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

Abstract

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.

Keywords

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

Abbreviations

AhR

Aryl hydrocarbon receptor

AP1

Activator protein 1

AR

Androgen receptor

CAR

Constitutive androstane receptor

cMINC

Circular MINC

Cx43

Connexin43

Cx43pq

Connexin43 plaques

CytoD

Cytochalasin D

DMSO

Dimethyl sulfoxide

EC

Effective concentration

EGF

Epidermal growth factor

ER

Estrogen receptor

FBS

Fetal bovine serum

FGF

Fibroblast growth factor

GJ

Gap junction

GJIC

Gap junction intercellular communication

hESC

Human embryonic stem cell

KE

Key event

logP

Hydrophobicity (octanol–water distribution coefficient)

MIE

Molecular initiation event

MTBE

Methyl-, tert-butyl-ether

MW

Molecular weight

NCC

Neural crest cell

PBLs

Peripheral blood-derived lymphocytes

PBS

Phosphate buffered saline

PCB

Polychlorinated biphenyl

PR

Progesterone receptor

PXR

Pregnane X receptor

RA

Retinoic acid

RyR

Ryanodine receptor

SAR

Structure–activity relationship

THR

Thyroid hormone receptor

VDR

Vitamin D receptor

Notes

Acknowledgements

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 http://hpc.uni.lu).

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)

References

  1. Al-Salman F, Plant N (2012) Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner. Toxicol Appl Pharmacol 263:7–13.  https://doi.org/10.1016/j.taap.2012.05.016 CrossRefPubMedGoogle Scholar
  2. Arvan P, Zhao X, Ramos-Castaneda J, Chang A (2002) Secretory pathway quality control operating in Golgi, plasmalemmal, and endosomal systems. Traffic 3:771–780CrossRefPubMedGoogle Scholar
  3. Aschner M et al. (2017) Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. ALTEX 34:49–74  https://doi.org/10.14573/altex.1604201 PubMedGoogle Scholar
  4. Bagamasbad P, Denver RJ (2011) Mechanisms and significance of nuclear receptor auto- and cross-regulation. Gen Comp Endocrinol 170:3–17.  https://doi.org/10.1016/j.ygcen.2010.03.013 CrossRefPubMedGoogle Scholar
  5. Bager Y, Kenne K, Krutovskikh V, Mesnil M, Traub O, Wärngàrd L (1994) Alteration in expression of gap junction proteins in rat liver after treatment with the tumour promoter 3,4,5,3′,4′-pentachiorobiphenyl. Carcinogenesis 15:2439–2443.  https://doi.org/10.1093/carcin/15.11.2439 CrossRefPubMedGoogle Scholar
  6. Bager Y, Kato Y, Kenne K, Warngard L (1997a) The ability to alter the gap junction protein expression outside GST-P positive foci in liver of rats was associated to the tumour promotion potency of different polychlorinated biphenyls. Chem Biol Interact 103:199–212CrossRefPubMedGoogle Scholar
  7. Bager Y, Lindebro MC, Martel P, Chaumontet C, Warngard L (1997b) Altered function, localization and phosphorylation of gap junctions in rat liver epithelial, IAR 20, cells after treatment with PCBs or TCDD. Environ Toxicol Pharmacol 3:257–266CrossRefPubMedGoogle Scholar
  8. Bates DC, Sin WC, Aftab Q, Naus CC (2007) Connexin43 enhances glioma invasion by a mechanism involving the carboxy terminus. Glia 55:1554–1564.  https://doi.org/10.1002/glia.20569 CrossRefPubMedGoogle Scholar
  9. Behrens J, Kameritsch P, Wallner S, Pohl U, Pogoda K (2010) The carboxyl tail of Cx43 augments p38 mediated cell migration in a gap junction-independent manner. Eur J Cell Biol 89:828–838.  https://doi.org/10.1016/j.ejcb.2010.06.003 CrossRefPubMedGoogle Scholar
  10. Boot MJ, Gittenberger-de Groot AC, Poelmann RE, Gourdie RG (2006) Connexin43 levels are increased in mouse neural crest cells exposed to homocysteine. Birth Defects Res A Clin Mol Teratol 76:133–137.  https://doi.org/10.1002/bdra.20220 CrossRefPubMedGoogle Scholar
  11. Brevini TA, Vassena R, Paffoni A, Francisci C, Fascio U, Gandolfi F (2004) Exposure of pig oocytes to PCBs during in vitro maturation: effects on developmental competence, cytoplasmic remodelling and communications with cumulus cells. Eur J Histochem 48:347–356PubMedGoogle Scholar
  12. Choi W, Eum SY, Lee YW, Hennig B, Robertson LW, Toborek M (2003) PCB 104-induced proinflammatory reactions in human vascular endothelial cells: relationship to cancer metastasis and atherogenesis. Toxicol Sci 75:47–56.  https://doi.org/10.1093/toxsci/kfg149 CrossRefPubMedGoogle Scholar
  13. Cina C, Maass K, Theis M, Willecke K, Bechberger JF, Naus CC (2009) Involvement of the cytoplasmic C-terminal domain of connexin43 in neuronal migration. J Neurosci 29:2009–2021.  https://doi.org/10.1523/JNEUROSCI.5025-08.2009 CrossRefPubMedGoogle Scholar
  14. Crespin S, Bechberger J, Mesnil M, Naus CC, Sin WC (2010) The carboxy-terminal tail of connexin43 gap junction protein is sufficient to mediate cytoskeleton changes in human glioma cells. J Cell Biochem 110:589–597.  https://doi.org/10.1002/jcb.22554 CrossRefPubMedGoogle Scholar
  15. Daneshian M, Kamp H, Hengstler J, Leist M, van de Water B (2016) Highlight report: launch of a large integrated European in vitro toxicology project: EU-ToxRisk. Arch Toxicol 90:1021–1024.  https://doi.org/10.1007/s00204-016-1698-7 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Davy A, Bush JO, Soriano P (2006) Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol 4:e315.  https://doi.org/10.1371/journal.pbio.0040315 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Dreser N et al (2015) Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling. Neurotoxicology 50:56–70.  https://doi.org/10.1016/j.neuro.2015.07.008 CrossRefPubMedGoogle Scholar
  18. Du J, Meledeo MA, Wang Z, Khanna HS, Paruchuri VD, Yarema KJ (2009) Metabolic glycoengineering: sialic acid and beyond. Glycobiology 19:1382–1401.  https://doi.org/10.1093/glycob/cwp115 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Elias LA, Wang DD, Kriegstein AR (2007) Gap junction adhesion is necessary for radial migration in the neocortex. Nature 448:901–907.  https://doi.org/10.1038/nature06063 CrossRefPubMedGoogle Scholar
  20. Ferris SP, Kodali VK, Kaufman RJ (2014) Glycoprotein folding and quality-control mechanisms in protein-folding diseases. Dis Model Mech 7:331–341.  https://doi.org/10.1242/dmm.014589 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Fiorini C et al (2008) Accelerated internalization of junctional membrane proteins (connexin 43, N-cadherin and ZO-1) within endocytic vacuoles: an early event of DDT carcinogenicity. Biochim Biophys Acta 1778:56–67.  https://doi.org/10.1016/j.bbamem.2007.08.032 CrossRefPubMedGoogle Scholar
  22. Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C (2011) Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. PLoS One 6:e26379.  https://doi.org/10.1371/journal.pone.0026379 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Fritsch EB, Pessah IN (2013) Structure-activity relationship of non-coplanar polychlorinated biphenyls toward skeletal muscle ryanodine receptors in rainbow trout (Oncorhynchus mykiss). Aquat Toxicol 140–141:204–212.  https://doi.org/10.1016/j.aquatox.2013.06.003 CrossRefPubMedGoogle Scholar
  24. Fushiki S, Perez Velazquez JL, Zhang L, Bechberger JF, Carlen PL, Naus CC (2003) Changes in neuronal migration in neocortex of connexin43 null mutant mice. J Neuropathol Exp Neurol 62:304–314CrossRefPubMedGoogle Scholar
  25. Garrison PM, Tullis K, Aarts JM, Brouwer A, Giesy JP, Denison MS (1996) Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. Fundam Appl Toxicol 30:194–203CrossRefPubMedGoogle Scholar
  26. Giepmans BN, Moolenaar WH (1998) The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein. Curr Biol 8:931–934CrossRefPubMedGoogle Scholar
  27. Groothuis FA, Heringa MB, Nicol B, Hermens JL, Blaauboer BJ, Kramer NI (2015) Dose metric considerations in in vitro assays to improve quantitative in vitro-in vivo dose extrapolations. Toxicology 332:30–40.  https://doi.org/10.1016/j.tox.2013.08.012 CrossRefPubMedGoogle Scholar
  28. Guan X, Ruch RJ (1996) Gap junction endocytosis and lysosomal degradation of connexin43-P2 in WB-F344 rat liver epithelial cells treated with DDT lindane. Carcinogenesis 17:1791–1798CrossRefPubMedGoogle Scholar
  29. Guo Y, Martinez-Williams C, Rannels DE (2003) Gap junction-microtubule associations in rat alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 285:L1213–L1221.  https://doi.org/10.1152/ajplung.00066.2003 CrossRefPubMedGoogle Scholar
  30. Hamers T et al (2011) In vitro toxicity profiling of ultrapure non-dioxin-like polychlorinated biphenyl congeners and their relative toxic contribution to PCB mixtures in humans. Toxicol Sci 121:88–100.  https://doi.org/10.1093/toxsci/kfr043 CrossRefPubMedGoogle Scholar
  31. Hauser MA, Legler DF (2016) Common and biased signaling pathways of the chemokine receptor CCR7 elicited by its ligands CCL19 and CCL21 in leukocytes. J Leukoc Biol 99:869–882.  https://doi.org/10.1189/jlb.2MR0815-380R CrossRefPubMedGoogle Scholar
  32. Hauser MA et al (2016) Inflammation-induced CCR7 oligomers form scaffolds to integrate distinct signaling pathways for efficient cell. Migr Immunity 44:59–72.  https://doi.org/10.1016/j.immuni.2015.12.010 CrossRefGoogle Scholar
  33. Hemming H, Warngard L, Ahlborg UG (1991) Inhibition of dye transfer in rat liver WB cell culture by polychlorinated biphenyls. Pharmacol Toxicol 69:416–420CrossRefPubMedGoogle Scholar
  34. Henry TR, DeVito MJ (2003) Non-dioxin-like PCBs: effects and consideration in ecological risk assessment. Ecological Risk Assessment Support Center, Office of Research and Development, US Environmental Protection AgencyGoogle Scholar
  35. Hestermann EV, Stegeman JJ, Hahn ME (2000) Relative contributions of affinity and intrinsic efficacy to aryl hydrocarbon receptor ligand potency. Toxicol Appl Pharmacol 168:160–172.  https://doi.org/10.1006/taap.2000.9026 CrossRefPubMedGoogle Scholar
  36. Huang GY, Cooper ES, Waldo K, Kirby ML, Gilula NB, Lo CW (1998) Gap junction-mediated cell-cell communication modulates mouse neural crest migration. J Cell Biol 143:1725–1734CrossRefPubMedPubMedCentralGoogle Scholar
  37. Hunter AW, Barker RJ, Zhu C, Gourdie RG (2005) Zonula occludens-1 alters connexin43 gap junction size and organization by influencing channel accretion. Mol Biol Cell 16:5686–5698.  https://doi.org/10.1091/mbc.E05-08-0737 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Jacobson JL, Jacobson SW (1996) Intellectual impairment in children exposed to polychlorinated biphenyls in utero. N Engl J Med 335:783–789.  https://doi.org/10.1056/NEJM199609123351104 CrossRefPubMedGoogle Scholar
  39. Jacobson JL, Jacobson SW, Humphrey HE (1990) Effects of exposure to PCBs and related compounds on growth and activity in children. Neurotoxicol Teratol 12:319–326CrossRefPubMedGoogle Scholar
  40. Jensen AA (1989) Background levels in humans. In: Kimbrough RD, Jensen AA (eds) Halogenated biphenyls, terphenyls, naphthalenes, dibenzodioxins and related products. Elsevier Science Publishers, Amsterdam, The Netherlands, pp 345–364Google Scholar
  41. Kang KS, Wilson MR, Hayashi T, Chang CC, Trosko JE (1996) Inhibition of gap junctional intercellular communication in normal human breast epithelial cells after treatment with pesticides, PCBs, and PBBs, alone or in mixtures. Environ Health Perspect 104:192–200PubMedPubMedCentralGoogle Scholar
  42. Kang K et al (2015) Tissue-based metabolic labeling of polysialic acids in living primary hippocampal neurons. Proc Natl Acad Sci USA 112:E241–E248.  https://doi.org/10.1073/pnas.1419683112 CrossRefPubMedPubMedCentralGoogle Scholar
  43. Kato Y, Kenne K, Haraguchi K, Masuda Y, Kimura R, Warngard L (1998) Inhibition of cell-cell communication by methylsulfonyl metabolites of polychlorinated biphenyl congeners in rat liver epithelial IAR 20 cells. Arch Toxicol 72:178–182CrossRefPubMedGoogle Scholar
  44. Kodavanti PR (2005) Neurotoxicity of persistent organic pollutants: possible mode(s) of action and further considerations. Dose Response 3:273–305.  https://doi.org/10.2203/dose-response.003.03.002 CrossRefGoogle Scholar
  45. Krug AK, Balmer NV, Matt F, Schonenberger F, Merhof D, Leist M (2013) Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87:2215–2231.  https://doi.org/10.1007/s00204-013-1072-y CrossRefPubMedGoogle Scholar
  46. Laird DW (2005) Connexin phosphorylation as a regulatory event linked to gap junction internalization and degradation. Biochim Biophys Acta 1711:172–182.  https://doi.org/10.1016/j.bbamem.2004.09.009 CrossRefPubMedGoogle Scholar
  47. Laird DW, Castillo M, Kasprzak L (1995) Gap junction turnover, intracellular trafficking, and phosphorylation of connexin43 in brefeldin A-treated rat mammary tumor cells. J Cell Biol 131:1193–1203CrossRefPubMedGoogle Scholar
  48. Langlois S, Cowan KN, Shao Q, Cowan BJ, Laird DW (2010) The tumor-suppressive function of Connexin43 in keratinocytes is mediated in part via interaction with caveolin-1. Cancer Res 70:4222–4232.  https://doi.org/10.1158/0008-5472.CAN-09-3281 CrossRefPubMedGoogle Scholar
  49. Lecanda F, Warlow PM, Sheikh S, Furlan F, Steinberg TH, Civitelli R (2000) Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction. J Cell Biol 151:931–944CrossRefPubMedPubMedCentralGoogle Scholar
  50. Leist M, Efremova L, Karreman C (2010) Food for thought … considerations and guidelines for basic test method descriptions in toxicology. ALTEX 27:309–317CrossRefPubMedGoogle Scholar
  51. Leist M et al. (2017) Adverse outcome pathways: opportunities, limitations and open questions Arch Toxicol.  https://doi.org/10.1007/s00204-017-2045-3
  52. Lemcke H, Nittel ML, Weiss DG, Kuznetsov SA (2013) Neuronal differentiation requires a biphasic modulation of gap junctional intercellular communication caused by dynamic changes of connexin43 expression. Eur J Neurosci 38:2218–2228.  https://doi.org/10.1111/ejn.12219 CrossRefPubMedGoogle Scholar
  53. Li J, Habbes HW, Eiberger J, Willecke K, Dermietzel R, Meier C (2007) Analysis of connexin expression during mouse Schwann cell development identifies connexin29 as a novel marker for the transition of neural crest to precursor cells. Glia 55:93–103.  https://doi.org/10.1002/glia.20427 CrossRefPubMedGoogle Scholar
  54. Machala M, Blaha L, Vondracek J, Trosko JE, Scott J, Upham BL (2003) Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: inhibitory potencies and screening for potential mode(s) of action. Toxicol Sci 76:102–111.  https://doi.org/10.1093/toxsci/kfg209 CrossRefPubMedGoogle Scholar
  55. Mariussen E, Andersson PL, Tysklind M, Fonnum F (2001) Effect of polychlorinated biphenyls on the uptake of dopamine into rat brain synaptic vesicles: a structure-activity study. Toxicol Appl Pharmacol 175:176–183.  https://doi.org/10.1006/taap.2001.9231 CrossRefPubMedGoogle Scholar
  56. Matesic DF, Rupp HL, Bonney WJ, Ruch RJ, Trosko JE (1994) Changes in gap-junction permeability, phosphorylation, and number mediated by phorbol ester and non-phorbol-ester tumor promoters in rat liver epithelial cells. Mol Carcinog 10:226–236CrossRefPubMedGoogle Scholar
  57. Niederwieser A, Spate AK, Nguyen LD, Jungst C, Reutter W, Wittmann V (2013) Two-color glycan labeling of live cells by a combination of Diels-Alder and click chemistry. Angew Chem Int Ed Engl 52:4265–4268.  https://doi.org/10.1002/anie.201208991 CrossRefPubMedGoogle Scholar
  58. Nyffeler J et al. (2017a) Combination of multiple neural crest migration assays to identify environmental toxicants from a proof-of-concept chemical library. Arch Toxicol.  https://doi.org/10.1007/s00204-017-1977-y PubMedCentralGoogle Scholar
  59. Nyffeler J, Karreman C, Leisner H, Kim YJ, Lee G, Waldmann T, Leist M (2017b) Design of a high-throughput human neural crest cell migration assay to indicate potential developmental toxicants. ALTEX 34:75–94.  https://doi.org/10.14573/altex.1605031 PubMedGoogle Scholar
  60. Pallocca G et al. (2017) Impairment of human neural crest cell migration by prolonged exposure to interferon-beta. Arch Toxicol.  https://doi.org/10.1007/s00204-017-1966-1 PubMedCentralGoogle Scholar
  61. Pau G, Fuchs F, Sklyar O, Boutros M, Huber W (2010) EBImage–an R package for image processing with applications to cellular phenotypes. Bioinformatics 26:979–981.  https://doi.org/10.1093/bioinformatics/btq046 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Pessah IN et al (2006) Structure-activity relationship for noncoplanar polychlorinated biphenyl congeners toward the ryanodine receptor-Ca2 + channel complex type 1 (RyR1). Chem Res Toxicol 19:92–101.  https://doi.org/10.1021/tx050196m CrossRefPubMedGoogle Scholar
  63. Pierucci F et al (2017) Non-dioxin-like organic toxicant PCB153 modulates sphingolipid metabolism in liver progenitor cells: its role in Cx43-formed gap junction impairment. Arch Toxicol 91:749–760.  https://doi.org/10.1007/s00204-016-1750-7 CrossRefPubMedGoogle Scholar
  64. Prescher JA, Bertozzi CR (2005) Chemistry in living systems. Nat Chem Biol 1:13–21.  https://doi.org/10.1038/nchembio0605-13 CrossRefPubMedGoogle Scholar
  65. Qin H, Shao Q, Igdoura SA, Alaoui-Jamali MA, Laird DW (2003) Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells. J Biol Chem 278:30005–30014.  https://doi.org/10.1074/jbc.M300614200 CrossRefPubMedGoogle Scholar
  66. R Core Team (2015) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  67. Rhee DY, Zhao XQ, Francis RJ, Huang GY, Mably JD, Lo CW (2009) Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development. Development 136:3185–3193.  https://doi.org/10.1242/dev.032334 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Ritz C, Streibig JC (2005) Bioassay analysis using R. J Stat Softw 12:1–22CrossRefGoogle Scholar
  69. Ruangvoravat CP, Lo CW (1992) Connexin 43 expression in the mouse embryo: localization of transcripts within developmentally significant domains. Dev Dyn 194:261–281.  https://doi.org/10.1002/aja.1001940403 CrossRefPubMedGoogle Scholar
  70. Safe SH (1994) Polychlorinated biphenyls (PCBs): environmental impact, biochemical and toxic responses, and implications for risk assessment. Crit Rev Toxicol 24:87–149.  https://doi.org/10.3109/10408449409049308 CrossRefPubMedGoogle Scholar
  71. Schalper KA, Carvajal-Hausdorf D, Oyarzo MP (2014) Possible role of hemichannels in cancer. Front Physiol 5:237.  https://doi.org/10.3389/fphys.2014.00237 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Shain W, Bush B, Seegal R (1991) Neurotoxicity of polychlorinated biphenyls: structure–activity relationship of individual congeners. Toxicol Appl Pharmacol 111:33–42CrossRefPubMedGoogle Scholar
  73. Simeckova P, Vondracek J, Andrysik Z, Zatloukalova J, Krcmar P, Kozubik A, Machala M (2009) The 2,2′,4,4′,5,5′-hexachlorobiphenyl-enhanced degradation of connexin 43 involves both proteasomal and lysosomal activities. Toxicol Sci 107:9–18.  https://doi.org/10.1093/toxsci/kfn202 CrossRefPubMedGoogle Scholar
  74. Sonneveld E, Jansen HJ, Riteco JA, Brouwer A, van der Burg B (2005) Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. Toxicol Sci 83:136–148.  https://doi.org/10.1093/toxsci/kfi005 CrossRefPubMedGoogle Scholar
  75. Stiegler NV, Krug AK, Matt F, Leist M (2011) Assessment of chemical-induced impairment of human neurite outgrowth by multiparametric live cell imaging in high-density cultures. Toxicol Sci 121:73–87.  https://doi.org/10.1093/toxsci/kfr034 CrossRefPubMedGoogle Scholar
  76. Tabb MM, Kholodovych V, Grun F, Zhou C, Welsh WJ, Blumberg B (2004) Highly chlorinated PCBs inhibit the human xenobiotic response mediated by the steroid and xenobiotic receptor (SXR). Environ Health Perspect 112:163–169CrossRefPubMedPubMedCentralGoogle Scholar
  77. van der Burg B, van der Linden S, Man Hy, Winter R, Jonker L, van Vugt-Lussenburg B, Brouwer A (2013) A panel of quantitative calux® reporter gene assays for reliable high-throughput toxicity screening of chemicals and complex mixtures high-throughput screening methods in toxicity. Testing 519–532:111853820XGoogle Scholar
  78. van der Linden SC, von Bergh ARM, van Vught-Lussenburg BMA, Jonker LRA, Teunis M, Krul CAM, van der Burg B (2014) Development of a panel of high-throughput reporter-gene assays to detect genotoxicity and oxidative stress. Mutat Res Genet Toxicol Environ Mutagenes 760:23–32%@ 1383–5718CrossRefGoogle Scholar
  79. van der Burg B et al (2015) A high throughput screening system for predicting chemically-induced reproductive organ deformities. Reprod Toxicol 55:95–103.  https://doi.org/10.1016/j.reprotox.2014.11.011 CrossRefPubMedGoogle Scholar
  80. Wassermann M, Wassermann D, Cucos S, Miller HJ (1979) World PCBs map: storage and effects in man and his biologic environment in the 1970s. Ann N Y Acad Sci 320:69–124%@ 1749–6632CrossRefPubMedGoogle Scholar
  81. Westerink RH (2014) Modulation of cell viability, oxidative stress, calcium homeostasis, and voltage- and ligand-gated ion channels as common mechanisms of action of (mixtures of) non-dioxin-like polychlorinated biphenyls and polybrominated diphenyl ethers. Environ Sci Pollut Res Int 21:6373–6383.  https://doi.org/10.1007/s11356-013-1759-x CrossRefPubMedGoogle Scholar
  82. Wiencken-Barger AE, Djukic B, Casper KB, McCarthy KD (2007) A role for Connexin43 during neurodevelopment. Glia 55:675–686.  https://doi.org/10.1002/glia.20484 CrossRefPubMedGoogle Scholar
  83. Wigestrand MB, Stenberg M, Walaas SI, Fonnum F, Andersson PL (2013) Non-dioxin-like PCBs inhibit [(3)H]WIN-35,428 binding to the dopamine transporter: a structure-activity relationship study. Neurotoxicology 39:18–24.  https://doi.org/10.1016/j.neuro.2013.07.005 CrossRefPubMedGoogle Scholar
  84. Willebrords J, Maes M, Yanguas SC, Vinken M (2017) Inhibitors of connexin and pannexin channels as potential therapeutics. Pharmacol Ther.  https://doi.org/10.1016/j.pharmthera.2017.07.001 PubMedPubMedCentralGoogle Scholar
  85. World Health Organization (2000) Air quality guidelines for Europe. WHO Regional Publications, Copenhagen, DenmarkGoogle Scholar
  86. Xu X et al (2001) Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions. J Cell Biol 154:217–230CrossRefPubMedPubMedCentralGoogle Scholar
  87. Xu X, Francis R, Wei CJ, Linask KL, Lo CW (2006) Connexin 43-mediated modulation of polarized cell movement and the directional migration of cardiac neural crest cells. Development 133:3629–3639.  https://doi.org/10.1242/dev.02543 CrossRefPubMedGoogle Scholar
  88. Yeakley JM, Shepard PJ, Goyena DE, VanSteenhouse HC, McComb JD, Seligmann BE (2017) A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One 12:e0178302.  https://doi.org/10.1371/journal.pone.0178302 CrossRefPubMedPubMedCentralGoogle Scholar
  89. Ziegler S et al (2017) Accelerated telomere shortening in peripheral blood lymphocytes after occupational polychlorinated biphenyls exposure. Arch Toxicol 91:289–300.  https://doi.org/10.1007/s00204-016-1725-8 CrossRefPubMedGoogle Scholar
  90. Zimmer B, Lee G, Balmer NV, Meganathan K, Sachinidis A, Studer L, Leist M (2012) Evaluation of developmental toxicants and signaling pathways in a functional test based on the migration of human neural crest cells. Environ Health Perspect 120:1116–1122.  https://doi.org/10.1289/ehp.1104489 CrossRefPubMedPubMedCentralGoogle Scholar
  91. Zimmer B et al (2014) Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery. Arch Toxicol 88:1109–1126.  https://doi.org/10.1007/s00204-014-1231-9 PubMedPubMedCentralGoogle Scholar

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

Personalised recommendations