title: Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues.
abstract: Polycyclic aromatic hydrocarbons (PAHs) and their alkylated forms are important components of crude oil. Both groups of PAHs have been reported to cause dioxin-like responses, mediated by aryl hydrocarbon receptor (AhR). Thus, characterization of binding affinity to the AhR of unsubstituted or alkylated PAHs is important to understand the toxicological consequences of oil contamination on ecosystems. We investigated the potencies of major PAHs of crude oil, e.g., chrysene, phenanthrene and dibenzothiophene, and their alkylated forms (n=17) to upregulate expression of AhR-mediated processes by use of the H4IIE-luc transactivation bioassay. In addition, molecular descriptors of different AhR activation potencies among PAHs were investigated by use of computational molecular docking models. Based on responses of the H4IIE-luc in vitro assay, it was shown that potencies of PAHs were determined by alkylation in addition to the number and conformation of rings. Potencies of AhR-mediated processes were generally greater when a chrysene group was substituted, especially in 1-methyl-chrysene. Significant negative correlations were observed between the in vitro dioxin-like potency measured in H4IIE-luc cells and the binding distance estimated from the in silico modeling. The difference in relative potency for AhR activation observed among PAHs and their alkylated forms could be explained by differences among binding distances in the ligand binding domain of the AhR caused by alkylation. The docking model developed in the present study may have utility in predicting risks of environmental contaminants of which toxicities are mediated by AhR binding.
authors.affiliation: School of Public Health, Seoul National University, Seoul, South Korea.
authors.forename: Sangwoo
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, South Korea.
authors.forename: Woong-Hee
authors.initials: WH
authors.lastname: Shin
authors.affiliation: School of Earth and Environmental Sciences & Research Institute of Oceanography, Seoul National University, Seoul, South Korea.
authors.forename: Seongjin
authors.initials: S
authors.lastname: Hong
authors.affiliation: School of Public Health, Seoul National University, Seoul, South Korea.
authors.forename: Habyeong
authors.initials: H
authors.lastname: Kang
authors.affiliation: School of Public Health, Seoul National University, Seoul, South Korea.
authors.forename: Dawoon
authors.initials: D
authors.lastname: Jung
authors.affiliation: Oil and POPs Research Group, Korea Institute of Ocean Science and Technology (KIOST), Geoje, South Korea.
authors.forename: Un Hyuk
authors.initials: UH
authors.lastname: Yim
authors.affiliation: Oil and POPs Research Group, Korea Institute of Ocean Science and Technology (KIOST), Geoje, South Korea.
authors.forename: Won Joon
authors.initials: WJ
authors.lastname: Shim
authors.affiliation: School of Earth and Environmental Sciences & Research Institute of Oceanography, Seoul National University, Seoul, South Korea.
authors.forename: Jong Seong
authors.initials: JS
authors.lastname: Khim
authors.affiliation: Department of Chemistry, Seoul National University, Seoul, South Korea.
authors.forename: Chaok
authors.initials: C
authors.lastname: Seok
authors.affiliation: Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, SK, Canada; Department of Zoology, and Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA; Department of Biology & Chemistry and State Key Laboratory in Marine Pollution, City University of Hong Kong, Kowloon, Hong Kong Special Administrative Region.
authors.forename: John P
authors.initials: JP
authors.lastname: Giesy
authors.affiliation: School of Public Health, Seoul National University, Seoul, South Korea. Electronic address: kyungho@snu.ac.kr.
authors.forename: Kyungho
authors.initials: K
authors.lastname: Choi
mesh_terms: D000478:Alkylation; D001681:Biological Assay; D002460:Cell Line; D002911:Chrysenes / Q000633:toxicity*; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D062105:Molecular Docking Simulation; D010578:Petroleum; D010616:Phenanthrenes / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D013876:Thiophenes / Q000633:toxicity*
chemical_list: D002911:Chrysenes; D004785:Environmental Pollutants; D010578:Petroleum; D010616:Phenanthrenes; D018336:Receptors, Aryl Hydrocarbon; D013876:Thiophenes; C031180:chrysene; C031181:phenanthrene; C016366:dibenzothiophene
keywords: Alkylation; Aryl hydrocarbon receptor; Docking model; H4IIE-luc; In vitro; Polycyclic aromatic hydrocarbon