Toxicologic and Metabonomic Characterization of Toxins and Metabolites in Skeletal Tissues for Forensic Prediction of Toxin Exposure Patterns

目的本研究的目标是通过对分解的骨骼组织中毒素浓度和代谢物之间的定量关系的模拟，来确定暴露于毒素的情况可以被区分的程度。本研究将开发定量的、高通量的质谱学方法来分析分解的骨骼组织中的模型毒素及其代谢物和内源性代谢物。假设不同的毒素暴露模式可以通过在分解的骨骼组织中测量的毒素、毒素代谢物和内源性代谢物的相对水平之间的关系来区分。大鼠将在不同的剂量模式下暴露于毒素(S)，剂量间隔基于毒素在大鼠体内的半衰期。接触安慰剂的动物将作为所研究的每一种毒素的对照组。对于每种暴露模式，将调查不同的死后环境(例如，温度、湿度、土壤条件、昆虫学活动和/或分解程度)。毒素和代谢物将从骨骼中提取出来，然后进行色谱和质谱分析。将研究毒素和代谢物水平之间的数学关系，以确定它们是否可以用来预测不同的毒素暴露模式。对骨骼遗骸的新颖性和信号毒理学分析知之甚少。根据骨骼中毒素和代谢物水平之间的数学关系的比较，可以区分不同的毒素暴露模式。这将为骨骼组织中的毒物学测量提供一个解释性框架，这目前是不可能的，这将对法医和环境科学产生重大影响。

OBJECTIVESThe objective of this research program is to determine the extent to which the circumstances of exposure to a toxin may be differentiated through modeling of quantitative relationships between concentrations of a toxin and metabolites in decomposed skeletal tissues.SCIENTIFIC APPROACHThis work will develop quantitative, high throughput mass spectrometric methods to analyze model toxins, their metabolites and endogenous metabolites in decomposed skeletal tissues. The hypothesis is that different patterns of toxin exposure may be differentiated through relationships between relative levels of toxin, toxin metabolites and endogenous metabolites measured in decomposed skeletal tissues. Rats will be exposed to toxin(s) under different dosing patterns, with dose intervals based on the half-life of the toxin in rats. Placebo exposed animals will serve as control groups for each toxin studied. For each pattern of exposure, various postmortem environments (e.g., temperature, humidity, soil conditions, entomological activity and/or degrees of decomposition) will be investigated. Toxins and metabolites will be extracted from bone prior to analysis by chromatography and mass spectrometry. Mathematical relationships between toxin and metabolite levels will be investigated in order to determine if they may be used to predict different patterns of toxin exposure.EXPECTED NOVELTY & SIGNIFICANCEToxicological analysis of skeletal remains is poorly understood. Discrimination between different patterns of toxin exposure may be possible based on comparison of the mathematical relationship between levels of toxin and metabolites in bone. This would provide an interpretive framework for toxicological measurements in skeletal tissues that is not currently possible, significantly impacting the forensic and environmental sciences.