Tributyltin (TBT), a common organotin environmental pollutant, has been widely used as a component of marine antifouling paints. We previously reported that exposure to TBT inhibits the expression and DNA binding of nuclear respiratory factor-1 (NRF-1) and causes neurotoxicity. In the present study, we focused on the epigenetic effects of TBT and investigated whether TBT decreases NRF-1 expression via epigenetic modifications in SH-SY5Y human neuroblastoma cells. First, we found that exposure to 300 nM TBT decreases NRF-1 expression. We examined epigenetic changes induced by TBT, and showed that TBT causes hypermethylation of the NRF-1 promoter region, increases the amount of methyl-CpG-binding protein 2 (MeCP2) bound to the NRF-1 promoter, and alters the expression of DNA methyltransferases and ten-eleven translocation (TET) demethylation enzymes. These results suggest that epigenetic changes play an important role in regulation of NRF-1 expression. Next, we investigated effect of NRF-1 expression decrease on cells, and TBT reduces mitochondrial membrane potential and overexpression of NRF-1 rescued this reduction in membrane potential. Thus, we suggested that NRF-1 is important for maintaining mitochondrial membrane potential. Our study indicates that TBT causes epigenetic changes such as hypermethylation, which increases recruitment of MeCP2 to the NRF-1 promoter and probably lead to decreased of NRF-1 expression and mitochondrial membrane potential. Therefore, this research provides new evidence of the epigenetic action caused by organotin.

中文翻译：

---

三丁基锡诱导表观遗传变化，并且降低核呼吸因子1的表达†

三丁基锡（TBT）是一种常见的有机锡环境污染物，已被广泛用作船舶防污漆的成分。我们以前曾报道过，接触TBT会抑制核呼吸因子1（NRF-1）的表达和DNA结合，并引起神经毒性。在本研究中，我们集中于TBT的表观遗传效应，并研究TBT是否通过以下途径降低NRF-1表达：SH-SY5Y人神经母细胞瘤细胞的表观遗传修饰。首先，我们发现暴露于300 nM TBT会降低NRF-1表达。我们检查了TBT诱导的表观遗传变化，发现TBT会导致NRF-1启动子区域甲基化，增加与NRF-1启动子结合的甲基-CpG结合蛋白2（MeCP2）的量，并改变DNA的表达甲基转移酶和十一十一易位（TET）去甲基化酶。这些结果表明表观遗传变化在调节NRF-1表达中起着重要作用。接下来，我们研究了NRF-1表达降低对细胞的影响，TBT降低了线粒体膜电位，NRF-1的过表达挽救了膜电位的这种降低。因此，我们认为NRF-1对于维持线粒体膜电位很重要。我们的研究表明，TBT会引起表观遗传变化，例如甲基化过高，从而增加MeCP2向NRF-1启动子的募集，并可能导致NRF-1表达和线粒体膜电位降低。因此，这项研究提供了由有机锡引起的表观遗传作用的新证据。