High and low dose responses of transcriptional biomarkers in ex vivo X-irradiated human blood.
OBJECTIVE
Modifications of gene expression following ionizing radiation (IR) exposure of cells in vitro and in vivo are well documented. However, little is known about the dose-responses of transcriptionally responsive genes, especially at low doses. In this study, we investigated these dose-responses and assessed inter-individual variability.


METHODS
High dose (0.5-4 Gy) and low dose (5-100 mGy) gene expression responses at 2 h and 24 h using 13 biomarkers transcriptionally regulated through the DNA damage response by the tumor suppressor p53 were investigated. Inter-individual variation was also examined.


RESULTS
High dose-response curves were best constructed using a polynomial fit while the low dose-response curves used a linear fit with linear R(2) values of 0.841-0.985. Individual variation was evident in the high and low dose ranges. The FDXR, DDB2 high dose gene combination produced a mean dose estimate of 0.7 Gy for 1 Gy irradiated 'unknown' samples (95% CIs of 0.3-1.1 Gy) and 1.4 Gy for 2 Gy exposure (95% CIs of 0.6-2.1 Gy). The FDXR, DDB2, CCNG1 low dose gene combination estimated 98 mGy (95% CIs of 27-169 mGy) for 100 mGy exposure.


CONCLUSIONS
These findings identify genes that fulfill some of the requirements of a good exposure biomarker even at low doses, such as sensitivity, reproducibility and simple proportionality with dose.
Biological Effects Department, Centre for Radiation, Chemical and Environmental Hazards, Health Protection Agency, Chilton, Didcot, Oxfordshire, UK.
Grainne
G
Manning
Sylwia
S
Kabacik
Paul
P
Finnon
Simon
S
Bouffler
Christophe
C
Badie
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism* / Q000528:radiation effects*; D008297:Male; D008875:Middle Aged; D011829:Radiation Dosage; D014157:Transcription Factors / Q000378:metabolism*; D014965:X-Rays
D015415:Biomarkers; D001798:Blood Proteins; D014157:Transcription Factors