PDF(Pubmed)
Abstract：
Organophosphate esters (OPEs) are widespread in various environmental media, and can disrupt thyroid endocrine signaling pathways. Mechanisms by which OPEs disrupt thyroid hormone (TH) signal transduction are not fully understood. Here, we present in vivo-in vitro-in silico evidence establishing OPEs as environmental THs competitively entering the brain to inhibit growth of zebrafish via multiple signaling pathways. OPEs can bind to transthyretin (TTR) and thyroxine-binding globulin, thereby affecting the transport of TH in the blood, and to the brain by TTR through the blood-brain barrier. When GH3 cells were exposed to OPEs, cell proliferation was significantly inhibited given that OPEs are competitive inhibitors of TH. Cresyl diphenyl phosphate was shown to be an effective antagonist of TH. Chronic exposure to OPEs significantly inhibited the growth of zebrafish by interfering with thyroperoxidase and thyroglobulin to inhibit TH synthesis. Based on comparisons of modulations of gene expression with the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases, signaling pathways related to thyroid endocrine functions, such as receptor-ligand binding and regulation of hormone levels, were identified as being affected by exposure to OPEs. Effects were also associated with the biosynthesis and metabolism of lipids, and neuroactive ligand-receptor interactions. These findings provide a comprehensive understanding of the mechanisms by which OPEs disrupt thyroid pathways in zebrafish.
摘要：
有机磷酸酯(OPEs)广泛存在于各种环境介质中,并能破坏甲状腺内分泌信号通路。OPEs破坏甲状腺激素（TH）信号转导的机制尚不完全清楚。这里,我们提供了体内-体外-计算机证据，将OPEs作为环境THs竞争性地进入大脑，通过多种信号通路抑制斑马鱼的生长。OPEs可以结合转甲状腺素蛋白（TTR）和甲状腺素结合球蛋白，从而影响血液中TH的运输，并通过血脑屏障通过TTR到达大脑。当GH3细胞暴露于OPEs时，鉴于OPEs是TH的竞争性抑制剂,细胞增殖被显著抑制.甲酚二苯基磷酸酯被证明是TH的有效拮抗剂。慢性暴露于OPEs通过干扰甲状腺过氧化物酶和甲状腺球蛋白抑制TH合成，显著抑制斑马鱼的生长。基于基因表达调控与基因本体论和京都百科全书的基因和基因组数据库的比较，与甲状腺内分泌功能相关的信号通路，如受体-配体结合和调节激素水平，被确定为受到暴露于OPEs的影响。影响还与脂质的生物合成和代谢有关，和神经活性配体-受体相互作用。这些发现为OPEs破坏斑马鱼甲状腺通路的机制提供了全面的理解。
