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

Pathol Int. 2017 Nov;67(11):564-574. doi: 10.1111/pin.12598. Epub 2017 Oct 13.


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.

Keywords: Fe-NTA; Mutyh-deficient mice; lymphoma; oxidative stress; renal cell carcinoma.

MeSH terms

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


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