2,2'-二硫二吡啶通过甲状腺干扰效应导致褐牙鲆变态延迟的分子机制研究

Our recent study shows that 2,2’-dipyridyldisulfide, one of the main degradation products of antifouling biocides metal pyrithiones, delays metamorphosis of oliver flounder (Paralichthys olivaceus) by thyroid disruption. However, the underlying molecular mechanisms are still unknown. This project plans to firstly determine the molecular initiating event by studying the interactions between 2,2’-dipyridyldisulfide and oliver flounder thyroid hormone receptors. We speculate that the competitive binding between thyroid hormones and 2,2’-dipyridyldisulfide to thyroid hormone receptors might lead to a series of key events at the molecular and cellular levels: a) thyroid hormone levels may be decreased by disruption of Drosha-miRNA-let 7d-iodothyroninedeiodinas mRNA pathway; b) thyroid hormone function may be resisted by interactions between 2,2’-dipyridyldisulfide-thyroid hormone receptor complex and nuclear receptor corepressor/coactivator; c) mRNA and protein profiles of genes positively regulated by thyroid hormones/thyroid hormone receptors may be down-regulated, finally leading to the delay of oliver flounder metamorphosis. The above-mentioned hypotheses will be inspected by theoretical arithmetic, in vivo and in vitro test, aiming to illuminate the molecular targets and action mechanisms of 2,2’-dipyridyldisulfide. The results will provide scientific basis for environmental management of antifouling biocides.

2,2'-二硫二吡啶是防污涂料杀生剂金属吡啶硫酮的主要降解产物，可通过甲状腺干扰效应导致褐牙鲆变态延迟，但其作用的分子机制尚不清楚。本项目首先研究2,2'-二硫二吡啶与甲状腺激素受体的相互作用，明确2,2'-二硫二吡啶的分子起始事件。推测与甲状腺激素竞争性结合受体会引发一系列分子关键事件和细胞应答事件：Drosha-miRNA-let 7d-脱碘酶mRNA通路受到干扰，导致甲状腺激素水平降低；2,2'-二硫二吡啶-甲状腺激素受体复合体与共抑制因子、共激活因子发生相互作用，导致甲状腺激素功能受拮抗；随后，甲状腺激素/甲状腺激素受体通路正向调控基因mRNA水平及蛋白含量下降，最终导致褐牙鲆变态延迟。本项目将理论计算、体内试验与体外实验相结合，对上述推测进行逐步检验，拟从分子水平揭示2,2'-二硫二吡啶的作用靶点与作用机制，为防污涂料杀生剂的环境管理提供科学依据。

2,2'-二硫二吡啶是防污涂料杀生剂金属吡啶硫酮的主要降解产物。本项目首先研究了2,2'-二硫二吡啶对褐牙鲆的甲状腺干扰效应，结果表明2,2'-二硫二吡啶通过甲状腺拮抗效应导致褐牙鲆变态延迟。本项目进一步从受体介导途径、非受体介导途径研究2,2´-二硫二吡啶通过甲状腺干扰效应诱导褐牙鲆变态延迟的分子机制与分子靶点。结果表明：2,2'-二硫二吡啶既能够通过受体介导途径作为拮抗剂与甲状腺激素受体β结合，干扰甲状腺激素行使其正常功能；2,2'-二硫二吡啶又能够通过非受体介导途径(miRNA-mRNA相互作用)，对褐牙鲆甲状腺轴上调控甲状腺激素合成、转化、代谢和发挥生物学作用的位点产生影响。本项目将理论计算、体内试验与体外实验相结合，从分子水平揭示了2,2'-二硫二吡啶的甲状腺干扰效应、作用靶点与作用机制，为防污涂料杀生剂的环境管理提供科学依据。