Journal Article

Aryl hydrocarbon receptor signaling plays a significant role in mediating benzo[<i>a</i>]pyrene- and cigarette smoke condensate-induced cytogenetic damage <i>in vivo</i>

Stephen D. Dertinger, Daniel A. Nazarenko, Allen E. Silverstone and Thomas A. Gasiewicz

in Carcinogenesis

Volume 22, issue 1, pages 171-177
Published in print January 2001 | ISSN: 0143-3334
Published online January 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.1.171
Aryl hydrocarbon receptor signaling plays a significant role in mediating benzo[a]pyrene- and cigarette smoke condensate-induced cytogenetic damage in vivo

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This laboratory has previously reported data suggesting that aryl hydrocarbon receptor (AhR) signaling may have a net potentiating effect on the DNA damaging potential of cigarette smoke. The experiments described in this report extend these studies by testing whether the potent AhR antagonist 3′-methoxy-4′-nitroflavone (3′M4′NF) can modify the in vivo genetic toxicity of benzo[a]pyrene (B[a]P) and the complex mixture of chemicals in cigarette smoke condensate (CSC). Initial experiments were designed to determine 3′M4′NF doses which can antagonize AhR in vivo but which have little effect on constitutive cytochrome P4501A (CYP1A) activity. These experiments took three forms: (i) zoxazolamine paralysis tests, a functional assay of cytochrome P450 CYP1A activity in 3′M4′NF-treated C57Bl/6J mice; (ii) co-treatment of Ahr null allele mice with 150 mg/kg B[a]P plus a range of 3′M4′NF concentrations in order to evaluate the potential of the flavone to interact with non-AhR targets which may affect B[a]P toxicity; (iii) an evaluation of the in vivo AhR antagonist activity of 3′M4′NF using transgenic mice which carry a dioxin-responsive element-regulated lacZ reporter. Once an appropriate dose range was determined, C57Bl/6J mice were challenged with B[a]P or CSC with and without 3′M4′NF co-treatment. Chromosome damage was measured by scoring the frequency of micronuclei in peripheral blood reticulocytes. Data presented herein suggest that 3′M4′NF can protect mice from B[a]P-induced bone marrow cytotoxicity and genotoxicity. Furthermore, CSC-associated genotoxicity was abolished by the flavonoid. These data add support to our hypothesis that AhR signaling has a net potentiating effect on the genetic toxicity and, presumably, carcinogenicity of cigarette smoke.

Keywords: AhR, aryl hydrocarbon receptor; B[a]P, benzo[a]pyrene; CSC, cigarette smoke condensate; DMSO, dimethyl sulfoxide; DRE, dioxin-responsive element; β-gal, β-galactosidase; 3′M4′NF, 3′-methoxy-4′-nitroflavone; MN-RET, micronucleated reticulocyte; PI, propidium iodide; RET, reticulocyte; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Journal Article.  5824 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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