Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide

Abstract

-The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.

Multiwall Carbon Nanotube Composites as Artificial Joint Materials

“…Even when the knees of mice genetically modified to develop cancer spontaneously (i.e., rasH2 mice) were injected with large amounts of MWCNTs under severe conditions as we did with the aforementioned rats, no cancer developed. With regard to this test in rasH2 mice, the US, EU, and Japanese regulatory authorities have already issued guidelines for accepting chemical substances data submitted as carcinogenicity study data. , More than one study has reported on bulk biomaterials . However, our study of MWCNTs implanted in subcutaneous tissue is the only published report on nanoparticle biomaterials such as MWCNTs to show that MWCNTs are not carcinogenic .…”

“…With regard to this test in rasH2 mice, the US, EU, and Japanese regulatory authorities have already issued guidelines for accepting chemical substances data submitted as carcinogenicity study data. 41,42 More than one study has reported on bulk biomaterials. 43 However, our study of MWCNTs implanted in subcutaneous tissue is the only published report on nanoparticle biomaterials such as MWCNTs to show that MWCNTs are not carcinogenic.…”

Role of Epiregulin in Lung Tumorigenesis and Therapeutic Resistance

“…Some environmental carcinogens have also been shown to induce EREG expression in the lungs. EREG expression was increased in lung tumors induced by the environmental carcinogen of urethane in a murine experimental model [46]. Recently, Chen et al [47] demonstrated that long-term exposure to 3-nitrobenzanthrone, which is a carcinogen in diesel exhaust, promotes malignant transformation in human bronchial epithelial cells through the EREG-mediated activation of the MEK/ERK and PI3K/AKT pathways.…”