Abstract 2506: Untargeted and targeted multiplatform metabolomic and lipidomic approaches for monitoring biological effects in serum from total body irradiated humans

Abstract

Abstract Investigation of responses to radiation therapy or exposure to radiation in an intentional or accidental manner have identified significant biomarkers for biodosimetry and monitoring of individuals in urine through metabolomics (1). We extend the investigation in serum by combining targeted and untargeted methodologies with a multiplatform approach. Serum was collected from patients exposed to total body irradiation (TBI) prior to hematopoietic stem cell transplantation at Memorial Sloan Kettering Cancer Center. The underlying diseases (chronic myelogenous leukemia, acute lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, or myelodysplastic syndrome) were in remission and the cohort included both males and females. Serum was collected prior to irradiation, at 3-8 h after a single dose of 1.25 Gy, and at 24h after three fractions of 1.25 Gy each. Untargeted metabolomic and lipidomic approaches with liquid chromatography (LC) mass spectrometry (MS) and gas chromatography (GC) MS demonstrated significant perturbations at the later time point and higher total dose. Alterations in circulating levels were observed in lipids from monoacylglycerol, triacylglycerol, phosphatidylcholine, phosphatidylglycerol, phosphatidylserine, and phosphatidic acid lipid classes. Fatty acids were some of the most dysregulated lipids, with increased levels linked to pro-inflammatory processes. To further investigate the presence of low abundance pro-inflammatory metabolites, we utilized a targeted and highly quantitative approach measuring downstream molecules from fatty acids, such as thromboxanes, prostaglandins, and leukotrienes that can act as signaling molecules and mediators of systemic inflammation. Results identified a rapid response within the first 3-8 hours primarily mediated through the enzymatic action of lipoxygenase (LOX) and cytochrome P450 (CYP450), although some dissipated at the later time point. Less significant alterations were observed in the anti-inflammatory pathway, although the fatty acid precursor α-linolenic acid remained elevated in both time points. Finally, as observed in our previous published study of a similar cohort (1), sex-dependent differences were analyzed and unlike the urinary results, females appeared to be more responsive to radiation effects as measured in serum with lipidomics and metabolomics. No sex differences were observed with the targeted approach. The ability to identify and quantify small molecules in blood following radiation exposure can therefore be utilized to not only monitor systemic effects of radiotherapy but also to generate signatures that can be utilized to identify accidentally exposed individuals that may require medical intervention. 1. Laiakis EC et al. Radiat Res 2014; 181: 350-361. Citation Format: Evagelia C. Laiakis, Evan L. Pannkuk, Siddheshwar Chauthe, Yi-Wen Wang, Ming Lian, Tytus D. Mak, Christopher A. Barker, Giuseppe Astarita, Albert J. Fornace. Untargeted and targeted multiplatform metabolomic and lipidomic approaches for monitoring biological effects in serum from total body irradiated humans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2506. doi:10.1158/1538-7445.AM2017-2506