Xenobiotic and Metabolite Profiling in Skeletal Remains for Classification of Xenobiotic Exposure Patterns

目的*本研究计划的目的是通过建立外源生物与腐烂骨骼组织中代谢物浓度之间的定量关系模型，来确定外源生物暴露环境的差异程度。本研究将发展定量、高通量的质谱学方法来分析腐烂骨骼组织中的模型外源生物及其代谢物和内源性代谢物。该假说认为，通过在腐烂的骨骼组织中测量到的异物、毒素代谢物和内源性代谢物的相对水平之间的关系，可以区分不同的异物暴露模式。大鼠将在不同的给药模式下暴露于异种生物(S)，剂量间隔基于异种生物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)。将从骨骼中提取异物和代谢物，然后进行色谱和质谱分析。将调查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于预测不同的异物暴露模式。*预期的新颖性和重要性*对骨骼遗骸的毒理学分析知之甚少。通过比较骨骼中异物和代谢物水平之间的数学关系，可以区分不同的异物暴露模式。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。

OBJECTIVES***The objective of this research program is to determine the extent to which the circumstances of exposure to a xenobiotic may be differentiated through modeling of quantitative relationships between concentrations of a xenobiotic and metabolites in decomposed skeletal tissues.******SCIENTIFIC APPROACH***This work will develop quantitative, high throughput mass spectrometric methods to analyze model xenobiotics, their metabolites and endogenous metabolites in decomposed skeletal tissues. The hypothesis is that different patterns of xenobiotic exposure may be differentiated through relationships between relative levels of xenobiotic, toxin metabolites and endogenous metabolites measured in decomposed skeletal tissues. Rats will be exposed to xenobiotic(s) under different dosing patterns, with dose intervals based on the half-life of the xenobiotic 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. Xenobiotics 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 xenobiotic exposure.******EXPECTED NOVELTY & SIGNIFICANCE***Toxicological analysis of skeletal remains is poorly understood. Discrimination between different patterns of xenobiotic exposure may be possible based on comparison of the mathematical relationship between levels of xenobiotic 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.