溴氰菊酯干扰斑马鱼多巴胺信号通路协同诱导生殖内分泌毒性的分子机制

Environmental organisms might interfered by environmental contaminants via a variety of molecular mechanisms. The pyrethroid pesticides are neurotoxic substance, which received more and more attention due to its widely application and the potential risks to environmental organisms and human beings. Deltamethrin is a typical pyrethroid pesticide，our previous studies have shown its neurotoxicity and reproductive disrupting effect on zebrafish. While the key target which was interfered with deltamethrin in nervous system and the effects on the reproductive system and the molecular mechanisms remain unclear. Based on mentioned above, we examined sexual hormones and neurotransmitters and the genes expression involved in synthesis and metabolism of dopamine signaling pathway after exposed to deltamethrin. Moreover, the key location where deltamethrin effects on, and the relationship between the nervous and the reproductive system were studied with the help of nervous system signaling pathway activator/inhibitor and knockdown, in order to better explain the molecular mechanism of deltamethrin disrupting effect on the dopamine signaling pathway and further co-inducing reproductive endocrine. The results of our study reveal the mechanism of environmental endocrine disruption of pyrethroids and further elucidate its environmental risks to aquatic ecosystems and potential health effects.

环境污染物可能通过多种分子作用机制对环境生物产生干扰作用。拟除虫菊酯类杀虫剂属于神经毒剂，因其广泛使用造成环境生物和人类潜在危害而备受关注。溴氰菊酯是典型的拟除虫菊酯类农药，申请人前期研究表明溴氰菊酯对斑马鱼同时具有神经毒性和生殖干扰作用，但干扰神经系统的关键环节、对生殖系统的影响与分子机制仍然不明。在此基础上,本研究拟采用斑马鱼为对象，分析鱼体内性激素和神经递质在溴氰菊酯曝露前后的变化，以及参与多巴胺信号通路合成、代谢相关酶基因的变化。进一步结合应用神经信号通路激活剂/抑制剂、基因沉默技术等，探讨溴氰菊酯诱导下神经系统与生殖系统的互作关系以及对神经信号的主要干扰环节，以期更好地解释溴氰菊酯影响多巴胺信号通路并协同诱导生殖内分泌干扰的分子机制。研究结果为揭示环境内分泌干扰的作用机制，全面评价拟除虫菊酯的环境健康风险提供理论依据。

溴氰菊酯是典型的拟除虫菊酯类农药，因其广泛使用造成环境生物潜在危害而备受关注，但是该药物对非靶标生物毒性效应的机制仍不明确。项目以斑马鱼为研究对象，探究了溴氰菊酯对神经系统和生殖系统的影响及互作机制。研究发现，溴氰菊酯通过干扰斑马鱼下丘脑-垂体-性腺轴（HPG轴），诱导斑马鱼体内雌二醇含量升高，从而表现出类雌激素效应。另一方面，溴氰菊酯对斑马鱼产生了神经毒性，造成神经递质含量减少、运动游动能力下降、社交行为异常等效应。结合特异性激动剂与抑制剂联合曝露分析，发现溴氰菊酯可能主要作用于酪氨酸氢化酶，引起多巴胺含量减少，造成斑马鱼行为异常，从而协同诱导了生殖内分泌干扰效应。研究进一步揭示了溴氰菊酯环境内分泌干扰的作用机制，为拟除虫菊酯类农药环境危害提供研究思路，也为我国全面评价拟除虫菊酯的环境健康风险提供分子毒理学数据支撑。