Article

K-ras Mutations in Lung Tumors and Tumors from Other Organs are Consistent with a Common Mechanism of Ethylene Oxide Tumorigenesis in the B6C3F1 Mouse

Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2007; 35(1):81-5. DOI: 10.1080/01926230601063839
Source: PubMed

ABSTRACT

Ethylene oxide is a multisite carcinogen in rodents and classified as a human carcinogen by the National Toxicology Program. In 2-year mouse studies, ethylene oxide (EO) induced lung, Harderian gland (HG), and uterine neoplasms. We evaluated representative EO-induced and equivalent spontaneous neoplasms for K-ras mutations in codons 12, 13, and 61. K-ras mutations were identified in 100% (23/23) of the EO-induced lung neoplasms and 25% (27/108) of the spontaneous lung neoplasms. Codon 12 G to T transversions were common in EO-induced lung neoplasms (21/23) but infrequent in spontaneous lung neoplasms (1/108). K-ras mutations were found in 86% (18/21) of the EO-induced HG neoplasms and 7% (2/27) of the spontaneous HG neoplasms. Codon 13 G to C and codon 12 G to T transversions were predominant in the EO-induced HG neoplasms but absent in spontaneous HG neoplasms (0/27). K-ras mutations occurred in 83% (5/6) of the EO-induced uterine carcinomas and all were codon 13 C to T transitions. These data show a strong predilection for development of K-ras mutations in EO-induced lung, Harderian gland, and uterine neoplasms. This suggests that EO specifically targets the K-ras gene in multiple tissue types and that this event is a critical component of EO-induced tumorigenesis.

Download full-text

Full-text

Available from: Christopher D Houle, Sep 01, 2014
  • Source
    • "lected for use in this study as it is a direct acting genotoxic agent with known mutagenic properties in vitro and in vivo [ Victorin and Stahlberg , 1988 ; Agurell et al . , 1991 ; Thier and Bolt , 2000 ] . A 2 - year exposure to EtO was found to preferentially induce GGT ! GTT mutations at codon 12 of K - ras in the lung tumours of B6C3F1 mice [ Hong et al . , 2007 ] . As Ras mutations are found in approxi - mately 30% of human nonsmall cell lung cancers [ Sagawa et al . , 1998 ] , this finding may be of relevance to human lung carcinogenesis . The nature of the EtO induced mutations at codon 12 of K - ras has recently been explored further , and it appears that the selective expan - sion of mutan"
    [Show abstract] [Hide abstract]
    ABSTRACT: Tobacco smoke is a complex mixture of over 6,000 individual chemical constituents. Approximately 150 of these have been identified as 'tobacco smoke toxicants' due to their known toxicological effects. A number of these toxicants are present in the gaseous phase of tobacco smoke. This presents a technical challenge when assessing the toxicological effects of these chemicals in vitro. We have adapted a commercially available tobacco smoke exposure system to enable the assessment of the contribution of individual smoke toxicants to the overall toxicological effects of whole mainstream cigarette smoke (WS). Here we present a description of the exposure system and the methodology used. We use the example of a gaseous tobacco smoke toxicant, ethylene oxide (EtO), a Group 1 IARC carcinogen and known mutagen, to illustrate how this methodology can be applied to the assessment of genotoxicity of gaseous chemicals in the context of WS. In the present study we found that EtO was positive in Salmonella typhimurium strain YG1042, a strain that is sensitive to tobacco smoke. However, EtO did not increase the mutagenicity of the WS mixture when it was added at greatly higher concentrations than those found typically in WS. The findings presented here demonstrate the suitability of this exposure system for the assessment of the mutagenic potential of gases in vitro. Whilst we have focused on tobacco smoke toxicants, this system has broad application potential in studying the biological effects of exposure to a wide range of gaseous compounds that are present within complex aerosol mixtures. Environ. Mol. Mutagen., 2014. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · Environmental and Molecular Mutagenesis

  • No preview · Article · Nov 2008 · Journal of Chemical Health and Safety
  • [Show abstract] [Hide abstract]
    ABSTRACT: The pulmonary system is one of the main targets for toxicity. In the industrial age, there has been a large increase in atmospheric pollutants, including industrial products, particulates (asbestos and silica), cigarette smoke, ozone, nitrogen oxides, and substantial number of miscellaneous materials. In lung tissues, many adverse reactions result from exposure to these pollutants; some principal ones include asthma, chronic obstructive pulmonary disease (COPD), and cancer. The emphasis of this review is on three mechanisms by which many pulmonary toxicants, usually as derived metabolites, induce their effects: electron transfer (ET) (electron movement from one site to another), reactive oxygen species (ROS), and oxidative stress (OS), involving cellular insults. The preponderance of bioactive substances or their metabolites have chemical groups that we believe may play an important role in the physiological responses connected with induction of pulmonary toxicity. Such chemical functionalities include quinones (or their phenolic precursors), metal complexes (or complexors), aromatic nitro compounds (or reduced hydroxylamine and nitroso derivatives), and conjugated imines (or iminium species).
    No preview · Article · Feb 2009 · Reviews of environmental contamination and toxicology
Show more