Effect of Sex on Biomarker Response in a Mouse Model of the Hematopoietic Acute Radiation Syndrome

Abstract

Gender is an important confounding variable in biomarker development that must be incorporated into biomarker discovery and validation. Additionally, understanding of gender as a biological variable is essential for effective translation of biomarkers in animal models to human populations. Towards these ends, we conducted high-throughput targeted metabolomics using LC-MS/MS and multiplexed immunoassay analyses using a Luminex-based system in both male and female mice in a model of total-body irradiation at a radiation dose consistent with the hematopoietic acute radiation syndrome. Metabolomic and immunoassay analyses identified metabolites and cytokines that were significantly different in plasma from naïve and irradiated C57BL/6 mice consisting of equal numbers of female and male mice at 3 days after 8.0 or 8.72 Gy, an approximate LD60-70/30 dose of total-body irradiation. An additional number of metabolites and cytokines had gender-specific responses after radiation. Analyses in sham-irradiated mice illustrate the presence of stress-related changes in several cytokines due simply to undergoing the irradiation procedure absent actual radiation exposure. Basal differences in metabolite levels between female and male were also identified as well as time-dependent changes in cytokines up to 9 days post-exposure. These studies provide data toward defining the influence of gender on plasma-based biomarker candidates in a well-defined mouse model of acute radiation syndrome.

Temporal Effects on Radiation Responses in Nonhuman Primates: Identification of Biofluid Small Molecule Signatures by Gas Chromatography–Mass Spectrometry Metabolomics

“…Leucine is a ketogenic branched chain amino acid (BCAA) that plays important roles in multiple conditions (along with other BCAAAs isoleucine and valine) including cachexia (muscle wasting), a known effect from radiation exposure [49], and the dynamic roles of BCAAs in radiation injury remains an interesting topic for future research. As sex differences have been reported in multiple animal models, including NHPs [28,46] and humans [23,50], it must be continually addressed further in biomarker response [51].…”

A Systematic Review of Metabolomic and Lipidomic Candidates for Biomarkers in Radiation Injury

“…IR exposure results in a cascade of biological events that is both time and dose dependent [52,67,68]. ARS manifests in four stages-the prodromal syndrome, the latent period, the manifestation of illness, and either death or recovery.…”

microRNA and Metabolite Signatures Linked to Early Consequences of Lethal Radiation

“…In the B6C3F1 strain, which is a cross between the two inbred strains, the value for LD50/30 was identified as 8.12 Gy, and in the CD2F1 strain, which is a cross between the BALB/c and DBA/2, the LD50/30 value is even higher at 8.65 Gy. Furthermore, the sex of the mouse changes the response to radiation exposure 5 . Mice experiencing hematopoietic ARS often exhibit decreased numbers of peripheral blood cells, leading to neutropenia and thrombocytopenia, which can result in death often from infection or bleeding.…”