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首页> 外文期刊>Reproductive toxicology >Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.
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Comparison of MeHg-induced toxicogenomic responses across in vivo and in vitro models used in developmental toxicology.

机译：在发育毒理学中使用的体内和体外模型比较MeHg诱导的毒理基因组反应。

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Toxicogenomic evaluations may improve toxicity prediction of in vitro-based developmental models, such as whole embryo culture (WEC) and embryonic stem cells (ESC), by providing a robust mechanistic marker which can be linked with responses associated with developmental toxicity in vivo. While promising in theory, toxicogenomic comparisons between in vivo and in vitro models are complex due to inherent differences in model characteristics and experimental design. Determining factors which influence these global comparisons are critical in the identification of reliable mechanistic-based markers of developmental toxicity. In this study, we compared available toxicogenomic data assessing the impact of the known teratogen, methylmercury (MeHg) across a diverse set of in vitro and in vivo models to investigate the impact of experimental variables (i.e. model, dose, time) on our comparative assessments. We evaluated common and unique aspects at both the functional (Gene Ontology) and gene level of MeHg-induced response. At the functional level, we observed stronger similarity in MeHg-response between mouse embryos exposed in utero (2 studies), ESC, and WEC as compared to liver, brain and mouse embryonic fibroblast MeHg studies. These findings were strongly correlated to the presence of a MeHg-induced developmentally related gene signature. In addition, we identified specific MeHg-induced gene expression alterations associated with developmental signaling and heart development across WEC, ESC and in vivo systems. However, the significance of overlap between studies was highly dependent on traditional experimental variables (i.e. dose, time). In summary, we identify promising examples of unique gene expression responses which show in vitro-in vivo similarities supporting the relevance of in vitro developmental models for predicting in vivo developmental toxicity.
机译：毒物基因组学评估可通过提供可与体内发育毒性相关反应相关的可靠机制标记，改善基于体外发育模型（例如全胚培养（WEC）和胚胎干细胞（ESC））的毒性预测。尽管理论上很有希望，但由于模型特征和实验设计的内在差异，体内和体外模型之间的毒物基因组比较非常复杂。确定影响这些全局比较的因素对于鉴定可靠的基于机理的发育毒性标记至关重要。在这项研究中，我们比较了现有的毒物基因组数据，评估了已知的致畸剂，甲基汞（MeHg）在各种体外和体内模型中的影响，以研究实验变量（即模型，剂量，时间）对我们的比较的影响评估。我们在功能（基因本体论）和基因水平上对MeHg诱导的反应进行了共同和独特的评估。在功能水平上，与肝脏，大脑和小鼠胚胎成纤维细胞MeHg研究相比，我们观察到子宫内暴露的小鼠胚胎在MeHg反应方面的相似性更强（2个研究），ESC和WEC。这些发现与MeHg诱导的发育相关基因标记的存在密切相关。此外，我们确定了特定的MeHg诱导的基因表达变化，这些变化与WEC，ESC和体内系统的发育信号和心脏发育有关。但是，研究之间重叠的重要性在很大程度上取决于传统的实验变量（即剂量，时间）。总而言之，我们确定了独特的基因表达反应的有前途的例子，这些例子显示了体外-体内相似性，支持了体外发育模型预测体内发育毒性的相关性。

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