Fenton reaction‐induced renal carcinogenesis in Mutyh‐deficient mice exhibits less chromosomal aberrations than the rat model. Issue 11 (13th October 2017)

• Record Type: Journal Article
• Authors: Li, Guang Hua; Akatsuka, Shinya; Chew, Shan Hwu; Jiang, Li; Nishiyama, Takahiro; Sakamoto, Akihiko; Takahashi, Takashi; Futakuchi, Mitsuru; Suzuki, Hiromu; Sakumi, Kunihiko; Nakabeppu, Yusaku; Toyokuni, Shinya
• Is Part Of: Pathology international. Volume 67:Issue 11(2017)
• Page Start: 564
• Page End: 574
• Publication Date: 2017-10-13
• Subjects: Fe‐NTA -- lymphoma -- Mutyh‐deficient mice -- oxidative stress -- renal cell carcinoma; Pathology -- Periodicals; 616.07
• DOI: 10.1111/pin.12598
• Languages: English
• ISSNs: 1320-5463

Abstract

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 p16 INK 4 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.