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Effect of ionizing radiation at low dose on transgenerational carcinogenesis by epigenetic regulation

Laboratory Animal Research volume 33, pages 92–97 (2017)Cite this article

Abstract

The objective of this study was to determine the effect of ionizing radiation (IR) exposure of parents on carcinogenesis of the next generation focusing on the epigenetic perspective to clarify the relationship between radiation dose and carcinogenesis in F1 generation SD rats. F1 generations from pregnant rats (F0) who were exposed to gamma rays were divided into three groups according to the dose of radiation: 10 rad, 30 rad, and untreated. They were intraperitoneally injected with 50 mg/kg of diethylnitrosamine (DEN). Carcinogenesis was analyzed by examining expression levels of tumor suppressor genes (TSG) and other related genes by methylation-specific polymerase chain reaction (MSP). DNA methylation in liver tissues was evaluated to discern epigenetic regulation of transgenerational carcinogenesis vulnerability following IR exposure. Numerous studies have proved that transcriptional inactivation due to hypermethylation of TSG preceded carcinogenesis. Results of this study revealed hypermethylation of tumor suppressor gene SOCS1 in group treated with 30 rad. In addition, genes related to DNA damage response pathway (GSTP1, ATM, DGKA, PARP1, and SIRT6) were epigenetically inactivated in all DEN treated groups. In the case of proto-oncogene c-Myc, DNA hypermethylation was identified in the group with low dose of IR (10 rad). Results of this study indicated that each TSG had different radiation threshold level (dose-independent way) and DEN treatment could affect DNA methylation profile irrelevant of ionizing radiation dose.

References

  1. Little JB. Radiation carcinogenesis. Carcinogenesis 2000; 21(3): 397–404.

    Article  CAS  Google Scholar 

  2. Brenner DJ, Doll R, Goodhead DT, Hall EJ, Land CE, Little JB, Lubin JH, Preston DL, Preston RJ, Puskin JS, Ron E, Sachs RK, Samet JM, Setlow RB, Zaider M. Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. Proc Natl Acad Sci U S A 2003; 100(24): 13761–13766.

    Article  CAS  Google Scholar 

  3. Modan B. Low-dose radiation carcinogenesis. Eur J Cancer 1992; 28(6-7): 1010–1012.

    Article  Google Scholar 

  4. Dasenbrock C, Tillmann T, Ernst H, Behnke W, Kellner R, Hagemann G, Kaever V, Kohler M, Rittinghausen S, Mohr U, Tomatis L. Maternal effects and cancer risk in the progeny of mice exposed to X-rays before conception. Exp Toxicol Pathol 2005; 56(6): 351–360.

    Article  Google Scholar 

  5. Jones PA. DNA methylation errors and cancer. Cancer Res 1996; 56(11): 2463–2467.

    CAS  PubMed  Google Scholar 

  6. Gonzalo S. Epigenetic alterations in aging. J Appl Physiol 2010; 109(2): 586–597.

    Article  CAS  Google Scholar 

  7. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006; 31(2): 89–97.

    Article  CAS  Google Scholar 

  8. Counts JL, Goodman JI. Alterations in DNA methylation may play a variety of roles in carcinogenesis. Cell 1995; 83(1): 13–15.

    Article  CAS  Google Scholar 

  9. Zingg JM, Jones PA. Genetic and epigenetic aspects of DNA methylation on genome expression, evolution, mutation and carcinogenesis. Carcinogenesis 1997; 18(5): 869–882.

    Article  CAS  Google Scholar 

  10. Lillycrop KA, Slater-Jefferies JL, Hanson MA, Godfrey KM, Jackson AA, Burdge GC. Induction of altered epigenetic regulation of the hepatic glucocorticoid receptor in the offspring of rats fed a protein-restricted diet during pregnancy suggests that reduced DNA methyltransferase-1 expression is involved in impaired DNA methylation and changes in histone modifications. Br J Nutr 2007; 97(6): 1064–1073.

    Article  CAS  Google Scholar 

  11. Liu WB, Liu JY, Ao L, Zhou ZY, Zhou YH, Cui ZH, Cao J. Epigenetic silencing of cell cycle regulatory genes during 3-methylcholanthrene and diethylnitrosamine-induced multistep rat lung cancer. Mol Carcinog 2010; 49(6): 556–565.

    CAS  PubMed  Google Scholar 

  12. Bird AP. DNA methylation and the frequency of CpG in animal DNA. Nucleic Acids Res 1980; 8(7): 1499–1504.

    Article  CAS  Google Scholar 

  13. Liu WB, Ao L, Zhou ZY, Cui ZH, Zhou YH, Yuan XY, Xiang YL, Cao J, Liu J Y. CpG island hypermethylation of multiple tumor suppressor genes associated with loss of their protein expression during rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. Biochem Biophys Res Commun 2010; 402(3): 507–514.

    Article  CAS  Google Scholar 

  14. Phillips T. The role of methylation in gene expression. Nature Education 2008; 1(1): 116.

    Google Scholar 

  15. Esteller M. Epigenetics in cancer. N Engl J Med 2008; 358: 1148-1159.

    Article  CAS  Google Scholar 

  16. Saha A, Wittmeyer J, Cairns BR. Chromatin remodelling: the industrial revolution of DNA around histones. Nat Rev Mol Cell Biol 2006; 7(6): 437–447.

    Article  CAS  Google Scholar 

  17. Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NC, Schreiber SL, Mellor J, Kouzarides T. Active genes are tri-methylated at K4 of histone H3. Nature 2002; 419(6905): 407–411.

    Article  CAS  Google Scholar 

  18. Liu WB, Liu JY, Ao L, Zhou Z Y, Zhou YH, Cui ZH, Yang H, Cao J. Dynamic changes in DNA methylation during multistep rat lung carcinogenesis induced by 3-methylcholanthrene and diethylnitrosamine. Toxicol Lett 2009; 189(1): 5–13.

    Article  CAS  Google Scholar 

  19. Kim T Y, Jong HS, Song SH, Dimtchev A, Jeong SJ, Lee JW, Kim TY, Kim NK, Jung M, Bang YJ. Transcriptional silencing of the DLC-1 tumor suppressor gene by epigenetic mechanism in gastric cancer cells. Oncogene 2003; 22(25): 3943–3951.

    Article  CAS  Google Scholar 

  20. Oue N, Sentani K, Yokozaki H, Kitadai Y, Ito R, Yasui W. Promoter methylation status of the DNA repair genes hMLH1 and MGMT in gastric carcinoma and metaplastic mucosa. Pathobiology 2001; 69(3): 143–149.

    Article  CAS  Google Scholar 

  21. Nuovo GJ, Plaia TW, Belinsky SA, Baylin SB, Herman JG. In situ detection of the hypermethylation-induced inactivation of the p16 gene as an early event in oncogenesis. Proc Natl Acad Sci U S A 1999; 96(22): 12754–12759.

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by grants from Ministry of Science, ICT and Future Planning of Korea to the National Research Foundation of Korea (C1008955-01-03) and by Grant from Kangwon National University (520150281).

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Author notes

  1. Min-Jae Lee

    Present address: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea

  2. These authors contributed equally to this study.

Authors and Affiliations

  1. Institute of Medical Science, Kangwon National University, Kangwon National University, 192-1 Hyoja-dong, Chuncheon, Gangwon, 200-701, Korea

    Lan Li

  2. Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kangwon National University, Chuncheon, Korea

    Jong-Hyun Kim, Hee-Tae Park & Jae-Hoon Lee

  3. Hugene bio, Chuncheon, Korea

    Min-Koo Park, Ji-Won Lee & Jeong-Chan Lee

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  1. Lan Li
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Li, L., Kim, JH., Park, HT. et al. Effect of ionizing radiation at low dose on transgenerational carcinogenesis by epigenetic regulation. Lab Anim Res 33, 92–97 (2017). https://doi.org/10.5625/lar.2017.33.2.92

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  • DOI: https://doi.org/10.5625/lar.2017.33.2.92

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