van der Burg Bart, Pieterse Bart, Buist Harrie, Lewin Geertje, van der Linden Sander C, Man Hai-yen, Rorije Emiel, Piersma Aldert H, Mangelsdorf Inge, Wolterbeek Andre P M, Kroese E Dinant, van Vugt-Lussenburg Barbara
BioDetection Systems BV, Amsterdam, The Netherlands.
BioDetection Systems BV, Amsterdam, The Netherlands.
Reprod Toxicol. 2015 Aug 1;55:95-103. doi: 10.1016/j.reprotox.2014.11.011. Epub 2014 Dec 18.
There is a great need for alternative testing methods for reproductive toxicants that are practical, fast, cost-effective and easy to interpret. Previously we followed a pragmatic approach using readily available tests, which was successful in predicting reproductive toxicity of chemicals [13]. This initial battery still contained apical tests and is fairly complex and low in its throughput. The current study aimed to simplify this screening battery using a mechanistic approach and a panel of high throughput CALUX reporter gene assays. A mechanistic approach was taken to validate this high throughput test battery. To this end it was challenged with two preselected sets of chemicals addressing two major apical effect classes relevant in reproductive toxicity. We found selectivity in this battery in that 82% of the compounds inducing reproductive organ deformities were predicted correctly, while for compounds inducing neural tube defects this was the case in 47% only. This is consistent with the mechanisms of toxicity covered in the battery. The most informative assays in the battery were ERalpha CALUX to measure estrogenicity and the AR-anti CALUX assay to measure androgen receptor antagonism.
对于生殖毒性物质，非常需要实用、快速、经济高效且易于解读的替代测试方法。此前我们采用了一种务实的方法，使用现成的测试，成功预测了化学物质的生殖毒性[13]。最初的这组测试仍包含顶端测试，相当复杂且通量较低。当前的研究旨在使用一种机制性方法和一组高通量CALUX报告基因检测来简化这种筛选测试组。采用了一种机制性方法来验证这个高通量测试组。为此，用两组预先选定的化学物质对其进行挑战，这两组化学物质针对生殖毒性中两个主要的顶端效应类别。我们发现该测试组具有选择性，即82%诱导生殖器官畸形的化合物被正确预测，而对于诱导神经管缺陷的化合物，只有47%的情况是这样。这与测试组所涵盖的毒性机制一致。该测试组中最具信息量的检测是用于测量雌激素活性的ERalpha CALUX检测和用于测量雄激素受体拮抗作用的AR-anti CALUX检测。
