Background The capacity to assess environmental inputs to biological phenotypes is limited by methods that can accurately and quantitatively measure these contributions. One such example can be seen in the context of exposure to ionizing radiation. Methods and Findings We have made use of gene expression analysis of peripheral blood (PB) mononuclear cells to develop expression profiles that accurately reflect prior radiation exposure. We demonstrate that expression profiles can be developed that not only predict radiation exposure in mice but also distinguish the level of radiation exposure, ranging from 50 cGy to 1,000 cGy. Likewise, a molecular signature of radiation response developed solely from irradiated human patient samples can predict and distinguish irradiated human PB samples from nonirradiated samples with an accuracy of 90%, sensitivity of 85%, and specificity of 94%. We further demonstrate that a radiation profile developed in the mouse can correctly distinguish PB samples from irradiated and nonirradiated human patients with an accuracy of 77%, sensitivity of 82%, and specificity of 75%. Taken together, these data demonstrate that molecular profiles can be generated that are highly predictive of different levels of radiation exposure in mice and humans. Conclusions We suggest that this approach, with additional refinement, could provide a method to assess the effects of various environmental inputs into biological phenotypes as well as providing a more practical application of a rapid molecular screening test for the diagnosis of radiation exposure.
References
[1]
Cardis E, Kesmeniene A, Ivanov V, Malakhova I, Shibata Y, et al. (2005) Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97: 724–732.
[2]
Pobel D, Viel J (1997) Case control study of leukemia among young people near La Hague nuclear reprocessing plant: The environmental hypothesis revisited. BMJ 314: 101–106.
[3]
Wing S, Richardson D, Wolf S, Mihlan G, Crawford-Brown D, et al. (2000) A case control study of multiple myeloma at four nuclear facilities. Ann Epidemiol 10: 144–153.
[4]
Iwamoto K, Mizuno T, Tokuoka S, Mabuchi K, Seyama T (1998) Frequency of p53 mutations in hepatocellular carcinomas from atomic bomb survivors. J Natl Cancer Inst 90: 1167–1168.
[5]
Hirai Y, Kusonoki Y, Kyoizumi S, Awa A, Pawel D, et al. (1995) Mutant frequency at the HPRT locus in peripheral blood T lymphocytes of atomic bomb survivors. Mutat Res 329: 183–196.
[6]
Takeshima Y, Seyama T, Bennet W, Akiyama M, Tokuoka S, et al. (1993) p53 mutations in lung cancers from from non-smoking atomic bomb survivors. Lancet 342: 1520–1521.
[7]
Neel J, Lewis S (1990) The comparison radiation genetics of humans and mice. Annu Rev Genet 24: 327–362.
[8]
Yoshimoto Y, Schull W, Kato H, Neel J (1991) Mortality among the offspring (F1) of atomic bomb survivors, 1946–1985. J Radiat Res (Tokyo) 32: 327–351.
[9]
Satoh C, Takahashi N, Asakawa J, Kodaira M, Kuick R, et al. (1996) Genetic analysis of children of atomic bomb survivors. Environ Health Perspect 104(Suppl 3): 511–519.
[10]
Wasalenko J, MacVittie T, Blakely W, Pesik N, Wiley A, et al. (2004) Medical management of the acute radiation syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group. Ann Intern Med 140: 1037–1051.
[11]
Mettler F, Voelz G (2002) Major radiation exposure - what to expect and how to respond. N Engl J Med 346: 1554–1561.
[12]
Dainiak N (2002) Hematologic consequences of exposure to ionizing radiation. Exp Hematol 30: 513–528.
[13]
Augustine AD, Gondre-Lewis T, McBride W, Miller L, Pellmar T, et al. (2005) Animal models for radiation injury, protection and therapy. Radiat Res 164: 100–109.
[14]
Jen K, Cheung V (2003) Transcriptional response of lymphoblastoid cells to ionizing radiation. Genome Res 13: 2092–2100.
[15]
Amundson S, Bittner M, Chen Y, Trent J, Meltzer P, et al. (1999) Fluorescent cDNA microarray hybridization reveals complexity and heterogeneity of cellular genotoxic stress responses. Oncogene 18: 3666–3672.
[16]
Amundson S, Bittner M, Meltzer P, Trent J, Fornace A (2001) Induction of gene expression as a monitor of exposure to ionizing radiation. Radiat Res 156: 657–661.
[17]
Falt S, Holmberg K, Lambert B, Wennborg A (2003) Long term global gene expression patterns in irradiated human lymphocytes. Carcinogenesis 24: 1837–1845.
[18]
Amundson S, Grace M, McLeland C, Epperly M, Yeager A, et al. (2004) Human in vivo radiation induced biomarkers: Gene expression changes in radiotherapy patients. Cancer Res 64: 6368–6371.
[19]
Bender M, Awa A, Brooks A, Evans H, Groer P, et al. (1998) Current status of cytogenetic procedures to detect and quantify previous exposures to radiation. Mutat Res 196: 103–159.
[20]
Chute J, Fung J, Muramoto G, Erwin R (2004) Ex vivo culture rescues hematopoietic stem cells with long term repopulating capacity following harvest from lethally irradiated animals. Exp Hematol 32: 308–317.
[21]
Huang E, Chen S, Dressman H, Pittman J, Tsou M, et al. (2003) Gene expression predictors of breast cancer outcome. Lancet 361: 1590–1596.
[22]
West M, Blanchette C, Dressman H, Huang E, Ishida S, et al. (2001) Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S A 98: 11462–11467.
Huang E, Ishida S, Pittman J, Dressman H, Bild A, et al. (2003) Gene expression phenotypic models that predict the activity of oncogenic pathways. Nat Genet 34: 226–230.
[25]
Patino W, Mian O, Kang J, Matoba S, Bartlett L, et al. (2005) Circulating transcriptome reveals markers of atherosclerosis. Proc Natl Acad Sci U S A 102: 3423–3428.
[26]
Whitney A, Diehn M, Popper S, Alizadeh A, Boldrick J, et al. (2003) Individuality and variation in gene expression changes in human blood. Proc Natl Acad Sci U S A 100: 1896–1901.
[27]
Chute J, Muramoto G, Dressman H, Wolfe G, Chao N, et al. (2006) Molecular profile and partial functional analysis of novel endothelial cell derived growth factors that regulate hematopoiesis. Stem Cells 24: 1315–1327.
[28]
Eisen MB, Spellman PT, Brown PO, Botstein D (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci U S A 95: 14863–14868.
[29]
Saldanha AJ (2004) Java Treeview-extensible visualization of microarray data. Bioinformatics 20: 3246–3248.
[30]
Gelman, A (2004) Bayesian data analysis. Boca Raton (Florida): Chapman and Hall/CRC Press. 668 p.
[31]
Zhao X, Ayer R, Davis S, Ames S, Florence B, et al. (2005) Apoptosis factor EI24/PIG8 is a novel endoplasmic reticulum-localized Bcl2 binding protein which is associated with suppression of breast cancer invasiveness. Cancer Res 65: 2125–2129.
[32]
Akkaraju G, Basu A (2000) Overexpression of protein kinase C-eta attenuates caspase activation and tumor necrosis factor-alpha-induced cell death. Biochem Biophys Res Commun 279: 103–107.
[33]
Zhu C, Mills K, Ferguson D, Lee C, Manis J, et al. (2002) Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 109: 811–821.
[34]
Liang Y, Tedder T (2001) Identification of a CD20-, FcepsilonRIbeta-, and HTm4-related gene family: sixteen new MS4A gene cluster on Chromosome 11q12. Genomics 72: 119–127.
[35]
Zsebo K, Smith K, Hartley C, Greenblatt M, Cooke K, et al. (1992) Radioprotection in mice by recombinant rat stem cell factor. Proc Natl Acad Sci U S A 89: 9464–9468.
[36]
Pestina T, Cleveland J, Yang C, Zambetti G, Jackson C (2001) Mpl ligand prevents lethal myelosuppression by inhibiting p53-dependent apoptosis. Blood 98: 2084–2090.
[37]
Yoshimura E, Umisedo N, Facure A, Anjos R, Okuno E (2001) Ambient dose equivalent rate in Goiania 12 years after the 137Cs radiological accident. Health Phys 80: 532–536.
[38]
Hong Y, Stambrook P (2004) Restoration of an absent G1 arrest and protection from apoptosis in embryonic stem cells after ionizing radiation. Proc Natl Acad Sci U S A 101: 14443–14448.
[39]
Eguchi-Kasai K, Kosaka T, Sato K, Kaneko I (1991) Reparability of DNA double strand breaks and radiation sensitivity in 5 mammalian cell lines. Int J Radiat Biol 59: 97–104.
[40]
LeMotte P, Little J (1983) A comparison of the lethal effects of intracellular radionuclides in human and rodent cells. Radiat Res 95: 359–369.
[41]
Sankaranarayanan K (1976) Evaluation and re-evaluation of genetic radiation hazards in man. II. The arm number hypothesis and the induction of reciprocal translocations in man. Mutat Res 35: 371–386.
