基于组学的污染物高通量毒理学筛查与风险评估

Omics-based high throughput toxicity screening and risk assessment of pollutants

从大量的环境污染物中筛查出具有高毒性、高风险的化学污染物是环境风险防控的前提和基础.有毒化学污染物经环境暴露进入生命体系后,可通过不同的分子靶标和生物学通路诱导有害健康结局.现有的高通量毒性筛查方法主要依赖少数且孤立的分子靶点,难以捕获致毒的关键生物学过程,无法确定化学污染物与疾病之间的直接关系.毒理基因组学利用组学技术所具有的全基因组覆盖、通量高、支持大数据分析等优势,实现了化学污染物高通量筛查和风险评估方法的革新.本文通过具体研究案例分析,从4个方面综述了毒理基因组学在化学污染物高通量毒理学筛查与风险评估方法学研究上的技术优势和最新进展.在分子事件上,毒理组学测试覆盖的分子靶点数目多,且靶点之间的关系可由通路连接.在生物学通路方面,单一组学、多组学联合以及有害结局路径从多生物学水平上为化学污染物筛查与健康风险评估提供机制信息.在人群疾病方面,功能基因组学为探究有毒化学污染物暴露下个体疾病风险和易感性的机制提供了新的手段.最后,针对复合污染,将组学技术与化学分析结合有助于精准地识别环境介质中构成生态与健康风险的关键化学物质.综上,未来基于组学的污染物高通量毒理学筛查技术的发展可有力支持传统和新污染物的精准环境风险评估.

Screening priority pollutants with high toxicity and risk potential from a large number of environmental chemical pollutants is the prerequisite for prevention and control of environmental risks. After entering the living system, toxic pollutants can induce adverse outcomes through a series of disturbed molecular targets and biological pathways. Existing high-throughput toxicity screening methods rely on few and isolated cellular or molecular endpoints, making it difficult to capture the key biological processes that cause toxicity and to determine the direct relationship between chemical pollutants and disease. Meanwhile, the awareness is increasing that we are exposed to a true cocktail of chemicals, among which only a fraction has been identified through analytical methods. Integrated bioanalytical approaches, such as effect-directed analysis and toxicity identification evaluation(TIE), have been used to identify risk drivers in complex mixture pollutants.However, it is still difficult to elucidate the molecular toxicological drivers of chemical stress in the environment.Toxicogenomics take advantage of genome-wide coverage, high throughput, and big data capacity that are associated with omics technologies to achieve technology innovation in screening and risk assessment of chemical pollutants. We reviewed the technical advantages and the recent progress of toxicogenomic methodology in high-throughput toxicological screening and risk assessment of chemical pollutants from four aspects with specific research cases. To identify the molecular events initiated by toxic pollutants, toxicogenomics could uncover a large number of molecular events and pathways potentially disturbed at the early development stage of toxicity. Dose-dependent transcriptomes for highthroughput chemical testing have been developed to quantitatively assess responses induced by chemical pollutants at the molecular level, which improve the sensitivity of identifying bioactivity by 1–3 orders of magnitude.To uncover the biological pathways of adverse health outcome by chemical pollutants, systemic toxicological assessment by omics strategies provide mechanistic information for chemical pollution screening and health risk assessment at multiple biological levels. Through biological pathway enrichment analysis, such as the gene ontology(GO) and kyoto encyclopedia of genes and genomes(KEGG) pathway, the molecular mechanistic information of toxicity could be captured. Moreover, multi-omics integration allows for multi-scale, comprehensive biological network analysis, which provide a systematic understanding of toxicity pathways or adverse outcome pathways(AOPs) to guide ecological and human health risk assessments.For human diseases diagnostics, functional genomics provide a new tool to explore mechanisms of individual disease risk and susceptibility under toxic pollutants exposure. Variations of individual susceptibility to toxicant-induced disease are largely due to genetic susceptibility across different populations. The direct relationship among pollutants, genes and adverse outcomes could be established by combining functional genomics and molecular epidemiological approaches.Finally, for risk management of complex mixture pollutants, it is important to assess the overall toxicity effects of the pool of pollutants and identify the key toxic pollutant. The combination of high-throughput bioassays and chemical analysis can be used to identify the highly bioactive fraction and to screen the key chemical pollutant that pose ecological and health risks. Recently, progresses have been made in integrating transcriptomic techniques with molecular toxicity identification and evaluation(mTIE) to assess the overall effects of mixtures and distinguish the key pollutants in inducing the corresponding biological responses. Particularly, dose-response transcriptome could be used to quantitatively evaluate the overall toxic effects and to guide the key toxicant identification by high mechanistic resolution.In summary, the development of omics-based high-throughput toxicity screening technologies will strongly support accurate environmental risk assessment of conventional and new pollutants in the future.