Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model

Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni

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Abstract

Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P = 0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16INK A inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

Original languageEnglish
Pages (from-to)564-574
Number of pages11
JournalPathology International
Volume67
Issue number11
DOIs
Publication statusPublished - Nov 2017

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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    Li, G. H., Akatsuka, S., Chew, S. H., Jiang, L., Nishiyama, T., Sakamoto, A., Takahashi, T., Futakuchi, M., Suzuki, H., Sakumi, K., Nakabeppu, Y., & Toyokuni, S. (2017). Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. Pathology International, 67(11), 564-574. https://doi.org/10.1111/pin.12598