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

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.

Fachgebiet (DDC)

570 Biowissenschaften, Biologie

Schlagwörter

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

Zitieren

ISO 690

NYFFELER, Johanna, Petra KRANASTER, Xenia DOLDE, Anna-Katharina HOLZER, Vladimir PURVANOV, Ilona KINDINGER, Anna KERINS, David HIGTON, Daniel F. LEGLER, Marcel LEIST, 2018. A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells : new roles for connexins. In: Archives of toxicology. 2018, 92(3), pp. 1225-1247. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-2125-4

BibTex

@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 Kranaster, Petra and Dolde, Xenia and Holzer, Anna-Katharina and Purvanov, Vladimir and Kindinger, Ilona and Kerins, Anna and Higton, David and Legler, Daniel F. and Leist, Marcel}
}

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Universitätsbibliographie

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Begutachtet

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