@article{Nyffeler2018-03struc-40884,
  year={2018},
  doi={10.1007/s00204-017-2125-4},
  title={A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells : new roles for connexins},
  number={3},
  volume={92},
  issn={0340-5761},
  journal={Archives of toxicology},
  pages={1225--1247},
  author={Nyffeler, Johanna and Chovancova, Petra and Dolde, Xenia and Holzer, Anna-Katharina and Purvanov, Vladimir and Kindinger, Ilona and Kerins, Anna and Higton, David and Legler, Daniel and Leist, Marcel}
}

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    <dc:contributor>Higton, David</dc:contributor>
    <dc:creator>Nyffeler, Johanna</dc:creator>
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    <dc:creator>Kindinger, Ilona</dc:creator>
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    <dcterms:title>A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells : new roles for connexins</dcterms:title>
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    <dc:contributor>Kerins, Anna</dc:contributor>
    <dc:contributor>Nyffeler, Johanna</dc:contributor>
    <dc:creator>Dolde, Xenia</dc:creator>
    <dcterms:abstract xml:lang="eng">Migration of neural crest cells (NCC) is a fundamental developmental process, and test methods to identify interfering toxicants have been developed. By examining cell function endpoints, as in the 'migration-inhibition of NCC (cMINC)' assay, a large number of toxicity mechanisms and protein targets can be covered. However, the key events that lead to the adverse effects of a given chemical or group of related compounds are hard to elucidate. To address this issue, we explored here, whether the establishment of two overlapping structure-activity relationships (SAR)-linking chemical structure on the one hand to a phenotypic test outcome, and on the other hand to a mechanistic endpoint-was useful as strategy to identify relevant toxicity mechanisms. For this purpose, we chose polychlorinated biphenyls (PCB) as a large group of related, but still toxicologically and physicochemically diverse structures. We obtained concentration-dependent data for 26 PCBs in the cMINC assay. Moreover, the test chemicals were evaluated by a new high-content imaging method for their effect on cellular re-distribution of connexin43 and for their capacity to inhibit gap junctions. Non-planar PCBs inhibited NCC migration. The potency (1-10 µM) correlated with the number of ortho-chlorine substituents; non-ortho-chloro (planar) PCBs were non-toxic. The toxicity to NCC partially correlated with gap junction inhibition, while it fully correlated (p &lt; 0.0004) with connexin43 cellular re-distribution. Thus, our double-SAR strategy revealed a mechanistic step tightly linked to NCC toxicity of PCBs. Connexin43 patterns in NCC may be explored as a new endpoint relevant to developmental toxicity screening.</dcterms:abstract>
    <dc:contributor>Holzer, Anna-Katharina</dc:contributor>
    <dc:creator>Chovancova, Petra</dc:creator>
    <dc:creator>Kerins, Anna</dc:creator>
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    <dc:creator>Legler, Daniel</dc:creator>
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    <dc:creator>Leist, Marcel</dc:creator>
    <dc:creator>Purvanov, Vladimir</dc:creator>
    <dc:contributor>Dolde, Xenia</dc:contributor>
    <dc:rights>terms-of-use</dc:rights>
    <dc:creator>Higton, David</dc:creator>
    <dc:creator>Holzer, Anna-Katharina</dc:creator>
    <dcterms:issued>2018-03</dcterms:issued>
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    <dc:contributor>Leist, Marcel</dc:contributor>
    <dc:contributor>Kindinger, Ilona</dc:contributor>
    <dc:contributor>Chovancova, Petra</dc:contributor>
    <dc:contributor>Legler, Daniel</dc:contributor>
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