Analysis of mixture toxicity for dual combinations of heavy metals and herbicides using toxicogenomic approach

使用毒物基因组学方法分析重金属和除草剂双重组合的混合物毒性

• 批准号: 20360235
• 负责人: OKABE Satoshi
• 金额: $ 11.9万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20360235/
• 关键词: 複合毒性評価; DNAマイクロアレイ; 重金属; 農薬; HepG2細胞

The single chemical cytotoxicity showed that heavy metals and silver nanoparticles had high toxicity, respectively, but herbicides had relatively low toxicity. In contrast, the dual combinations cytotoxicity showed that the combination of silver nanoparticles and heavy metals tended to be much more toxic than silver nanoparticles or heavy metals alone, excluding the combination of silver nanoparticles and chromium (AgNPs-Cr). However, the toxicity of the combination of herbicides and heavy metals was similar to that of herbicides exposure alone. From cytotoxicity results, 5 μM of silver nanoparticles, 2.6 μM of cadmium, 7μM of arsenic and 1.1 μM of chromium were used for the DNA microarray analyses to further elucidate the mechanisms of mixture toxicity. The treatments with AgNPs-Cd (70% cytoviability), AgNPs-As (100% cytoviability) and AgNPs-Cr (140% cytoviability) altered the expression levels of 107 genes, 500 genes and 196 genes, respectively. There was a significant difference between 2 combinations (AgNPs-Cr and AgNPs-Cd) and silver nanoparticles alone on DNA replication genes such as MCM2, MCM5, MCM6, and GINS2 that are important for DNA replication fork. Furthermore, FABP1 gene was down regulated 41-fold by AgNPs-As combination. FABPs play an important role in the transport of lipids to specific compartments in the cell. In conclusion, toxicogenomic approach could elucidate synergistic toxicity by AgNPs and heavy metals, which clearly demonstrate the possible use of DNA microarray analysis for evaluation of mixture toxicity.

单个化学细胞毒性表明，重金属和银纳米颗粒的毒性分别高，但除草剂的毒性相对较低。相比之下，双重组合细胞毒性表明，银纳米颗粒和重金属的组合往往比单独的银纳米颗粒或重金属更具毒性，不包括银纳米颗粒和铬（Agnps-CR）的组合。然而，除草剂和重金属的组合的毒性与仅除草剂暴露的毒性相似。从细胞毒性结果中，使用了5μM银纳米颗粒，2.6μM镉，7μM砷和1.1μM的铬用于DNA微阵列分析，以进一步阐明混合毒性的机制。用AGNPS-CD（70％的细胞化度），AGNPS-AS（100％细胞溶解）和AGNPS-CR（140％细胞溶解）处理的处理分别改变了107个基因，500个基因和196个基因的表达水平。在DNA复制基因（例如MCM2，MCM5，MCM6和GINS2）上，两种组合（AGNPS-CR和AGNPS-CD）与单独的银纳米颗粒之间存在显着差异，这对于DNA复制叉很重要。此外，Fabp1基因通过AGNPS-AS组合下调了41倍。 Fabps在脂质向细胞中特定隔室的运输中起重要作用。总之，毒性方法可以阐明AGNP和重金属的协同毒性，这清楚地证明了可能使用DNA微阵列分析来评估混合毒性。

项目成果

Comparison of Gene Expression Profiles in HepG2 Cells Exposed to Arsenic, Cadmium, Nickel, and Three Model Carcinogens for Investigating the Mechanisms of Metal Carcinogenesis

• DOI: 10.1002/em.20438
• 发表时间: 2009-01-01
• 期刊: ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
• 影响因子: 2.8
• 作者: Kawata, Koji;Shimazaki, Ryuhei;Okabe, Satoshi
• 通讯作者: Okabe, Satoshi

In Vitro Toxicity of Silver Nanoparticles at Noncytotoxic Doses to HepG2 Human Hepatoma Cells

• DOI: 10.1021/es900754q
• 发表时间: 2009-08-01
• 期刊: ENVIRONMENTAL SCIENCE & TECHNOLOGY
• 影响因子: 11.4
• 作者: Kawata, Koji;Osawa, Masato;Okabe, Satoshi
• 通讯作者: Okabe, Satoshi

ヒトDNAマイクロアレイを用いた濃度依存的ヒ素毒性の評価

使用人类 DNA 微阵列评估浓度依赖性砷毒性

• 发表时间: 2009
• 作者: 多賀哲平;川田耕司;岡部聡
• 通讯作者: 岡部聡