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

* 本研究计划的目的是通过模拟分解骨骼组织中异生素浓度和代谢物浓度之间的定量关系，确定暴露于异生素的情况在多大程度上可以区分。科学方法 * 这项工作将开发定量，高通量质谱方法来分析模型外源性物质，其代谢物和内源性代谢物在分解的骨骼组织。该假设是，不同模式的外源性暴露可以区分通过相对水平的外源性，毒素代谢物和内源性代谢物之间的关系，在分解的骨骼组织测量。大鼠将在不同给药模式下暴露于异生物质，给药间隔基于异生物质在大鼠中的半衰期。安慰剂暴露动物将作为研究的每种毒素的对照组。对于每种暴露模式，各种死后环境（例如，温度、湿度、土壤条件、昆虫活动和/或分解程度）进行调查。在通过色谱法和质谱法进行分析之前，将从骨中提取外源性物质和代谢物。将研究毒素和代谢物水平之间的数学关系，以确定它们是否可用于预测不同的外源性接触模式。预期的新奇和重要性 * 对骨骼遗骸的毒理学分析知之甚少。通过比较骨中生物外源性物质和代谢物水平之间的数学关系，可以区分不同的生物外源性物质暴露模式。这将为目前不可能的骨骼组织毒理学测量提供一个解释性框架，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.