Abstract
PurposeTranscriptome changes can be expected in survivors after lethal irradiation. We aimed to characterize these in males and females and after different cytokine treatments 60 days after irradiation.Material and methodsMale and female rhesus macaques (n = 142) received a whole-body exposure with 700 cGy, from which 60 animals survived. Peripheral whole blood was drawn pre-exposure and before sacrificing the surviving animals after 60 days.ResultsWe evaluated gene expression in a three-phase study design. Phase I was a whole-genome screening (NGS) for mRNAs using five pre- and post-exposure RNA samples from both sexes (n = 20). Differential gene expression (DGE) was calculated between samples of survivors and pre-exposure samples (reference), separately for males and females. 1,243 up- and down-regulated genes were identified with 30–50% more deregulated genes in females. 37 candidate mRNAs were chosen for qRT-PCR validation in phase II using the remaining samples (n = 117). Altogether 17 genes showed (borderline) significant (t-test) DGE in groups of untreated or treated animals. Nine genes (CD248, EDAR, FAM19A5, GAL3ST4, GCNT4, HBG2/1, LRRN1, NOG, SYT14) remained with significant changes and were detected in at least 50% of samples per group. Panther analysis revealed an overlap between both sexes, related to the WNT signaling pathway, cell adhesion and immunological functions. For phase III, we validated the nine genes with candidate genes (n = 32) from an earlier conducted study on male baboons. Altogether 14 out of 41 genes showed a concordantly DGE across both species in a bilateral comparison.ConclusionsSixty days after radiation exposure, we identified (1) sex and cytokine treatment independent transcriptional changes, (2) females with almost twice as much deregulated genes appeared more radio-responsive than males, (3) Panther analysis revealed an association with immunological processes and WNT pathway for both sexes.
Highlights
Gene expression changes caused by high dose irradiation have been investigated intensively over the last decades [1]
Differential gene expression (DGE) was calculated between samples of survivors and pre-exposure samples, separately for males and females. 1,243 upand down-regulated genes were identified with 30–50% more deregulated genes in females. 37 candidate mRNAs were chosen for qRT-PCR validation in phase II using the remaining samples (n = 117)
Sixty days after radiation exposure, we identified (1) sex and cytokine treatment independent transcriptional changes, (2) females with almost twice as much deregulated genes appeared more radio-responsive than males, (3) Panther analysis revealed an association with immunological processes and WNT pathway for both sexes
Summary
Gene expression changes caused by high dose irradiation have been investigated intensively over the last decades [1]. Radiation-induced long-term effects are known [2] and for example, stable chromosomal aberrations changes after high dose irradiation are used for retrospective dosimetry [3]. As almost two-third of all cancer patients undergo partial or whole body radiotherapy [10], the overall number of people with radiation-associated long-term effects is high making the topic pivotal [11]. Delayed effects of acute radiation exposure (DEARE) are other known health effects occurring after high radiation exposures. They are associated with degenerative and inflammatory conditions affecting multiple organs [12] and induce cerebrovascular injury [13] or lung injury [14]. DEARE or long term effects have to be expected in survivors of these scenarios [6, 16]
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