Gene Expression Analysis in Mayak Workers With Prolonged Occupational Radiation Exposure

Abstract

The authors evaluated gene expression in the peripheral blood in relation to occupational exposure in Mayak workers to find out about the existence of a permanent post exposure signature. Workers were exposed to combined incorporated ²³⁹Pu and external gamma rays (n = 82) or to external gamma rays only (n = 18), and 50 unexposed individuals served as controls. Peripheral blood was taken from workers older than 70 y. RNA was isolated, converted into cDNA, and stored at -20°C. A two-stage study design was performed focusing on examinations on the transcriptional (mRNA) and post-transcriptional level (microRNA). In the first stage, 40 samples were identified for screening purposes and selection of candidate genes. For examinations on the transcriptional level, whole genome microarrays and qRT-PCR were employed on the post-transcriptional level (667 microRNAs). Candidate genes were assessed by (1) introducing a twofold difference in gene expression over the reference group and (2) showing a significant p-value using the Kruskal-Wallis test. From 42,545 transcripts of the whole genome microarray, 376 candidate genes (80 up-regulated and 296 down-regulated relative to the reference group) were selected. Expression of almost all of these genes (70-98%) appeared significantly associated with internal ²³⁹Pu and to a lesser extent were associated with external gamma-ray exposure (2-30%). Associations in the same direction were found for 45 microRNAs. Although both exposures led to modulations of different gene sets in different directions, the authors could detect no differences in gene set enrichment analysis.

Utility of gene expression studies in relation to radiation exposure and clinical outcomes: thyroid cancer in the Ukrainian-American cohort and late health effects in a MAYAK worker cohort

“…In our recently published work, we performed a gene expression study on a group of Mayak workers who were exposed either to combined internal alpha particles due to incorporated Plutonium-239 (239Pu) and external gamma rays, or to external gamma rays only (Abend et al 2014a(Abend et al , 2014bAbend, Azizova, et al 2015). Peripheral blood was taken from workers older than 70 years of age, suffering from 29 different chronic diseases such as atherosclerotic disease or diabetes.…”

“…In previous work, we examined changes in gene expression following radiation exposure in two different cohorts, namely the Ukrainian-American cohort (UkrAm) of residents exposed to the Chernobyl fallout during childhood (Abend et al 2012(Abend et al , 2013 and the Mayak production association (MPA) radiation workers cohort (Abend et al 2014a(Abend et al , 2014bAbendm, Azizova, et al 2015). The average iodine-131 (I-131) thyroid dose received from the Chernobyl accident by thyroid cancer patients in the UkrAm cohort was 1.25 Gy ± 1.68 (stdev), ranging from 0.008 to 8.6 Gy (Abend et al 2012).…”

“…The group working in the nuclear reactor facility on average received an external gamma ray dose to the red bone marrow of 1.3 Gy (range: 0.4-3.1 Gy). The other group employed in plutonium (Pu) manufacturing/processing facilities on average absorbed an external total gamma dose of 0.5 Gy as well as an internal Pu dose to the red bone marrow of 0.1 Gy (range: 0.03-1 Gy, Abend et al 2014a).…”

“…Regarding examinations in the Mayak cohort, we developed a strategy of searching for target genes for which transcription was altered following radiation and which were also associated with late health effects, namely the development of cardiovascular disease (Abend et al 2014a(Abend et al , 2014bAbend, Azizova, et al 2015). The Mayak radiation workers were employed either in plutonium manufacturing/processing facilities or in a nuclear reactor facility.…”

Ionizing radiation biomarkers in epidemiological studies – An update

“…Translocations, complex chromosomal rearrangements and micronuclei in peripheral blood lymphocytes (see above) are also potentially useful to estimate cumulated red bone marrow doses resulting from protracted mixed exposure to internal and external IR following moderate to high doses, although further work is needed for complete validation [12,56,59,60,268]. Gender specific mRNA and miRNA gene expression patterns to internal 239 Pu exposure have been deciphered in former Mayak workers [269,270], which are promising markers of internal alpha-particle exposure and warrant further validation.…”