Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands; Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht, The Netherlands.
Toxicol Appl Pharmacol. 2013 Oct 1;272(1):161-71. doi: 10.1016/j.taap.2013.05.037. Epub 2013 Jun 14.
The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, d-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity.
斑马鱼胚胎毒性测试是一种很有前途的发育毒性替代检测方法。传统上，通过评估胚胎的形态学来评估化合物暴露的影响。然而，通过应用差异基因表达分析，可以提高测试的灵敏度和预测性。为了定义发育毒性的基因表达特征，我们探索了使用基于共同表达的单个基因和基于调节基因途径的化合物暴露的基因表达特征的可能性。在浓度反应设计中测试了四种发育毒性化合物，即咖啡因、卡马西平、视黄酸和丙戊酸，并包括了两种非胚胎毒性化合物，即 D-甘露醇和糖精。通过转录组分析，我们能够识别出暴露于胚胎毒性物质后共同表达的基因，这些基因大多与发育有关。我们还鉴定了胚胎毒性物质调节的基因途径，提示其作用模式。此外，虽然途径可能被所有化合物调节，但这些途径中的单个基因表达可能因每种化合物而异。总的来说，本研究表明，使用单个基因表达特征和途径调节可能是定义预测胚胎毒性的基因生物标志物的有用起点。
