor incidence was a reflection of decreased tumor initiation, by testing the formation of DMBA-DNA adducts and preneoplastic lesions, induction of cytochrome P450s, and cell proliferation. None of these markers of tumor initiation differed between vehicle- and TCDD-treated animals. The expression of CXCL12 and CXCR4 was also measured to address their possible role in tumorigenesis. Taken together, our results suggest that AhR activation by TCDD slows the promotion of preneoplastic lesions to overt mammary tumors.

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Section: Resultssupporting

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Aryl hydrocarbon receptor activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA‐induced mammary tumors

Wang

Gavin

Arlt

et al. 2011

Intl Journal of Cancer

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“…The authenticity of 3-NBA and 3-ABA was confirmed by ultraviolet–visible spectroscopy, electrospray mass spectrometry and high-field proton nuclear magnetic resonance spectroscopy. N -OH-3-ABA was prepared as reported ( 20 ).…”

Section: Methodsmentioning

confidence: 99%

“…N -oxidation of 3-ABA catalysed by cytochrome P450 (CYP) enzymes (e.g. CYP1A1) also leads to the formation of N -OH-3-ABA ( 19 , 20 ). The major DNA adducts formed by 3-NBA both in vitro and in vivo after its metabolic activation by reduction of the nitro group are 2-(2ʹ-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG- N 2 -3-ABA) and N -(2ʹ-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG-C8- N -3-ABA) ( 21 , 22 ).…”

Section: Introductionmentioning

confidence: 99%

The impact of p53 function on the metabolic activation of the carcinogenic air pollutant 3-nitrobenzanthrone and its metabolites 3-aminobenzanthrone and N-hydroxy-3-aminobenzanthrone in human cells

et al. 2018

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The tumour suppressor p53, encoded by TP53, is a key player in a wide network of signalling pathways. We investigated its role in the bioactivation of the environmental carcinogen 3-nitrobenzanthrone (3-NBA)found in diesel exhaust and its metabolites 3-aminobenzanthrone (3-ABA) and N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) in a panel of isogenic human colorectal HCT116 cells differing only with respect to their TP53 status [i.e. TP53(+/+), TP53(+/−), TP53(−/−), TP53(R248W/+) or TP53(R248W/−)]. As a measure of metabolic competence, DNA adduct formation was determined using 32P-postlabelling. Wild-type (WT) p53 did not affect the bioactivation of 3-NBA; no difference in DNA adduct formation was observed in TP53(+/+), TP53(+/−) and TP53(−/−) cells. Bioactivation of both metabolites 3-ABA and N-OH-3-ABA on the other hand was WT-TP53 dependent. Lower 3-ABA- and N-OH-3-ABA-DNA adduct levels were found in TP53(+/−) and TP53(−/−) cells compared to TP53(+/+) cells, and p53’s impact was attributed to differences in cytochrome P450 (CYP) 1A1 expression for 3-ABA whereas for N-OH-3-ABA, an impact of this tumour suppressor on sulphotransferase (SULT) 1A1/3 expression was detected. Mutant R248W-p53 protein function was similar to or exceeded the ability of WT-p53 in activating 3-NBA and its metabolites, measured as DNA adducts. However, identification of the xenobiotic-metabolising enzyme(s) (XMEs), through which mutant-p53 regulates these responses, proved difficult to decipher. For example, although both mutant cell lines exhibited higher CYP1A1 induction after 3-NBA treatment compared to TP53(+/+) cells, 3-NBA-derived DNA adduct levels were only higher in TP53(R248W/−) cells but not in TP53(R248W/+) cells. Our results show that p53’s influence on carcinogen activation depends on the agent studied and thereby on the XMEs that mediate the bioactivation of that particular compound. The phenomenon of p53 regulating CYP1A1 expression in human cells is consistent with other recent findings; however, this is the first study highlighting the impact of p53 on sulphotransferase-mediated (i.e. SULT1A1) carcinogen metabolism in human cells.

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“…It induces squamous cell carcinomas in the lungs of F344 rats following intratracheal instillation (31), but did not initiate tumour formation in NMRI mouse skin (32). Mechanistic investigations have shown that the nitro group is reduced by cytosolic nitroreductases such as NAD(P)H:quinone oxidoreductase (33–35).…”

Section: Introductionmentioning

confidence: 99%

Quantitative relationships betweenlacZmutant frequency and DNA adduct frequency in Muta™Mouse tissues and cultured cells exposed to 3-nitrobenzanthrone

White

Douglas

Phillips

et al. 2017

MUTAGE

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The frequency of stable DNA adducts in a target tissue can be used to assess biologically effective dose; however, the utility of the metric in a risk assessment context depends on the likelihood that the DNA damage will be manifested as mutation. Previously, we employed the Muta™Mouse system to examine the induction of lacZ mutants and DNA adducts following exposure to the well-studied mutagenic carcinogen 3-nitrobenzanthrone (3-NBA). In this follow-up work, we examined the empirical relationships between total adduct frequency and mutant frequency (MF) in tissues and cultured cells following acute 3-NBA exposure. The results show a significant induction of DNA damage and lacZ mutants in liver, colon and bone marrow, as well as FE1 pulmonary epithelial cells. In contrast, lung and small intestine samples had low, but significantly elevated adduct levels, with no significant increases in lacZ MF. Additional analyses showed a significant relationship between the mutagenic efficiency of total adducts, measured as the slope of the relationships between MF and total adduct frequency, and tissue-specific mitotic index (MI). The lack of mutation response in lung, in contrast to the high in vitro MF in FE-1 lung cells, is likely related to the 100-fold difference in MI. The lack of small intestine mutagenic response may be related to limited metabolic capacity, differences in DNA repair, and /or chemically induced apoptosis that has been observed for other potent mutagens. The results indicate that interpretation of adduct frequency values in a risk assessment context can be improved by considering the MI of the target tissue; however, more generalised interpretation is hampered by tissue-specific variations in metabolic capacity and damage processing. The work provides a proof of principle regarding the use of the Muta™Mouse system to critically examine the health risks associated with tissue-specific adduct loads.

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The genotoxic air pollutant 3-nitrobenzanthrone and its reactive metabolite N-hydroxy-3-aminobenzanthrone lack initiating and complete carcinogenic activity in NMRI mouse skin

Cited by 8 publications

References 53 publications

Aryl hydrocarbon receptor activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA‐induced mammary tumors

Aryl hydrocarbon receptor activation during pregnancy, and in adult nulliparous mice, delays the subsequent development of DMBA‐induced mammary tumors

The impact of p53 function on the metabolic activation of the carcinogenic air pollutant 3-nitrobenzanthrone and its metabolites 3-aminobenzanthrone and N-hydroxy-3-aminobenzanthrone in human cells

Quantitative relationships betweenlacZmutant frequency and DNA adduct frequency in Muta™Mouse tissues and cultured cells exposed to 3-nitrobenzanthrone

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