Lipidomic Signatures of Nonhuman Primates with Radiation-Induced Hematopoietic Syndrome

Evan L Pannkuk,Evagelia C Laiakis,Vijay K Singh,Albert J Fornace

doi:10.1038/s41598-017-10299-w

Abstract

Concern over potential exposures of ionizing radiation (IR) to large populations has emphasized the need for rapid and reliable methods of biodosimetry to determine absorbed dose and required triage. Lipidomics has emerged as a powerful technique for large-scale lipid identification and quantification. Indirect effects from IR exposure generate reactive oxygen species (ROS) through water hydrolysis and may subsequently damage cellular lipids. Thus, rapid identification of specific affected lipid molecules represents possible targets for biodosimetry. The current study addresses temporal changes in the serum lipidome from 4 h to 28 d in nonhuman primates (NHPs) with radiation-induced hematopoietic syndrome (6.5 Gy exposure, LD50/60). Statistical analyses revealed a highly dynamic temporal response in the serum lipidome after IR exposure. Marked lipidomic perturbations occurred within 24 h post-irradiation along with increases in cytokine levels and C-reactive protein. Decreases were observed in di- and triacylglycerides, sphingomyelins (SMs), lysophosphatidylcholines (LysoPCs), and esterified sterols. Conversely, free fatty acids and monoacylglycerides significantly increased. Decreased levels of SMs and increased levels of LysoPCs may be important markers for biodosimetry ~2 d–3 d post-irradiation. The biphasic and dynamic response to the serum lipidome post-irradiation emphasize the importance of determining the temporal long-term response of possible radiation markers.

Highlights

Concern over potential exposures of ionizing radiation (IR) to large populations has emphasized the need for rapid and reliable methods of biodosimetry to determine absorbed dose and required triage
The normalized dataset for electrospray ionization (ESI+ and ESI−) modes were processed through MetaboLyzer and a standard singular value decomposition based principal component analysis (PCA) was performed
This study reports changes in nonhuman primates (NHPs) serum lipidomic signatures spanning 28 d following exposure to 6.5 Gy radiation and how lipid changes correlate with complete blood count (CBC) parameters, cytokine levels, and NHP clinical signs

Summary

Introduction

Concern over potential exposures of ionizing radiation (IR) to large populations has emphasized the need for rapid and reliable methods of biodosimetry to determine absorbed dose and required triage. The biphasic and dynamic response to the serum lipidome post-irradiation emphasize the importance of determining the temporal long-term response of possible radiation markers. A global lipidomic analysis reported general decreases in lipid levels but high increases at 10 Gy in lipids with 20:4 (arachidonic acid) and 22:6 (docosahexaenoic acid) acyl moieties, which are important precursors in lipoxygenase (LOX) and cyclooxygenase (COX) mediated inflammation[13]. A subsequent targeted approach confirmed this pattern in PCs and ePCs, where PC (38:6), ePC (40:3) and (40:5) increased at 10 Gy14 While these studies indicate clear changes in lipid levels after IR exposure, their scope is limited due to the analysis of a single time point (7 d post-irradiation). While lipid levels are biphasic and highly dynamic after IR exposure, we found high perturbations to the NHP lipidome within the first 24 h post-irradiation. The biphasic response exhibited by these molecules highlights the importance in timing for sample collection if used for biodosimetry after irradiation

Methods

Results

Conclusion