lncRNA在手性氟西汀诱导斑马鱼心律失常的立体选择性调控机制

Fluoxetine, as an antidepressant of selective serotonin reuptake inhibitor, has been continuously detected in aquatic environment in recent years. The trace levels of fluoxetine in water still have accumulative toxicity on aquatic organisms. Even worse, the chirality of fluoxetine makes the toxicity to aquatic ecosystem more complicated. In this study, chronic rac-/S-(+)-/ R-(-)- fluoxetine exposure at environmental levels were carried out to make sure the enantioselective accumulations and effects on cardiac rhythm in adult zebrafish (Danio rerio). The changes of the indicators of calcium cycling in heart were also investigated to explore the influence of calcium cycling on cardiac rhythm. Furthermore, the enantioselective expressions of lncRNAs were analyzed to find out the molecular biomarkers related to calcium cycling in exposed groups, and then to explore the enantioselective mechanism on arrhythmias in zebrafish after chiral fluoxetine exposure. The above information is helpful to clarify the toxicity of fluoxetine on the aquatic ecosystem at the enantioselective level, and provides more evidence for the prevention and control of chiral fluoxetine in water.

氟西汀，作为一线选择性5-羟色胺再摄取抑制剂类抗抑郁药，近年来在水体中不断被检出。虽氟西汀的检出为痕量水平，但可对水生生物产生累计毒性效应。氟西汀具有手性，使其对水生生物的毒性效应及作用机制更加复杂。本项目以斑马鱼为试验对象，通过开展长期环境浓度的氟西汀及异构体暴露试验，明确手性氟西汀在斑马鱼在斑马鱼体内的立体选择性蓄积转化行为及对斑马鱼心脏节律的立体选择性影响。通过测定心脏组织中Ca2+循环相关指标的变化及相关性分析，明确Ca2+循环对心脏节律的影响。在此基础上，运用高通量测序和生物信息学分析，鉴定与Ca2+循环相关的差异lncRNAs，通过预测机制，探究lncRNAs对Ca2+循环的调控机制，以期阐明手性氟西汀对斑马鱼心脏节律的立体选择性调控机制。项目的实施有助于从对映体水平上明确氟西汀对水生态系统的毒害作用，为水体中手性氟西汀的防控监管工作提供科学依据。

氟西汀，作为一线选择性5-羟色胺再摄取抑制剂类抗抑郁药，近年来在水体中不断被检出。虽氟西汀的检出为痕量水平，但可对水生生物产生累计毒性效应。氟西汀具有手性，使其对水生生物的毒性效应及作用机制更加复杂。本项目以斑马鱼为试验对象，通过开展长期环境浓度的氟西汀及异构体暴露试验发现氟西汀在斑马鱼体内可代谢为去甲氟西汀，并异构体之间未发生转化。手性氟西汀可对斑马鱼心脏节律、Ca2+循环造成立体选择性影响，其中S-氟西汀暴露尤为严重。运用高通量测序和生物信息学分析，分别在雄鱼及雌鱼体内筛选出lncRNAs (MSTRG.26600.1) /camk2a 和lncRNAs (MSTRG.46688.1) /camk2db靶标关系，解析了lncRNAs对Ca2+循环的调控机制，进而阐明了手性氟西汀对斑马鱼心脏节律的立体选择性调控机制。项目的实施有助于从对映体水平上明确氟西汀对水生态系统的毒害作用，为水体中手性氟西汀的防控监管工作提供科学依据。