National Center for Environmental Assessment, Office of Research and Development (ORD), U.S. Environmental Protection Agency (EPA), Washington, DC, USA.
National Center for Computational Toxicology, ORD, U.S. EPA, Research Triangle Park, North Carolina, USA.
Environ Health Perspect. 2019 Sep;127(9):95001. doi: 10.1289/EHP5297. Epub 2019 Sep 5.
Extensive clinical and experimental research documents the potential for chemical disruption of thyroid hormone (TH) signaling through multiple molecular targets. Perturbation of TH signaling can lead to abnormal brain development, cognitive impairments, and other adverse outcomes in humans and wildlife. To increase chemical safety screening efficiency and reduce vertebrate animal testing, in vitro assays that identify chemical interactions with molecular targets of the thyroid system have been developed and implemented.
We present an adverse outcome pathway (AOP) network to link data derived from in vitro assays that measure chemical interactions with thyroid molecular targets to downstream events and adverse outcomes traditionally derived from in vivo testing. We examine the role of new in vitro technologies, in the context of the AOP network, in facilitating consideration of several important regulatory and biological challenges in characterizing chemicals that exert effects through a thyroid mechanism.
There is a substantial body of knowledge describing chemical effects on molecular and physiological regulation of TH signaling and associated adverse outcomes. Until recently, few alternative nonanimal assays were available to interrogate chemical effects on TH signaling. With the development of these new tools, screening large libraries of chemicals for interactions with molecular targets of the thyroid is now possible. Measuring early chemical interactions with targets in the thyroid pathway provides a means of linking adverse outcomes, which may be influenced by many biological processes, to a thyroid mechanism. However, the use of in vitro assays beyond chemical screening is complicated by continuing limits in our knowledge of TH signaling in important life stages and tissues, such as during fetal brain development. Nonetheless, the thyroid AOP network provides an ideal tool for defining causal linkages of a chemical exerting thyroid-dependent effects and identifying research needs to quantify these effects in support of regulatory decision making. https://doi.org/10.1289/EHP5297.
大量临床和实验研究证明，化学物质可以通过多种分子靶点干扰甲状腺激素（TH）信号。TH 信号的紊乱会导致人类和野生动物的大脑发育异常、认知障碍和其他不良后果。为了提高化学安全性筛选效率并减少脊椎动物动物测试，已经开发并实施了体外测定法，以识别与甲状腺系统分子靶标相互作用的化学物质。
我们提出了一个不良结局途径（AOP）网络，将从测量化学物质与甲状腺分子靶标相互作用的体外测定中获得的数据与传统上从体内测试中获得的下游事件和不良结局联系起来。我们研究了新的体外技术在 AOP 网络中的作用，以促进在表征通过甲状腺机制发挥作用的化学物质时考虑几个重要的监管和生物学挑战。
有大量知识描述了化学物质对 TH 信号的分子和生理调节的影响及其相关的不良结局。直到最近，还没有多少可供选择的非动物测定法来研究化学物质对 TH 信号的影响。随着这些新工具的发展，现在可以筛选大量化学物质文库，以研究它们与甲状腺分子靶标的相互作用。测量化学物质与甲状腺途径中靶标的早期相互作用提供了一种将可能受到许多生物学过程影响的不良结局与甲状腺机制联系起来的方法。然而，由于我们对重要生命阶段和组织（如胎儿大脑发育期间）的 TH 信号的了解仍存在局限性，因此超出化学筛选使用体外测定法变得复杂。尽管如此，甲状腺 AOP 网络提供了一个理想的工具，用于定义化学物质发挥甲状腺依赖性作用的因果关系，并确定量化这些作用以支持监管决策的研究需求。https://doi.org/10.1289/EHP5297.
