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

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 p16INKA 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.

• Authors: 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
• Journal: Pathology international (Pathol Int) Vol. 67 Issue 11 Pg. 564-574 (Nov 2017) ISSN: 1440-1827 [Electronic] Australia
• PMID: 29027306 (Publication Type: Journal Article)
• Copyright: © 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

Chemical References

• Ferric Compounds
• DNA Glycosylases
• mutY adenine glycosylase
• Nitrilotriacetic Acid
• ferric nitrilotriacetate

Topics

• Animals
• Chromosome Aberrations (chemically induced)
• DNA Glycosylases (deficiency)
• Disease Models, Animal
• Ferric Compounds (toxicity)
• Kidney Neoplasms (chemically induced, genetics)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitrilotriacetic Acid (analogs & derivatives, toxicity)
• Oxidative Stress (physiology)
• Rats
• Species Specificity