Dvorakova Marketa, Kejlová Kristina, Rucki Marian, Jírová Dagmar
Charles University in Prague, Third Faculty of Medicine, Ruská 87, Prague, Czech Republic.
National Institute of Public Health, Centre of Toxicology and Health Safety, Šrobárova 48, Prague, Czech Republic.
Neuro Endocrinol Lett. 2018 Dec;39(5):409-416.
The aim of this study was to detect endocrine disruption potential of selected bisphenols and phthalates, compare in silico prediction with results from two in vitro methods and bring up-to-date information on development of EU legislation, available in vitro methods and biomechanisms involved in endocrine disruption.
In silico approach based on the OECD QSAR Toolbox was used for prediction of estrogen receptor α binding. OECD TG 455 assay and a yeast-based YES/YAS assay was used to determine the interactions with human estrogen (ERα) and androgen receptors.
In silico results predicted the screened phthalates as non binders and bisphenols as very strong binders of the ERα. In vitro results differed from in silico prediction in several cases but exhibited concordance mainly for strong binders of ERα. Most of the substances exhibited parallel activity (agonist-antagonist) on both estrogen and androgen receptors. Agonistic studies showed the effective concentration of 10% activity (EC10) from 5.0E-07 for strong agonists (e.g. BPC, BPTMC). Cytotoxicity was observed after 48 h exposure of S. cerevisiae to BPFL, BPG, BPM, BPTMC in concentrations starting at 3.6E-05 mol/l.
Our results suggest multiple parallel interactions of tested compounds and emphasize the importance of determination of an appropriate battery of in vitro methods that will include more receptors and will be appropriate to target specific molecular mechanisms involved in endocrine disruption. Results in agonistic studies indicate agonistic potential and are supported by results of antagonistic studies with consideration of possible multiple interactions.
本研究旨在检测选定双酚和邻苯二甲酸酯的内分泌干扰潜力，将计算机模拟预测结果与两种体外方法的结果进行比较，并提供有关欧盟立法进展、可用体外方法以及内分泌干扰所涉及生物机制的最新信息。
基于经合组织QSAR工具箱的计算机模拟方法用于预测雌激素受体α结合情况。经合组织TG 455试验和基于酵母的YES/YAS试验用于确定与人类雌激素（ERα）和雄激素受体的相互作用。
计算机模拟结果预测所筛选的邻苯二甲酸酯为非结合剂，双酚为ERα的极强结合剂。体外结果在若干情况下与计算机模拟预测不同，但主要在ERα的强结合剂方面表现出一致性。大多数物质在雌激素和雄激素受体上均表现出平行活性（激动剂 - 拮抗剂）。激动剂研究表明，强激动剂（如BPC、BPTMC）的10%活性有效浓度（EC10）为5.0E - 07。在酿酒酵母暴露于浓度起始为3.6E - 05 mol/l的BPFL、BPG、BPM、BPTMC 48小时后观察到细胞毒性。
我们的结果表明测试化合物存在多种平行相互作用，并强调确定一组合适的体外方法的重要性，该方法应包括更多受体且适合针对内分泌干扰所涉及的特定分子机制。激动剂研究结果表明存在激动剂潜力，并得到拮抗剂研究结果的支持，同时考虑到可能的多种相互作用。
