Heijne Wilbert H M, Lamers Robert-Jan A N, van Bladeren Peter J, Groten John P, van Nesselrooij Joop H J, van Ommen Ben
TNO Nutrition and Food Research, 3700 AJ Zeist, The Netherlands.
Toxicol Pathol. 2005;33(4):425-33. doi: 10.1080/01926230590958146.
This study investigated whether integrated analysis of transcriptomics and metabolomics data increased the sensitivity of detection and provided new insight in the mechanisms of hepatotoxicity. Metabolite levels in plasma or urine were analyzed in relation to changes in hepatic gene expression in rats that received bromobenzene to induce acute hepatic centrilobular necrosis. Bromobenzene-induced lesions were only observed after treatment with the highest of 3 dose levels. Multivariate statistical analysis showed that metabolite profiles of blood plasma were largely different from controls when the rats were treated with bromobenzene, also at doses that did not elicit histopathological changes. Changes in levels of genes and metabolites were related to the degree of necrosis, providing putative novel markers of hepatotoxicity. Levels of endogenous metabolites like alanine, lactate, tyrosine and dimethylglycine differed in plasma from treated and control rats. The metabolite profiles of urine were found to be reflective of the exposure levels. This integrated analysis of hepatic transcriptomics and plasma metabolomics was able to more sensitively detect changes related to hepatotoxicity and discover novel markers. The relation between gene expression and metabolite levels was explored and additional insight in the role of various biological pathways in bromobenzene-induced hepatic necrosis was obtained, including the involvement of apoptosis and changes in glycolysis and amino acid metabolism. The complete Table 2 is available as a supplemental file online at http://taylorandfrancis.metapress.com/openurlasp?genre=journal&issn=0192-6233. To access the file, click on the issue link for 33(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.
本研究调查了转录组学和代谢组学数据的综合分析是否提高了检测的敏感性，并为肝毒性机制提供了新的见解。在接受溴苯诱导急性肝小叶中心坏死的大鼠中，分析了血浆或尿液中的代谢物水平与肝脏基因表达变化的关系。仅在3个剂量水平中的最高剂量处理后才观察到溴苯诱导的损伤。多变量统计分析表明，当用溴苯处理大鼠时，血浆代谢物谱与对照组有很大差异，即使在未引起组织病理学变化的剂量下也是如此。基因和代谢物水平的变化与坏死程度相关，提供了肝毒性的推定新标志物。丙氨酸、乳酸、酪氨酸和二甲基甘氨酸等内源性代谢物的水平在处理组和对照组大鼠的血浆中有所不同。发现尿液的代谢物谱反映了暴露水平。这种肝脏转录组学和血浆代谢组学的综合分析能够更敏感地检测与肝毒性相关的变化并发现新的标志物。探索了基因表达与代谢物水平之间的关系，并获得了对各种生物途径在溴苯诱导的肝坏死中的作用的更多见解，包括细胞凋亡的参与以及糖酵解和氨基酸代谢的变化。完整的表2可作为补充文件在线获取，网址为http://taylorandfrancis.metapress.com/openurlasp?genre=journal&issn=0192-6233。要访问该文件，请点击33(4)的期链接，然后选择本文。在本摘要底部会出现下载选项。为了在线访问全文，您必须拥有个人订阅或通过www.toxpath.org访问的会员订阅。
