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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
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Univ Utrecht, Inst Risk Assessment Sci, Endocrine Toxicol Grp, NL-3508 TD Utrecht, Netherlands.
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Univ Utrecht, Inst Risk Assessment Sci, Endocrine Toxicol Grp, NL-3508 TD Utrecht, Netherlands.
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2014 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 27, no 7, 1120-1132 p.Article in journal (Refereed) Published
Abstract [en]

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,(REP20TCDD). REP20TCDD 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 CALLTX 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',4,4',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 REP20TCDD 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 REP20TCDD values for all WHO-TEF assigned compounds, quantitative structure activity 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 silica derived REP20TCDD 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.

Place, publisher, year, edition, pages
2014. Vol. 27, no 7, 1120-1132 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:umu:diva-92269DOI: 10.1021/tx5001255ISI: 000339462700005OAI: oai:DiVA.org:umu-92269DiVA: diva2:746315
Available from: 2014-09-12 Created: 2014-08-25 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
Open this publication in new window or tab >>Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are omnipresent and persistent environmental pollutants. In particular, 29 congeners are of special concern, and these are usually referred to as dioxin-like compounds (DLCs). In the European Union, the risks associated with DLCs in food products are estimated by a weighted sum of the DLCs’ concentrations. These weights, also called toxic equivalency factors (TEFs), compare the DLCs’ potencies to the most toxic congener, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (2378- TCDD). The toxicological effects of PCDD/Fs and PCBs are diverse, ranging from chloracne and immunological effects in humans to severe weight loss, thymic atrophy, hepatotoxicity, immunotoxicity, endocrine disruption, and carcinogenesis in rodents.

Here, the molecular structures of DLCs were used as the basis to study the congeneric differences in in vitro data from both human and rodent cell responses related to the aryl hydrocarbon receptor (AhR). Based on molecular orbital densities and partial charges, we developed new ways to describe DLCs, which proved to be useful in quantitative structure-activity relationship modeling. This thesis also provides a new approach, the calculation of the consensus toxicity factor (CTF), to condense information from a battery of screening tests. The current TEFs used to estimate the risk of DLCs in food are primarily based on in vivo information from rat and mouse experiments. Our CTFs, based on human cell responses, show clear differences compared to the current TEFs. For instance, the CTF of 23478-PeCDF is as high as the CTF for 2378-TCDD, and the CTF of PCB 126 is 30 times lower than the corresponding TEF. Both of these DLCs are common congeners in fish in the Baltic Sea. Due to the severe effects of DLCs and their impact on environmental and human health, it is crucial to determine if other compounds have similar effects. To find such compounds, we developed a virtual screening protocol and applied it to a set of 6,445 industrial chemicals. This protocol included a presumed 3D representation of AhR and the structural and chemical properties of known AhR ligands. This screening resulted in a priority list of 28 chemicals that we identified as potential AhR ligands.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2017. 66 p.
Keyword
dioxin-like compounds, multivariate analysis, toxic equivalency factor, quantitative structure-activity relationship, descriptors, virtual screening, in vitro, species variation, aryl hydrocarbon receptor
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-139487 (URN)978-91-7601-736-4 (ISBN)
Public defence
2017-10-19, KB.E3.01 (Lilla Hörsalen), KBC-huset, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2017-09-28 Created: 2017-09-14 Last updated: 2017-10-02Bibliographically approved

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