Table 4. Overview of testing status of DNT reference compounds, with respect to NAMs.
A subset of chemicals with strong evidence for a DNT hazard in vivo (as described in Aschner et al., 2017) was selected. A literature search was performed to retrieve data on in vitro testing of these compounds. Data for 11 assays have been compiled here. Grey fields indicate that no clear test data have been retrieved. Green fields indicate that the compound has been examined in the respective test method, and was found to show a positive effect. Orange fields indicate that the compound has been tested, but did not show any effect specific of DNT. In the latter two cases, the literature evidence is indicated. Each assay allows testing of specific DNT endpoints as indicated below: NEP differentiation: neural tube formation. Neurospheres: NPC proliferation; radial glia migration; neuron and glia differentiation; neurite outgrowth. ReNcell: NPC proliferation. MINC: NCC migration. hESC/hiPS: neuron, astrocyte and oligodendrocyte differentiation; neurite outgrowth. UKN4 (NeuriTox): DA neuron differentiation; neurite outgrowth. 3D human: neuron, astrocyte and oligodendrocyte differentiation,; synaptogenesis; myelination; neuronal network formation. 3D rat: neuron, astrocyte and oligodendrocyte differentiation; synaptogenesis; myelination; neuronal network formation; neuroinflammation. 2D murine: neuron and glia differentiation; synaptogenesis; neuronal network formation. UKN5 (PeriTox): neurogenesis. Zebra fish: brain development. Literature as indicated by numbers in the orange and green fields: 1. Zimmer et al., 2014; 2. Dreser et al., 2015; 3. Pallocca et al., 2016; 4. Zhou et al., 2015; 5. Chattopadhyay et al., 2002; 6. Breier et al., 2008; 7. Culbreth et al., 2012; 8. Gulisano et al., 2009; 9. Monnet-Tschudi et al., 1993; 10. Tasneem et al., 2016; 11. Chow et al., 2008; 12. Selderslaghs et al., 2013; 13. Baumann et al., 2016; 14. Lee et al., 2014; 15. Krug et al., 2013b; 16. Monnet-Tschudi et al., 2000; 17. Slotkin et al., 2012; 18. Crumpton et al., 2000; 19. Visan et al., 2012; 20. Dingemans et al., 2016; 21. Lee et al., 2017; 22. McCarthy et al., 2011; 23. Shang et al., 2007; 24. Harrill et al., 2011; 25. Moors et al., 2012; 26. Ninomiya et al., 2014; 27. Bramanti et al., 2010; 28. Khor et al., 2013; 29. Perez-Gomez et al., 2012; 30. Hogberg et al., 2011; 31. Tiedeken et al., 2005; 32. Palmer et al., 2012; 33. Talens-Visconti et al., 2011; 34. Nash et al., 2012; 35. Guadagnoli et al., 2016; 36. Parker et al., 2014; 37. Benninghoff et al., 2013; 38. Bai et al., 2013; 39. Slikker et al., 2015; 40. Hondebrink et al., 2017; 41. Zimmer et al., 2012; 42. Senut et al., 2014; 43. Zurich et al., 2002; 44. Monnet-Tschudi et al., 1999; 45. Dou et al., 2011; 46. Chen et al., 2012; 47. Hoareau et al., 2006; 48. Suarez-Isla et al., 1984; 49. Kindlundh-Hogberg et al., 2010; 50. Hondebrink et al., 2016; 51. Santos-Fandila et al., 2015; 52. Stummann et al., 2009; 53. Schmuck et al., 2016; 54. Moors et al., 2009; 55. Wilson et al., 2014; 56. Pallocca et al., 2013; 57. Stiegler et al., 2011; 58. Sandström et al., 2017; 59. Hoelting et al., 2013; 60. He et al., 2012; 61. Monnet-Tschudi et al., 1996; 62. Popova et al, 2014; 63. Yao et al., 2017; 64. Coronas et al., 2000; 65. Sandström von Tobel et al., 2014; 66. Schreiber et al., 2010; 67. Hirsch et al., 2017; 68. Xiong et al., 2012; 69. Tofighi et al., 2011; 70. Yang et al., 2014; 71. Markus et al., 2010; 72. Colleoni et al., 2011; 73. Orsolits et al., 2013; 74. Addae et al., 2012; 75. Colleoni et al., 2012; 76. Wang et al., 2015; 77. Zimmermann et al., 2015.
| Cellular system | NEP diff. | Neuro- spheres |
ReNcell | Neural crest migration | hESC
/ hiPS based diff. |
CNS neurons |
3D human cell culture | 3D rat cell culture | 2D murine cell culture | PNS neurons |
Zebra fish |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Name of assay | NEP diff. | NPC 1–6 | ReNcell | UKN2 (cMINC) |
UKN1 | UKN4 (NeuriTox) |
3Dh | 3Dr | 2Dm | UKN5 (PeriTox) |
ZFE |
| COMPOUNDS | |||||||||||
| Arsenic | 1–3 | 4,5 | |||||||||
| Cadmium | 6,7 | 2 | 8 | 9 | 10 | 11 | |||||
| Chlorpromazine | 1 | 12 | |||||||||
| Chlorpyrifos | 13 | 7 | 14 | 15 | 16 | 17–20 | |||||
| Cocaine | 21 | 22 | 23 | ||||||||
| Dexamethasone | 6 | 24–26 | 27 | 28 | |||||||
| Diphenyldantoin | |||||||||||
| Domoic acid | 29,30 | 31 | |||||||||
| Ethanol | 32–34 | 35 | 36 | ||||||||
| Haloperidol | 15 | 37 | |||||||||
| Heroin | |||||||||||
| Hexachlorophene | |||||||||||
| Ketamine | 38 | 39,40 | |||||||||
| Lead | 6 | 41 | 24,42 | 43,44 | 10,19 | 45,46 | |||||
| Lindane | |||||||||||
| MAM | 13 | 47 | |||||||||
| Maneb | |||||||||||
| Manganese | 48 | ||||||||||
| MDMA | 49,50 | ||||||||||
| Methanol | 51 | ||||||||||
| Methyl mercury | 52 | 13,53,54 | 6 | 41 | 24,55,56 | 15,57 | 58–60 | 61 | 10,19,20,62 | 12 | |
| MPTP | 63 | ||||||||||
| Nicotine | 50,64 | ||||||||||
| Paraquat | 15 | 58 | 65 | ||||||||
| PBDE | 66 | 3,67 | 68 | ||||||||
| PCB | 2 | 69 | 70 | ||||||||
| Perfluorate-PFOA | |||||||||||
| Perfluorate-PFOS | |||||||||||
| Terbutaline | 71 | ||||||||||
| Toluene | |||||||||||
| Trans retinoic acid | 72 | 6,7 | 24 | 73,74 | |||||||
| Triethyl tin | |||||||||||
| Valproic acid | 75 | 13 | 2,3,41 | 76 | 77 |