Ó Broin Pilib, Vaitheesvaran Bhavapriya, Saha Subhrajit, Hartil Kirsten, Chen Emily I, Goldman Devorah, Fleming William Harv, Kurland Irwin J, Guha Chandan, Golden Aaron
Department of Genetics, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York; Department of Mathematical Sciences, Yeshiva University, New York, New York.
Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York.
Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):360-7. doi: 10.1016/j.ijrobp.2014.10.023.
Assessing whole-body radiation injury and absorbed dose is essential for remediation efforts following accidental or deliberate exposure in medical, industrial, military, or terrorist incidents. We hypothesize that variations in specific metabolite concentrations extracted from blood plasma would correlate with whole-body radiation injury and dose.
Groups of C57BL/6 mice (n=12 per group) were exposed to 0, 2, 4, 8, and 10.4 Gy of whole-body gamma radiation. At 24 hours after treatment, all animals were euthanized, and both plasma and liver biopsy samples were obtained, the latter being used to identify a distinct hepatic radiation injury response within plasma. A semiquantitative, untargeted metabolite/lipid profile was developed using gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry, which identified 354 biochemical compounds. A second set of C57BL/6 mice (n=6 per group) were used to assess a subset of identified plasma markers beyond 24 hours.
We identified a cohort of 37 biochemical compounds in plasma that yielded the optimal separation of the irradiated sample groups, with the most correlated metabolites associated with pyrimidine (positively correlated) and tryptophan (negatively correlated) metabolism. The latter were predominantly associated with indole compounds, and there was evidence that these were also correlated between liver and plasma. No evidence of saturation as a function of dose was observed, as has been noted for studies involving metabolite analysis of urine.
Plasma profiling of specific metabolites related to pyrimidine and tryptophan pathways can be used to differentiate whole-body radiation injury and dose response. As the tryptophan-associated indole compounds have their origin in the intestinal microbiome and subsequently the liver, these metabolites particularly represent an attractive marker for radiation injury within blood plasma.
在医疗、工业、军事或恐怖事件中，意外或故意暴露后，评估全身辐射损伤和吸收剂量对于补救工作至关重要。我们假设从血浆中提取的特定代谢物浓度变化与全身辐射损伤和剂量相关。
将C57BL/6小鼠分组（每组n = 12），分别接受0、2、4、8和10.4 Gy的全身γ辐射。治疗后24小时，对所有动物实施安乐死，获取血浆和肝脏活检样本，后者用于确定血浆中独特的肝脏辐射损伤反应。使用气相色谱 - 质谱联用和液相色谱 - 串联质谱联用技术建立了半定量、非靶向代谢物/脂质谱，鉴定出354种生化化合物。使用另一组C57BL/6小鼠（每组n = 6）评估24小时后鉴定出的血浆标志物子集。
我们在血浆中鉴定出一组37种生化化合物，这些化合物能实现辐照样本组的最佳分离，与嘧啶代谢（正相关）和色氨酸代谢（负相关）相关的代谢物相关性最高。后者主要与吲哚化合物有关，并且有证据表明这些化合物在肝脏和血浆之间也存在相关性。未观察到剂量函数的饱和证据，这与涉及尿液代谢物分析的研究结果一致。
与嘧啶和色氨酸途径相关的特定代谢物的血浆分析可用于区分全身辐射损伤和剂量反应。由于与色氨酸相关的吲哚化合物起源于肠道微生物群，随后进入肝脏，这些代谢物特别代表了血浆中辐射损伤的一个有吸引力的标志物。
