多因素多水平的实验设计方法和高速细胞定量分析技术，使我们探索“WHO列出引起重大公共卫生的4种重金属联合暴露致早期健康损害效应研究”成为可能。我们通过L_49（7^4）、L_16（2^4）正交设计及U8（8^5）均匀设计等，经过近5百次的实验研究，基本确定了具有实际意义的上述重金属联合作用剂量，奠定了3种以上重金属之间交互作用毒性研究的基础。借此，本项目拟抓住常见神经精神疾病共同典型病理特征“神经元树突棘异常”为切入点，围绕“低剂量重金属联合暴露认知障碍-神经元树突棘异常-LIMK1/SSH1磷酸化修饰Cofilin调控树突棘动态变化”科学假说首次开展研究。拟采用激光共聚焦、膜片钳、细胞定量分析以及siRNA等分子生物学和神经生物学技术，试图从多水平、多层面、多维度，研究回答本项目所提出的关键科学问题，为开展多种重金属污染的健康危险度评价，保护和促进人群健康、防治神经精神疾病提供科学依据。

Multi-factor and multi-level experiments design and high-speed cell quantitative analysis, they make it possible to challenge facing the difficulties in studying that the heavy metals (Pb, Cd, As and Hg) of major public health concern listed by the WHO cause early health adverse effects in co-exposure. We have identified the interaction dose between heavy metals after we did nearly 500 hundreds of experiments by the L_49（7^4）、L_16（2^4）orthogonal design and U8（8^5） uniform design. It starts the studies on the joint toxicity of more than three kinds of heavy metals. In this project, we will grasp the common typical pathological features of neuropsychiatric disease “abnormal neuron dendritic spines” as breakthrough point, and for first time carry out the research around the scientific hypothesis of “Low level heavy metals co-exposure to cognitive impairment--abnormal neuron dendritic spines--regulation and control of dendritic spines dynamic change by LIMK1 / SSH1 modification of phosphorylated cofilin”. Applying Confocal Laser Scanning Microscope, Patch Clamp Amplifier System, Flow Cytometry, morphologic quantitative analysis, as well as cellular and molecular techniques of siRNA, and so on, we will try to elucidate and answer the key scientific problems put forward in this project from multiple levels, multi-azimuth and multi-dimensional. Our study will provide a scientific basis for further to their health risk assessment, to protect and improve public health, prevention and treatment of neuropsychiatric disease.