College of Life Science, Taizhou University, Taizhou, Zhejiang, 318000, China.
Key Laboratory of Microbial Technology for Industrial Pollution Control of Zhejiang Province, College of Environment, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, China.
Environ Pollut. 2019 Jun;249:362-371. doi: 10.1016/j.envpol.2019.03.038. Epub 2019 Mar 15.
Fipronil, a broad-spectrum chiral insecticide, has been documented to induce significant neurotoxicity to nontarget aquatic species; however, whether its neurotoxicity behaves enantioselectively and what molecular mechanisms correspond to the neurotoxicity remain unanswered. To date, few investigations have focused on the genomic mechanisms responsible for the enantioselective toxicity of chiral pesticides. The epigenetic modifications, especially DNA methylation, caused by the pesticides are also blind spot of the research works. Video tracking showed that R-fipronil exhibited more intense neurotoxicity, as well as the induction of more severe anxiety-like behavior, such as boosted swimming speed and dysregulated photoperiodic locomotion, to embryonic and larval zebrafish compared with S-fipronil. The MeDIP-Seq analysis, combined with Gene Ontology and KEGG, revealed that R-fipronil disrupted five signaling pathways (MAPK, Calcium signaling, Neuroactive ligand-receptor interaction, Purine metabolism, and Endocytosis) to a greater extent than S-fipronil through the hypermethylation of several important neuro-related genes, whereas no significant alterations of global DNA methylation were observed on the two enantiomers. To summarize, our data indicated that the fipronil-conducted enantioselective neurotoxicity likely applied its enantioselectivity by the dysregulation of DNA methylation. Our study also provided novel epigenetic insights into the study of enantioselective biological effects and the relevant underlying mechanisms of chiral insecticide.
氟虫腈是一种广谱手性杀虫剂，已被证实对非靶标水生生物具有显著的神经毒性；然而，其神经毒性是否表现出对映体选择性，以及与神经毒性相对应的分子机制仍未得到解答。迄今为止，很少有研究关注手性农药对映体选择性毒性的基因组机制。农药引起的表观遗传修饰，尤其是 DNA 甲基化，也是研究工作的盲点。视频跟踪显示，与 S-氟虫腈相比，R-氟虫腈对胚胎和幼鱼斑马鱼表现出更强的神经毒性，以及更严重的焦虑样行为的诱导，如游泳速度加快和光周期运动失调。MeDIP-Seq 分析结合基因本体论和 KEGG 揭示，R-氟虫腈通过几个重要神经相关基因的过度甲基化，比 S-氟虫腈更大程度地破坏了五个信号通路（MAPK、钙信号、神经活性配体-受体相互作用、嘌呤代谢和内吞作用），而两种对映体的全基因组 DNA 甲基化没有明显变化。总之，我们的数据表明，氟虫腈引起的对映体选择性神经毒性可能通过 DNA 甲基化的失调来发挥其对映体选择性。我们的研究还为手性杀虫剂对映体选择性生物效应及其相关潜在机制的研究提供了新的表观遗传见解。
