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Computational methods for analyzing dioxin-like compounds and identifying potential aryl hydrocarbon receptor ligands: multivariate studies based on human and rodent in vitro data
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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 [en]
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: urn:nbn:se:umu:diva-139487ISBN: 978-91-7601-736-4 (print)OAI: oai:DiVA.org:umu-139487DiVA: diva2:1141251
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
List of papers
1. On the use of electronic descriptors for QSAR modelling of PCDDs, PCDFs and dioxin-like PCBs£:
Open this publication in new window or tab >>On the use of electronic descriptors for QSAR modelling of PCDDs, PCDFs and dioxin-like PCBs£:
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2013 (English)In: SAR and QSAR in environmental research (Print), ISSN 1062-936X, E-ISSN 1029-046X, Vol. 24, no 6, 461-479 p.Article in journal (Refereed) Published
Abstract [en]

The electronic properties of 29 polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls that have been included in the toxic equivalency factor system have been investigated and used to derive quantum mechanical (QM) chemical descriptors for QSAR modelling. Their utility in this context was investigated alongside descriptors based on ultraviolet absorption data and traditional 2D descriptors including log Kow, polarizability, molecular surface properties, van der Waals volume and selected connectivity indices. The QM descriptors were calculated using the semi-empirical AM1 method and the density functional theory method B3-LYP/6-31G(∗∗). Atom-specific and molecular quantum chemical descriptors were calculated to compare the electronic properties of dioxin-like compounds regardless of their chemical class, with particular emphasis on the lateral positions. Multivariate analysis revealed differences between the chemical classes in terms of their electronic properties and also highlighted differences between congeners. The results obtained demonstrated the importance of considering molecular orbital energies, but also indicated that the ratios of the coefficients of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) at the lateral carbons were important. In addition, the digitalized UV spectra contained chemical information that provided crucial insights into dioxin-like activity.

Place, publisher, year, edition, pages
Taylor & Francis Group, 2013
Keyword
Dioxins, ultraviolet, electronic descriptors, density functional theory, semi-empirical, QSAR, toxic equivalency factor
National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-71652 (URN)10.1080/1062936X.2013.791719 (DOI)000320184100003 ()23724952 (PubMedID)
Note

Special issue: 15th International Workshop on Quantitative Structure-Activity Relationships in Environmental and Health Sciences (QSAR2012). 

Available from: 2013-06-04 Created: 2013-06-04 Last updated: 2017-09-14Bibliographically approved
2. 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
Open this publication in new window or tab >>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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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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-92269 (URN)10.1021/tx5001255 (DOI)000339462700005 ()
Available from: 2014-09-12 Created: 2014-08-25 Last updated: 2017-09-14Bibliographically approved
3. Consensus Toxicity Factors for Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Combining in Silico Models and, Extensive in Vitro Screening of AhR-Mediated Effects in Human and Rodent Cells
Open this publication in new window or tab >>Consensus Toxicity Factors for Polychlorinated Dibenzo-p-dioxins, Dibenzofurans, and Biphenyls Combining in Silico Models and, Extensive in Vitro Screening of AhR-Mediated Effects in Human and Rodent Cells
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2015 (English)In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 28, no 4, 641-650 p.Article in journal (Refereed) Published
Abstract [en]

Consensus toxicity factors (CTFs) were developed as a novel approach to establish toxicity factors for risk assessment of dioxin-like compounds (DLCs). Eighteen polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs), and biphenyls (PCBs) with assigned World Health Organization toxic equivalency factors (WHO-TEFs) and two additional PCBs were screened in 17 human and rodent bioassays to assess their induction of aryl hydrocarbon receptor-related responses. For each bioassay and compound, relative effect potency values (REPs) compared to 2,3,7,8-tetrachlorodibenzo-p-dioxin were calculated and analyzed. The responses in the human and rodent cell bioassays generally differed. Most notably, the human cell models responded only weakly to PCBs, with 3,3',4,4',5-pentachlorobiphenyl (PCB126) being the only PCB that frequently evoked sufficiently strong responses in human cells to permit us to calculate REP values. Calculated REPs for PCB126 were more than 30 times lower than the WHO-TEF value for PCB126. CTFs were calculated using score and loading vectors from a principal component analysis to establish the ranking of the compounds and, by rescaling, also to provide numerical differences between the different congeners corresponding to the TEF scheme. The CTFs were based on rat and human bioassay data and indicated a significant deviation for PCBs but also for certain PCDD/Fs from the WHO-TEF values. The human CTFs for 2,3,4,7,8-pentachlorodibenzofuran, 1,2,3,4,7,8-hexachlorodibenzofuran, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, and 1,2,3,4,7,8,9-heptachlorodibenzofuran were up to 10 times greater than their WHO-TEF values. Quantitative structure-activity relationship models were used to predict CTFs for untested WHO-TEF compounds, suggesting that the WHO-TEF value for 1,2,3,7,8-pentachlorodibenzofuran could be underestimated by an order of magnitude for both human and rodent models. Our results indicate that the CTF approach provides a powerful tool for condensing data from batteries of screening tests using compounds with similar mechanisms of action, which can be used to improve risk assessment of DLCs.

National Category
Pharmacology and Toxicology Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-106369 (URN)10.1021/tx500434j (DOI)000353429700011 ()25654323 (PubMedID)
Available from: 2015-07-15 Created: 2015-07-14 Last updated: 2017-09-14Bibliographically approved
4. Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals
Open this publication in new window or tab >>Identification of potential aryl hydrocarbon receptor ligands by virtual screening of industrial chemicals
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have developed a virtual screening procedure to identify potential ligands to the aryl hydrocarbon receptor (AhR) among a set of industrial chemicals. AhR is a key target for dioxin-like compounds, which is related to these compounds’ potential to induce cancer and a wide range of endocrine and immune system related effects. The virtual screening procedure included an initial filtration aiming at identifying chemicals with structural similarities to 66 known AhR binders, followed by three enrichment methods run in parallel. These include two ligand-based methods (structural fingerprints and nearest neighbor analysis) and one structure-based method using an AhR homology model. A set of 6,445 commonly used industrial chemicals was processed, and each step identified unique potential ligands. Seven compounds were identified by all three enrichment methods, and these compounds included known activators and suppressors of AhR. Only approximately 0.7% (41 compounds) of the studied industrial compounds was identified as potential AhR ligands and among these, 28 compounds have to our knowledge not been tested for AhR-mediated effects or have been screened with low purity. We suggest assessment of AhR-related activities of these compounds and in particular 2-chlorotrityl chloride, 3-p-hydroxyanilino-carbazole, and 3-(2-chloro-4-nitrophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:umu:diva-139486 (URN)
Available from: 2017-09-14 Created: 2017-09-14 Last updated: 2017-09-14

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