Archives of Toxicology

, Volume 92, Issue 3, pp 1225–1247 | Cite as

A structure–activity relationship linking non-planar PCBs to functional deficits of neural crest cells: new roles for connexins

  • Johanna Nyffeler
  • Petra Chovancova
  • Xenia Dolde
  • Anna-Katharina Holzer
  • Vladimir Purvanov
  • Ilona Kindinger
  • Anna Kerins
  • David Higton
  • Steve Silvester
  • Barbara M. A. van Vugt-Lussenburg
  • Enrico Glaab
  • Bart van der Burg
  • Richard Maclennan
  • Daniel F. Legler
  • Marcel Leist
Organ Toxicity and Mechanisms


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 < 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.


Cell migration Cell tracking Cytotoxicity High-content imaging Developmental toxicity Human stem cells 



Aryl hydrocarbon receptor


Activator protein 1


Androgen receptor


Constitutive androstane receptor


Circular MINC




Connexin43 plaques


Cytochalasin D


Dimethyl sulfoxide


Effective concentration


Epidermal growth factor


Estrogen receptor


Fetal bovine serum


Fibroblast growth factor


Gap junction


Gap junction intercellular communication


Human embryonic stem cell


Key event


Hydrophobicity (octanol–water distribution coefficient)


Molecular initiation event


Methyl-, tert-butyl-ether


Molecular weight


Neural crest cell


Peripheral blood-derived lymphocytes


Phosphate buffered saline


Polychlorinated biphenyl


Progesterone receptor


Pregnane X receptor


Retinoic acid


Ryanodine receptor


Structure–activity relationship


Thyroid hormone receptor


Vitamin D receptor



This work was supported by the Land BW, the Doerenkamp-Zbinden foundation, the DFG (RTG1331, KoRS-CB) and the European Project EU-ToxRisk. We are grateful to M. Kapitza, H. Leisner, K. Semperowitsch, M. Brüll, the staff of the University of Konstanz bioimaging center (BIC) and the flow cytometry center (FlowKon) for invaluable experimental support. EG acknowledges support by the Fonds Nationale de la Recherche (FNR) through the National Centre of Excellence in Research (NCER) on Parkinson’s disease (I1R-BIC-PFN-15NCER). Computational analyses presented in this paper were carried out in part using the HPC facilities of the University of Luxembourg (see

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

204_2017_2125_MOESM1_ESM.pdf (2.4 mb)
Supplementary material 1 (PDF 2464 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Johanna Nyffeler
    • 1
    • 2
  • Petra Chovancova
    • 1
    • 3
  • Xenia Dolde
    • 1
    • 3
  • Anna-Katharina Holzer
    • 1
  • Vladimir Purvanov
    • 4
  • Ilona Kindinger
    • 4
  • Anna Kerins
    • 5
  • David Higton
    • 5
  • Steve Silvester
    • 5
  • Barbara M. A. van Vugt-Lussenburg
    • 6
  • Enrico Glaab
    • 7
  • Bart van der Burg
    • 6
  • Richard Maclennan
    • 5
  • Daniel F. Legler
    • 2
    • 3
    • 4
  • Marcel Leist
    • 1
    • 2
    • 3
  1. 1.In vitro Toxicology and Biomedicine, Department Inaugurated by the Doerenkamp-Zbinden FoundationUniversity of KonstanzKonstanzGermany
  2. 2.Research Training Group RTG1331KonstanzGermany
  3. 3.Konstanz Research School Chemical Biology (KoRS-CB)KonstanzGermany
  4. 4.Biotechnology Institute Thurgau at the University of KonstanzKreuzlingenSwitzerland
  5. 5.Cyprotex DiscoveryCheshireUK
  6. 6.BioDetection Systems bvAmsterdamThe Netherlands
  7. 7.Luxembourg Centre for Systems Biomedicine (LCSB)University of LuxembourgEsch-sur-AlzetteLuxembourg

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