Gene expression changes in male and female rhesus macaque 60 days after irradiation

Abstract

Purpose Transcriptome 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 methods Male 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. Results We 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. Conclusions 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.

Lung transcriptome of nonhuman primates exposed to total- and partial-body irradiation

“… 11 , 12 , 13 Several studies from various investigators have profiled transcriptomic changes in various tissues of nonhuman primates (NHPs). 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 However, the majority of these publications are with baboons, which are no longer used for such studies. Therefore, there is a need for studies performed with rhesus and cynomolgus, which are commonly used NHPs.…”

“…Though significant progress has been made with transcriptomic studies using radiation injury models of NHPs, additional investigation is required to ensure that signatures are robust. 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 …”

“…Though significant progress has been made with transcriptomic studies using radiation injury models of NHPs, additional investigation is required to ensure that signatures are robust. 16,[18][19][20][21][22][23][24][25][26][27][28] NHP models of radiation injury have several advantages over both small animal models, including rodents, and large animal models, including swine (minipig) and canines. 3,29,30 NHPs closely resemble humans and have several advantages with respect to their organ structure, genetic homology sharing with more than 95% DNA sequence similarity, metabolism, response to physiological pathways, cell receptors, suitability for gastrointestinal symptoms (vomiting), long life span, and the ease of sequential sampling for monitoring radiation response and recovery.…”