In Vitro and in Silico Derived Relative Effect Potencies of Ah-Receptor-Mediated Effects by PCDD/Fs and PCBs in Rat, Mouse, and Guinea Pig CALUX Cell Lines

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• 作者：Mehdi Ghorbanzadeh ; Karin I. van Ede ; Malin Larsson ; Majorie B. M. van Duursen ; Lorenz Poellinger ; Sandra L眉cke-Johansson ; Miroslav Machala ; Kate艡ina P臎n膷铆kov谩 ; Jan Vondr谩膷ek ; Martin van den Berg ; Michael S. Denison ; Tine Ringsted ; Patrik L. Andersson
• 刊名：Chemical Research in Toxicology
• 出版年：2014
• 出版时间：July 21, 2014
• 年：2014
• 卷：27
• 期：7
• 页码：1120-1132
• 全文大小：532K
• ISSN：1520-5010

文摘

For a better understanding of species-specific relative effect potencies (REPs), responses of dioxin-like compounds (DLCs) were assessed. REPs were calculated using chemical-activated luciferase gene expression assays (CALUX) derived from guinea pig, rat, and mouse cell lines. Almost all 20 congeners tested in the rodent cell lines were partial agonists and less efficacious than 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). For this reason, REPs were calculated for each congener using concentrations at which 20% of the maximal TCDD response was reached (REP_20TCDD). REP_20TCDD values obtained for PCDD/Fs were comparable with their toxic equivalency factors assigned by the World Health Organization (WHO-TEF), while those for PCBs were in general lower than the WHO-TEF values. Moreover, the guinea pig cell line was the most sensitive as indicated by the 20% effect concentrations of TCDD of 1.5, 5.6, and 11.0 pM for guinea pig, rat, and mouse cells, respectively. A similar response pattern was observed using multivariate statistical analysis between the three CALUX assays and the WHO-TEFs. The mouse assay showed minor deviation due to higher relative induction potential for 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,6,7,8-hexachlorodibenzofuran and lower for 1,2,3,4,6,7,8-heptachlorodibenzofuran and 3,3鈥?4,4鈥?5-pentachlorobiphenyl (PCB126). 2,3,7,8-Tetrachlorodibenzofuran was more than two times more potent in the mouse assay as compared with that of rat and guinea pig cells, while measured REP_20TCDD for PCB126 was lower in mouse cells (0.05) as compared with that of the guinea pig (0.2) and rat (0.07). In order to provide REP_20TCDD values for all WHO-TEF assigned compounds, quantitative structure鈥揳ctivity relationship (QSAR) models were developed. The QSAR models showed that specific electronic properties and molecular surface characteristics play important roles in the AhR-mediated response. In silico derived REP_20TCDD values were generally consistent with the WHO-TEFs with a few exceptions. The QSAR models indicated that, e.g., 1,2,3,7,8-pentachlorodibenzofuran and 1,2,3,7,8,9-hexachlorodibenzofuran were more potent than given by their assigned WHO-TEF values, and the non-ortho PCB 81 was predicted, based on the guinea-pig model, to be 1 order of magnitude above its WHO-TEF value. By combining in vitro and in silico approaches, REPs were established for all WHO-TEF assigned compounds (except OCDD), which will provide future guidance in testing AhR-mediated responses of DLCs and to increase our understanding of species variation in AhR-mediated effects.