de Jong Esther, van Beek Lianne, Piersma Aldert H
Institute for Risk Assessment Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands; Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Laboratory for Health Protection Research, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Reprod Toxicol. 2014 Sep;48:62-71. doi: 10.1016/j.reprotox.2014.03.012. Epub 2014 Apr 2.
One of the most studied alternative embryotoxicity assays is the embryonic stem cell test, in which the effect of compounds on cardiomyocyte differentiation is evaluated (subsequently termed the ESTc). This single differentiation endpoint may limit the predictive value of the assay. We recently published a novel embryonic stem cell based osteoblast differentiation assay (subsequently termed the ESTo), in which we studied the effect of six embryotoxic compounds. Differentiation is monitored via the differential expression of three genes related to osteogenesis (Runx2, SPARC and collagen type I). In the current study, we evaluated the effect of 14 additional compounds in the ESTo, to assess its added value as compared to the ESTc. To this end, we compared the effects of the compounds in the ESTo to their effects in the ESTc and to their published in vivo developmental toxicity profiles. The results show that there is a high overall correlation between compound potencies as regards inhibition of osteoblast and cardiomyocyte differentiation. Moreover, the results in both the ESTo and ESTc showed a significant correlation to in vivo developmental toxicity potency ranking of compounds tested. Interestingly, the embryotoxic effect of TCDD could only be detected using the ESTo, which can be explained based on its mechanism of action and its known inhibitory effect on osteogenesis. The results of TCDD suggest that incorporating the ESTo into a testing battery together with the ESTc could improve the overall predictive value of the battery.
研究最多的替代胚胎毒性试验之一是胚胎干细胞试验，该试验评估化合物对心肌细胞分化的影响（随后称为ESTc）。这个单一的分化终点可能会限制该试验的预测价值。我们最近发表了一种基于胚胎干细胞的新型成骨细胞分化试验（随后称为ESTo），我们在该试验中研究了六种胚胎毒性化合物的作用。通过与骨生成相关的三个基因（Runx2、SPARC和I型胶原蛋白）的差异表达来监测分化。在本研究中，我们在ESTo中评估了另外14种化合物的作用，以评估其与ESTc相比的附加值。为此，我们将化合物在ESTo中的作用与其在ESTc中的作用以及已发表的体内发育毒性概况进行了比较。结果表明，化合物在抑制成骨细胞和心肌细胞分化方面的效力总体上具有高度相关性。此外，ESTo和ESTc的结果均与所测试化合物的体内发育毒性效力排名显著相关。有趣的是，只能使用ESTo检测到TCDD的胚胎毒性作用，这可以根据其作用机制及其对骨生成的已知抑制作用来解释。TCDD的结果表明，将ESTo与ESTc一起纳入测试组合可以提高该组合的整体预测价值。
