拟除虫菊酯是新一代仿生杀虫剂，在农业、居家灭虫中使用广泛。流行病学研究显示，人体内存在的微量拟除虫菊酯可能与儿童的智力发育相关。位于内质网控制细胞内Ca2+释放的利阿诺定受体（RyR）能够调节神经元的生长发育。我们提出拟除虫菊酯通过增强RyR的功能从而影响神经元钙振荡及其下游信号路径进而介导神经发育毒性的假说。本课题将以联苯菊酯和溴氰菊酯为代表研究环境暴露剂量拟除虫菊酯（<1mg/kg）对神经系统发育的影响，并探讨不同发育阶段神经系统对拟除虫菊酯的敏感性，证实环境暴露剂量拟除虫菊酯的神经发育毒性；利用生物学、药理学、电生理学的方法在分子及细胞水平研究联苯菊酯和溴氰菊酯对RyR功能的影响及其对神经突生长/突触形成的调控作用；最后探讨携带功能增强型RyR的基因插入鼠对联苯菊酯和溴氰菊酯的敏感性，阐明RyR引起的钙振荡紊乱是其神经发育毒性的新靶点及新机制，为安全使用拟除虫菊酯提供科学依据。

Pyrethroids are a novel class of synthetic insecticides which are heavily used in the agriculture and household for insecticidal purpose. Studies have demonstrated the existence of pyrethroids and metabolites in human breast milk, blood as well as urine samples. Moreover, recent epidemiological studies suggested that low concentrations of pyrethroids may be associated with increased risk of Attention-Deficit Hyperactive Disorder (ADHD) and/or Mental Retardation. Previous researches were focusing on the acute neurotoxicity of high dose pyrethroids whose primary targets are voltage-gated sodium channels at the concentration ranges of (1 μM-100 μM). Our recent study has demonstrated that low, environmental relevant concentration of bifenthrin (10 nM) is sufficient to alter the developmental trajectory of neurite outgrowth which is independent of Na+ channel modification. Our data showed that ryanodine receptor (RyR) may represent a novel target for pyrethroid interaction. The overarching hypothesis is that low, environmental relevant concentrations of pyrethroids can affect the neuronal development through RyR gain-of function induced spontaneous Ca2+ oscillations dysregulation. In this project, we will use bifenthrin and deltamethrin as type I and II pyrthroids representatives to investigate the developmental neurotoxicity of low doses (environmental exposure relevant) of pyrethroids especially to investigate the susceptibility of neurons at different developmental stages to pyrethoids exposure. We will investigate the influence of bifenthrin and deltamethrin on spontaneous Ca2+ oscillations, neurite outgrowth, synapse formation, and how bifenthrin and deltamethrin affect neurite outgrowth, synapse formation. We will also utilize biological, pharmacological and electrophysiological approaches to investigate the physical binding of bifenthrin and deltamethrin to ryanodine receptor (RyR) and how can they modulate RyR function. Finally, we will investigate the sensitivity of mice carrying either wild type RyR or gain-of-function RyR (T4826I-RyR) to bifenthrin and deltamethrin exposure to demonstrate whether RyR is the molecular target of bifenthrin and deltamethrin-induced developmental neurotoxicity. Our goal is to demonstrate whether the evidences that pyrethroids affect neuron development from epidemiological studies can be extended to animal models. We will also demonstrate the sensitivity of neurons at distinct developmental stages to pyrethroids exposure. Molecular targets and signaling pathways profiling will help us to understand how environmental relevant concentrations of pyrethroids affect the neuron development. Our study can provide scientific evidences for how to use pyrethroids safely.