title: Activation of AhR-mediated toxicity pathway by emerging pollutants polychlorinated diphenyl sulfides.
abstract: Polychlorinated diphenyl sulfides (PCDPSs) are a group of environmental pollutants for which limited toxicological information is available. This study tested the hypothesis that PCDPSs could activate the mammalian aryl hydrocarbon receptor (AhR) mediated toxicity pathways. Eighteen PCDPSs were tested in the H4IIE-luc transactivation assay, with 13/18 causing concentration-dependent AhR activation. Potencies of several congeners were similar to those of mono-ortho substituted polychlorinated biphenyls. A RNA sequencing (RNA-seq)-based transcriptomic analysis was performed on H4IIE cells treated with two PCDPS congeners, 2,2',3,3',4,5,6-hepta-CDPS, and 2,4,4',5-tetra-CDPS. Results of RNA-seq revealed a remarkable modulation on a relatively short gene list by exposure to the tested concentrations of PCDPSs, among which, Cyp1 responded with the greatest fold up-regulation. Both the identities of the modulated transcripts and the associated pathways were consistent with targets and pathways known to be modulated by other types of AhR agonists and there was little evidence for significant off-target effects within the cellular context of the H4IIE bioassay. The results suggest AhR activation as a toxicologically relevant mode of action for PCDPSs suggests the utility of AhR-related toxicity pathways for predicting potential hazards associated with PCDPS exposure in mammals and potentially other vertebrates.
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Junjiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China. Electronic address: howard50003250@yahoo.com.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Pu
authors.initials: P
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Guanyong
authors.initials: G
authors.lastname: Su
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR 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, Kowloon Tong, Hong Kong, China.
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Zunyao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: United States Environmental Protection Agency, Mid-Continent Ecology Division, Duluth, MN, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Villeneuve
authors.affiliation: State Key Laboratory of Pollution Control & Resource Reuse, School of the Environment, Nanjing University, Nanjing, 210023, PR China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D001681:Biological Assay; D045744:Cell Line, Tumor; D004785:Environmental Pollutants / Q000378:metabolism / Q000633:toxicity*; D015386:Hazardous Substances / Q000378:metabolism / Q000633:toxicity*; D008156:Luciferases / Q000235:genetics; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000633:toxicity*; D012313:RNA / Q000235:genetics; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D013440:Sulfides / Q000378:metabolism / Q000633:toxicity*; D014162:Transfection
chemical_list: D004785:Environmental Pollutants; D015386:Hazardous Substances; D018336:Receptors, Aryl Hydrocarbon; D013440:Sulfides; D012313:RNA; C444009:diphenyl sulfide; D011078:Polychlorinated Biphenyls; D008156:Luciferases
keywords: Cyp1A; Ligand binding domain; Molecular initiating event; RNA-seq; Toxicogenomics; Xenobiotic metabolism