K- ras cancer gene mutations in lung tumors from female Swiss (CD-1) mice exposed transplacentally to 3′-azido-3′-deoxythymidine
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. Environmental and Molecular Mutagenesis
(Impact Factor: 2.63).
12/2008; 49(9):720-6. DOI: 10.1002/em.20420
A transplacental carcinogenicity study was conducted by exposing pregnant Swiss (CD-1) mice to 0, 50, 100, 200, or 300 mg 3'-azido-3'-deoxythymidine (AZT)/kg body weight (BW) daily for the duration of gestation (18-19 days) [National Toxicology Program,2006]. The incidence of alveolar/bronchiolar adenomas and carcinomas in the 200 and 300 mg/kg groups was significantly higher (P = 0.027 and 0.007, respectively) in male offspring, but not in females (P = 0.338 and 0.315, respectively). The purpose of the present study was to evaluate K-ras mutation status in lung tumors from the female offspring in AZT exposed groups and to determine whether at the molecular level there were signature K-ras mutations in lung tumors that were different from spontaneous tumors. K-ras mutation was detected by cycle sequencing of polymerase chain reaction (PCR)-amplified DNA, isolated from formalin-fixed, paraffin-embedded lung tumors. K-ras mutations were detected in 17 of 28 (61%) lung tumors from the female offspring in AZT exposed groups. No K-ras mutations were detected in the 8 tumors examined from the female control group. The predominant mutations were Codon 12 G-->T transversions in the 50, 100, and 300 mg/kg groups, and Codon 12 G-->C transversions in the 200 and 300 mg/kg groups. K-ras Codon 12 G-->T transversions (TGT mutations) may be induced by oxidative DNA damage and 8-oxoguanine (8-oxoG), while K-ras Codon 12 G-->C transversions (CGT mutations) may be due to further oxidative lesions of guanine and 8-oxoG.
Available from: Hue-Hua L Hong
- "Kras and Tp53 mutations were not present in normal lung or spontaneous alveolar/bronchiolar lung tumors from CD-1 mice (Hong, Dunnick, et al. 2007). Our laboratory determined that AZT-induced pulmonary tumors in both male and female CD-1 mice resulted from molecular alterations in the same pathways as human lung cancer and that genotoxic damage from AZT or its metabolites may contribute to the development of lung tumors in these mice (Hong, Dunnick, et al. 2007; Koujitani et al. 2008). This suggests that the response in the mouse may be of relevance to the mechanism of carcinogenicity in humans. "
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ABSTRACT: Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds.
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ABSTRACT: Epidemiological and animal studies indicate that carcinogenesis may start as early as the prenatal period. Modifying the prenatal environment may alter genes through the epigenetic route, and, these alterations may be inherited by the offspring. Epigenetic factors like nutritional factors, endocrine disruptors, infection and lifestyle may affect tumour development, or, target cell differentiation to increase susceptibility to cancer. In this chapter, we discuss the evidence related to embryo-fetal origins of tumours. © Springer Science+Business Media Dordrecht 2014. All rights are reserved.
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