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Non-dioxin-like PCBs inhibit [3H]WIN-35,428 binding to dopamine active transporter:  a structure activity relationship study
Umeå University, Faculty of Science and Technology, Department of Chemistry.
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2013 (English)In: Naunyn-Schmiedeberg's Archives of Pharmacology, ISSN 0028-1298, E-ISSN 1432-1912Article in journal (Other academic) Submitted
Place, publisher, year, edition, pages
2013.
National Category
Other Chemistry Topics
Research subject
Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-50610OAI: oai:DiVA.org:umu-50610DiVA: diva2:465834
Available from: 2011-12-15 Created: 2011-12-15 Last updated: 2017-12-08Bibliographically approved
In thesis
1. In silico tools in risk assessment: of industrial chemicals in general and non-dioxin-like PCBs in particular
Open this publication in new window or tab >>In silico tools in risk assessment: of industrial chemicals in general and non-dioxin-like PCBs in particular
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Industrial chemicals in European Union produced or imported in volumes above 1 tonne annually, necessitate a registration within REACH. A common problem, concerning these chemicals, is deficient information and lack of data for assessing the hazards posed to human health and the environment. Animal studies for the type of toxicological information needed are both expensive and time consuming, and to that an ethical aspect is added. Alternative methods to animal testing are thereby requested. REACH have called for an increased use of

in silico tools for non-testing data as structure-activity relationships (SARs), quantitative structure-activity relationships (QSARs), and read-across. The main objective of the studies underlying this thesis is related to explore and refine the use of in silico tools in a risk assessment context of industrial chemicals. In particular, try to relate properties of the molecular structure to the toxic effect of the chemical substance, by using principles and methods of computational chemistry. The initial study was a survey of all industrial chemicals; the Industrial chemical map was created. A part of this map was identified including chemicals of potential concern. Secondly, the environmental pollutants, polychlorinated biphenyls (PCBs) were examined and in particular the non-dioxin-like PCBs (NDL-PCBs). A set of 20 NDL-PCBs was selected to represent the 178 PCB congeners with three to seven chlorine substituents. The selection procedure was a combined process including statistical molecular design for a representative selection and expert judgements to be able to include congeners of specific interest. The 20 selected congeners were tested in vitro in as much as 17 different assays. The data from the screening process was turned into interpretable toxicity profiles with multivariate methods, used for investigation of potential classes of NDL-PCBs. It was shown that NDL-PCBs cannot be treated as one group of substances with similar mechanisms of action. Two groups of congeners were identified. A group including in general lower chlorinated congeners with a higher degree of ortho substitution showed a higher potency in more assays (including all neurotoxic assays). A second group included abundant congeners with a similar toxic profile that might contribute to a common toxic burden. To investigate the structure-activity pattern of PCBs effect on DAT in rat striatal synaptosomes, ten additional congeners were selected and tested in vitro. NDL-PCBs were shown to be potent inhibitors of DAT binding. The congeners with highest DAT inhibiting potency were tetra- and penta-chlorinated with 2-3 chlorine atoms in ortho-position. The model was not able to distinguish the congeners with activities in the lower μM range, which could be explained by a relatively unspecific response for the lower ortho chlorinated PCBs.

Abstract [sv]

Den europeiska kemikalielagstiftningen REACH har fastställt att kemikalier som produceras eller importeras i en mängd över 1 ton per år, måste registreras och riskbedömmas. En uppskattad siffra är att detta gäller för 30 000 kemikalier. Problemet är dock att data och information ofta är otillräcklig för en riskbedömning. Till stor del har djurförsök använts för effektdata, men djurförsök är både kostsamt och tidskrävande, dessutom kommer den etiska aspekten in. REACH har därför efterfrågat en undersökning av möjligheten att använda in silico verktyg för att bidra med efterfrågad data och information. In silico har en ungefärlig betydelse av i datorn, och innebär beräkningsmodeller och metoder som används för att få information om kemikaliers egenskaper och toxicitet. Avhandlingens syfte är att utforska möjligheten och förfina användningen av in silico verktyg för att skapa information för riskbedömning av industrikemikalier. Avhandlingen beskriver kvantitativa modeller framtagna med kemometriska metoder för att prediktera, dvs förutsäga specifika kemikaliers toxiska effekt.

I den första studien (I) undersöktes 56 072 organiska industrikemikalier. Med multivariata metoder skapades en karta över industrikemikalierna som beskrev dess kemiska och fysikaliska egenskaper. Kartan användes för jämförelser med kända och potentiella miljöfarliga kemikalier. De mest kända miljöföroreningarna visade sig ha liknande principal egenskaper och grupperade i kartan. Genom att specialstudera den delen av kartan skulle man kunna identifiera fler potentiellt farliga kemiska substanser. I studie två till fyra (II-IV) specialstuderades miljögiftet PCB. Tjugo PCBs valdes ut så att de strukturellt och fysiokemiskt representerade de 178 PCB kongenerna med tre till sju klorsubstituenter. Den toxikologiska effekten hos dessa 20 PCBs undersöktes i 17 olika in vitro assays. De toxikologiska profilerna för de 20 testade kongenerna fastställdes, dvs vilka som har liknande skadliga effekter och vilka som skiljer sig åt. De toxicologiska profilerna användes för klassificering av PCBs. Kvantitativa modeller utvecklades för prediktioner, dvs att förutbestämma effekter hos ännu icke testade PCBs, och för att få ytterligare kunskap om strukturella egenskaper som ger icke önskvärda effekter i människa och natur. Information som kan användas vid en framtida riskbedömning av icke-dioxinlika PCBs. Den sista studien (IV) är en struktur-aktivitets studie som undersöker de icke-dioxinlika PCBernas hämmande effekt av signalsubstansen dopamin i hjärnan.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 62 p.
Keyword
Chemometrics, industrial chemicals, in silico tools, molecular descriptors, non-dioxin-like PCBs, partial least-squares (PLS), principal component analysis (PCA), quantitative structure-activity relationship (QSAR), REACH, risk assessment (RA), statistical molecular design, structure-activity relationship (SAR)
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:umu:diva-50609 (URN)978-91-7459-342-6 (ISBN)
Public defence
2012-01-16, KBC-huset, KB3B1, Umeå universitet, Umeå, 13:00 (English)
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Supervisors
Available from: 2011-12-23 Created: 2011-12-15 Last updated: 2011-12-15Bibliographically approved

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