Fraunhofer Attract Eco'n'OMICs, Fraunhofer Institute for Molecular Biology and Applied Ecology, Schmallenberg, Germany; Department Evolutionary Ecology and Environmental Toxicology, Faculty Biological Sciences, Goethe University Frankfurt, Frankfurt, Germany.
Fraunhofer Attract Eco'n'OMICs, Fraunhofer Institute for Molecular Biology and Applied Ecology, Schmallenberg, Germany.
Sci Total Environ. 2021 Mar 15;760:143914. doi: 10.1016/j.scitotenv.2020.143914. Epub 2020 Dec 10.
Endocrine disruption (ED) can trigger far-reaching effects on environmental populations, justifying a refusal of market approval for chemicals with ED properties. For the hazard assessment of ED effects on the thyroid system, regulatory decisions mostly rely on amphibian studies. Here, we used transcriptomics and proteomics for identifying molecular signatures of interference with thyroid hormone signaling preceding physiological effects in zebrafish embryos. For this, we analyzed the thyroid hormone 3,3',5-triiodothyronine (T3) and the thyroid peroxidase inhibitor 6-propyl-2-thiouracil (6-PTU) as model substances for increased and repressed thyroid hormone signaling in a modified zebrafish embryo toxicity test. We identified consistent gene expression fingerprints for both modes-of-action (MoA) at sublethal test concentrations. T3 and 6-PTU both significantly target the expression of genes involved in muscle contraction and functioning in an opposing fashion, allowing for a mechanistic refinement of key event relationships in thyroid-related adverse outcome pathways in fish. Furthermore, our fingerprints identify biomarker candidates for thyroid disruption hazard screening approaches. Perspectively, our findings will promote the AOP-based development of in vitro assays for thyroidal ED assessment, which in the long term will contribute to a reduction of regulatory animal tests.
内分泌干扰（ED）可能对环境种群产生深远影响，这证明拒绝批准具有 ED 特性的化学品进入市场是合理的。为了对 ED 对甲状腺系统的危害进行评估，监管决策主要依赖于对两栖动物的研究。在这里，我们使用转录组学和蛋白质组学来识别在斑马鱼胚胎出现生理效应之前，干扰甲状腺激素信号的分子特征。为此，我们分析了甲状腺激素 3,3',5-三碘甲状腺原氨酸（T3）和甲状腺过氧化物酶抑制剂 6-丙基-2-硫代尿嘧啶（6-PTU），作为在改良的斑马鱼胚胎毒性试验中增强和抑制甲状腺激素信号的模型物质。我们在亚致死测试浓度下，为两种作用模式（MoA）确定了一致的基因表达特征。T3 和 6-PTU 都显著靶向参与肌肉收缩和功能的基因的表达，以相反的方式作用，这使得鱼类中与甲状腺相关的不良结局途径的关键事件关系的机制得到了细化。此外，我们的指纹还确定了用于甲状腺干扰危害筛选方法的生物标志物候选物。从长远来看，我们的研究结果将促进基于 AOP 的甲状腺 ED 评估的体外检测方法的发展，这将有助于减少监管动物试验。
