Lab Anim Res.  2017 Jun;33(2):92-97. 10.5625/lar.2017.33.2.92.

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

• Li L
• Kim JH
• Park HT
• Lee JH
• Park MK
• Lee JW
• Lee JC
• Lee MJ

• KMID: 2407421
• DOI: http://doi.org/10.5625/lar.2017.33.2.92

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.

Keyword

Radiation; DNA methylation; carcinogenesis; tumor suppressor gene

MeSH Terms

Animals
Carcinogenesis*
Diethylnitrosamine
DNA
DNA Damage
DNA Methylation
Epigenomics*
Family Characteristics
Gamma Rays
Genes, Tumor Suppressor
Humans
Liver
Parents
Polymerase Chain Reaction
Proto-Oncogenes
Radiation, Ionizing*
Rats
DNA
Diethylnitrosamine

Figure

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  Figure 1 Expressions of SOCS1 and c-Myc were detected by MSP. SOCS1 showed methylation from 30 rad (the second experimental group) and c-Myc showed methylation from 10 rad group. The sample having asterisk represents PCR positive. Abbreviations; S.L: 100bp size ladder, NC: negative control, F: female, M: male.

• 

  Figure 2 Expression of MGMT was detected by MSP. Methylation change of MGMT was observed in all experimental groups. It suggests MGMT is not dependent on IR concentration, but related to exposure to IR by itself. Samples having asterisk represent PCR positives. Abbreviations; S.L: 100bp size ladder, NC: negative control, F: female, M: male.

• 

  Figure 3 Expression of COX2 was detected by MSP by MSP. COX2, a major gene related to inflammation response, showed methylation changes in all experimental and control groups. Samples having asterisk represent PCR positives. Abbreviations; S.L: 100bp size ladder, NC: negative control, F: female, M: male.

• 

  Figure 4 Expressions of genes (DGKA, SIRT6, ATM, PARP1, GSTP1) related to DNA damage were detected by MSP. Genes related to DNA damage also showed methylation in all experimental groups and controls. Methylation was also observed in the control group without exposure to IR, DEN injection affected the result. Samples having asterisk represent PCR positives. Abbreviations; S.L: 100bp size ladder, NC: negative control, F: female, M: male.

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