在不良结果通路 (AOP) 网络中确定OTNE诱导的甲状腺影响
Etje Hulzebos1, Todd Stedeford2, Paul Sterchele3
1International Flavors & Fragrances Inc., Liebergerweg 72-98, 1221 JT, Hilversum, the Netherlands.
概括
八四甲基-纳夫他林-乙 (OTNE) 香水成分导致甲状腺作用继而影响肝脏. 新的方法方法证实受体激活是分子启动事件,而不是直接的甲状腺危害.
科学领域:
- 毒理学 毒理学 毒理学
- 内分泌学 在内分泌学.
- 计算毒理学计算毒理学
背景情况:
- 八-四甲基-纳乙烯-乙 (OTNE) 是一种合成香料成分,在毒理学研究中观察到它对甲状腺有影响.
- 这些效应表明,下丘脑-垂体-甲状腺轴的扰动,需要进一步研究底层机制.
研究的目的:
- 调查分子启动事件 (MIEs),关键事件 (KEs) 和OTNE诱导的甲状腺干扰的不良结果.
- 为OTNE使用新方法方法 (NAM) 构建一个不利结果途径 (AOP) 网络.
主要方法:
- 在人体,小鼠和老鼠受体 (CAR,FXR,LXRα,PPARs,PXR,AhR) 上使用了体外受体结合试验来探索MIEs.
- 应用了NAM来生成用于绘制OTNE诱导的甲状腺影响和识别MIE的数据.
主要成果:
- 在AOP网络中,CAR,FXR和PXR激活被确定为MIE.
- 甲状腺干扰被确定为次要效应,是肝脏效应的下游影响.
- 激活受体-连接体结合被确定为MIE,减少了进一步体内测试的需要.
结论:
- 由OTNE引起的甲状腺影响是肝脏影响的次要因素,不应该是评估人类健康危害的首要依据.
- NAM提供了一种可靠的方法来评估香料成分的毒性和绘制AOP.
- 该研究为OTNE建立了一个清晰的AOP网络,强调受体激活是关键的启动事件.
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