UHPLC/MS-Based Serum Metabolomics Reveals the Mechanism of Radiation-Induced Thrombocytopenia in Mice.

Abstract

Radiation-induced thrombocytopenia is a common and life-threatening side effect of ionizing radiation (IR) therapy. However, the underlying pathological mechanisms remain unclear. In the present study, irradiation was demonstrated to significantly reduce platelet levels, inhibit megakaryocyte differentiation, and promote the apoptosis of bone marrow (BM) cells. A metabolomics approach and a UHPLC-QTOF MS system were subsequently employed for the comprehensive analysis of serum metabolic profiles of normal and irradiated mice. A total of 66 metabolites were significantly altered, of which 56 were up-regulated and 10 were down-regulated in irradiated mice compared to normal mice on day 11 after irradiation. Pathway analysis revealed that disorders in glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, sphingolipid metabolism, inositol phosphate metabolism, and tryptophan metabolism were involved in radiation-induced thrombocytopenia. In addition, three important differential metabolites, namely L-tryptophan, LysoPC (17:0), and D-sphinganine, which were up-regulated in irradiated mice, significantly induced the apoptosis of K562 cells. L-tryptophan inhibited megakaryocyte differentiation of K562 cells. Finally, serum metabolomics was performed on day 30 (i.e., when the platelet levels in irradiated mice recovered to normal levels). The contents of L-tryptophan, LysoPC (17:0), and D-sphinganine in normal and irradiated mice did not significantly differ on day 30 after irradiation. In conclusion, radiation can cause metabolic disorders, which are highly correlated with the apoptosis of hematopoietic cells and inhibition of megakaryocyte differentiation, ultimately resulting in thrombocytopenia. Further, the metabolites, L-tryptophan, LysoPC (17:0), and D-sphinganine can serve as biomarkers for radiation-induced thrombocytopenia.