功能基因组学在环境化学品毒性机制研究中的应用

Applications of Functional Genomics in Uncovering the Toxicity Mechanisms of Environmental Chemicals

认识化学品的毒性机制是开展化学品健康风险评估的基础。掌握化学品有害效应的遗传易感性机制是开展精准的健康风险评估的前提。传统的毒理基因组学主要分析化学品暴露诱导的组学表达图谱,不能建立生物学表型与特定基因/通路表达的直接关联。功能基因组学通过敲除或者敲降全基因组或者特定的基因集,建立基因-化学品毒性的直接关联,进而研究化学品致毒的过程和机制,同时可以提供与化学品暴露的遗传易感性相关的分子响应信息。本论文综述了功能基因组学技术的原理及其主要发展,介绍了酵母、鸡DT40细胞和RNA干扰等功能基因组学测试方法的优缺点。同时,详述了CRISPR功能基因组学的原理和特点,以及其在化学品毒性机制研究中的应用,展望了联合应用分子流行病学和CRISPR功能基因组学,开展化学品有害效应的易感性机制研究。

Understanding the biological mechanisms of toxic effects is essential for human health risk assessments of environmental chemicals.Significant uncertainties in risk assessment were caused by the different susceptibility of human individuals due to genetic variation.Knowledge of the molecular mechanisms underlying the genetic susceptibility to adverse effects of environmental chemicals could enhance the assessment of health risk.Conventional toxicogenomics approaches,such as transcriptomics,have been proved to facilitate the discovery of potential toxicological mechanisms of environmental chemicals by measuring the differentially expressed genes.However,these approaches failed to identify the direct connections between expressions of genes/pathways and toxicological phenotypes.Functional genomics screens could identify the direct links between specific genes and adverse effects of environmental chemicals by systematic knockout or knockdown of genes or gene sets in a genome-scale.Therefore,functional genomics screens can reveal the mechanisms of action of toxic chemicals and uncover key genes which are involved in the variated susceptibility to chemicals exposure.This review presented the recent advances in functional toxicogenomic of environmental chemicals,and the strength and limitations of some conventional functional genomics,including yeast,chicken DT40 cells,haploid mammalian cells and RNA interference.Furthermore,this review clarified the mechanisms and characteristics of CRISPR-Cas9 functional genomic screen of environmental chemicals.Finally,it is prospected that the biological mechanisms underlying the genetic susceptibility to adverse effects of environmental chemicals could be uncovered by combined using of CRISPR screen and molecular epidemiology analysis.