title: Hypermethylation of gene promoters in peripheral blood leukocytes in humans long term after radiation exposure.
abstract: Some human genes known to undergo age-related promoter hypermethylation. These epigenetic modifications are similar to those occurring in the course of certain diseases, e.g. some types of cancer, which in turn may also associate with age. Given external genotoxic factors may additionally contribute to hypermethylation, this study was designed to analyzes, using methylation-sensitive polymerase chain reaction (PCR), the CpG island hypermethylation in RASSF1A, CDKN2A (including p16/INK4A and p14/ARF) and GSTP1 promoters in peripheral blood leukocytes of individuals exposed to ionizing radiation long time ago. One hundred and twenty-four irradiated subjects (24-77 years old at sampling: 83 Chernobyl Nuclear Power Plant clean-up workers, 21 nuclear workers, 20 residents of territories with radioactive contamination) and 208 unirradiated volunteers (19-77 years old at sampling) were enrolled. In addition, 74 non-exposed offspring (2-51 years old at sampling) born to irradiated parents were examined. The frequency of individuals displaying promoter methylation of at least one gene in exposed group was significantly higher as compared to the control group (OR=5.44, 95% CI=2.62-11.76, p=3.9×10(-7)). No significant difference was found between the frequency of subjects with the revealed promoter methylation in the group of offspring born to irradiated parents and in the control group. The increase in the number of methylated loci of RASSF1A and p14/ARF was associated with age (β=0.242; p=1.7×10(-5)). In contrast, hypermethylation of p16/INK4A and GSTP1 genes correlated with the fact of radiation exposure only (β=0.290; p=1.7×10(-7)). The latter finding demonstrates that methylation changes in blood leukocytes of healthy subjects exposed to radiation resemble those reported in human malignancies. Additional studies are required to identify the dose-response of epigenetic markers specifically associating with radiation-induced premature aging and/or with the development of age-associated cancer and non-cancer diseases.
authors.affiliation: N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia. Electronic address: nin-kuzmin@youndex.ru.
authors.forename: Nina S
authors.initials: NS
authors.lastname: Kuzmina
authors.affiliation: N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Nellya Sh
authors.initials: NSh
authors.lastname: Lapteva
authors.affiliation: N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Rubanovich
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018899:CpG Islands / Q000528:radiation effects; D019175:DNA Methylation / Q000528:radiation effects*; D005260:Female; D051549:Glutathione S-Transferase pi / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007962:Leukocytes / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000528:radiation effects*; D000069079:Radiation Exposure; D012426:Russia; D055815:Young Adult
chemical_list: D018797:Cell Cycle Proteins; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi
keywords: CpG islands; DNA hypermethylation; Human; Leukocytes; Radiation