title: Classification and toxicity mechanisms of novel flame retardants (NFRs) based on whole genome expression profiling.
abstract: Recently some novel alternative flame retardants (NFRs), which have been widely applied to meet demands for mandated flame retardation of products, have been detected in various matrices of the environment. However, knowledge on toxic effects and associated molecular mechanisms of these chemicals was limited. Here, toxic mechanisms of action of six NFRs, bis (2-ethylhexyl) phosphate (BEHP), chlorendic acid (Het acid), 2,2-bis (bromomethyl)-1,3-propanediol (BMP), tris (2-butoxyethyl) phosphate (TBEP), triethyl phosphate (TEP), tributyl phosphate (TBP) were investigated by use of a library containing ∼1820 modified green fluorescent protein (GFP) expressing promoter reporter vectors constructed from Escherichia coli K12(E.coli). BEHP, Het acid, BMP, TBEP, TEP, TBP inhibited growth of E. coli with 4 h 10%-inhibition concentrations of 53.0-3102.3 μM. A total of 119, 44, 26, 131, 62, 103 genes out of 336 genes selected during preliminary screening were significantly altered with fold-changes greater than 1.5 by BEHP, Het acid, BMP, TBEP, TEP and TBP, respectively. GO analyses of responsive genes suggested that RNA and primary metabolism process were involved in molecular mechanisms of toxicity. Chemical clustering based on expression of 62 multi-responsive genes showed that BEHP, TBP and TBEP were grouped together, which is consistent with similarity of their chemical structures, especially for BEHP and TBP. Clustering by molecular descriptors and molecular activity by use of the multivariate classification system ToxCast was consistent with that by profiles of multi-responsive genes. The results of this study demonstrated the utility of the E. coli, whole-cell assay for determining mechanisms of toxic action of chemicals.
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse & School of the Environment, Nanjing University, Nanjing, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Guan
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse & School of the Environment, Nanjing University, Nanjing, China.
authors.forename: Guanyong
authors.initials: G
authors.lastname: Su
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse & School of the Environment, Nanjing University, Nanjing, China; Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Department of Zoology, and Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; School of Biological Sciences, University of Hong Kong, Hong Kong, China; Department of Biology, Hong Kong Baptist University, Hong Kong, China.
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.affiliation: State Key Laboratory of Pollution Control and Resource Reuse & School of the Environment, Nanjing University, Nanjing, China. Electronic address: zhangxw@nju.edu.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D004785:Environmental Pollutants / Q000145:classification / Q000633:toxicity*; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics; D005411:Flame Retardants / Q000145:classification / Q000633:toxicity*; D005798:Genes, Bacterial / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D059467:Transcriptome
chemical_list: D004785:Environmental Pollutants; D005411:Flame Retardants
keywords: Clustering; E coli; GFP reporter; Genomics; NFRs; Toxic mechanism