Revolutionizing developmental neurotoxicity testing – A journey from animal models to advanced in vitro systems
Article Sidebar
Main Article Content
Abstract
Developmental neurotoxicity (DNT) testing has seen enormous progress over the last two decades. Preceding even the publication of the animal-based OECD test guideline for DNT testing in 2007, a series of non-animal technology workshops and conferences that started in 2005 has shaped a community that has delivered a comprehensive battery of in vitro test methods (DNT IVB). Its data interpretation is now covered by a very recent OECD guidance (No. 377). Here, we overview the progress in the field, focusing on the evolution of testing strategies, the role of emerging technologies, and the impact of OECD test guidelines on DNT testing. In particular, this is an example of the targeted development of an animal-free testing approach for one of the most complex hazards of chemicals to human health. These developments started literally from a blank slate, with no proposed alternative methods available. Over two decades, cutting-edge science enabled the design of a testing approach that spares animals and enables throughput to address this challenging hazard. While it is evident that the field needs guidance and regulation, the massive economic impact of decreased human cognitive capacity caused by chemical exposure should be prioritized more highly. Beyond this, the claim to fame of DNT in vitro testing is the enormous scientific progress it has brought for understanding the human brain, its development, and how it can be perturbed.
Plain language summary
Developmental neurotoxicity (DNT) testing predicts the hazard of exposure to chemicals to human brain development. Comprehensive advanced non-animal testing strategies using cutting-edge technology can now replace animal-based approaches to assess this complex hazard. These strategies can assess large numbers of chemicals more accurately and efficiently than the animal-based approach. Recent OECD test guidance has formalized this battery of in vitro test methods for DNT, marking a pivotal achievement in the field. The shift towards non-animal testing reflects both a commitment to animal welfare and a growing recognition of the economic and public health impacts associated with impaired cognitive function caused by chemical exposures. These innovations ultimately contribute to safer chemical management and better protection of human health, especially during the vulnerable stages of brain development.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
Articles are distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is appropriately cited (CC-BY). Copyright on any article in ALTEX is retained by the author(s).
Algharably, E. A., Di Consiglio, E., Testai, E. et al. (2023). Prediction of in vivo prenatal chlorpyrifos exposure leading to developmental neurotoxicity in humans based on in vitro toxicity data by quantitative in vitro-in vivo extrapolation. Front Pharmacol 14, 1136174. doi:10.3389/fphar.2023.1136174
Ankley, G. T., Bennett, R. S., Erickson, R. J. et al. (2010). Adverse outcome pathways: A conceptual framework to support ecotoxicology research and risk assessment. Environ Toxicol Chem 29, 730-741. doi:10.1002/etc.34
Arts, J. H. E., Faulhammer, F., Schneider, S. et al. (2023). Investigations on learning and memory function in extended one-generation reproductive toxicity studies – When considered needed and based on what? Crit Rev Toxicol 53, 372-384. doi:10.1080/10408444.2023.2236134
Arzuaga, X., Smith, M. T., Gibbons, C. F. et al. (2019). Proposed key characteristics of male reproductive toxicants as an approach for organizing and evaluating mechanistic evidence in human health hazard assessments. Environ Health Perspect 127, 065001. doi:10.1289/ehp5045
Aschner, M., Ceccatelli, S., Daneshian, M. et al. (2017). Selection of reference compounds for characterization and development of alternative methods for developmental neurotoxicity (DNT) testing. ALTEX 34, 49-74. doi:10.14573/altex.1604201
Bal-Price, A., Hogberg, H. T., Buzanska, L. et al. (2010). In vitro developmental neurotoxicity (DNT) testing: Relevant models and endpoints. Neurotoxicology 31, 545-554. doi:10.1016/j.neuro.2009.11.006
Bal-Price, A. K., Coecke, S., Costa, L. et al. (2012). Advancing the science of developmental neurotoxicity (DNT): Testing for better safety evaluation. ALTEX 29, 202-215. doi:10.14573/altex.2012.2.202
Bal-Price, A., Crofton, K. M., Sachana, M. et al. (2015a). Putative adverse outcome pathways relevant to neurotoxicity. Crit Rev Toxicol 45, 83-91. doi:10.3109/10408444.2014.981331
Bal-Price, A., Crofton, K. M., Leist, M. et al. (2015b). International STakeholder NETwork (ISTNET): Creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes. Arch Toxicol 89, 269-287. doi:10.1007/s00204-015-1464-2
Bal-Price, A. and Meek, M. E. (2017). Adverse outcome pathways: Application to enhance mechanistic understanding of neurotoxicity. Pharmacol Ther 179, 84-95. doi:10.1016/j.pharmthera.2017.05.006
Bal-Price, A., Hogberg, H. T., Crofton, K. M. et al. (2018a). t4 workshop report: Recommendation on test readiness criteria for new approach methods in toxicology: Exemplified for developmental neurotoxicity. ALTEX 35, 306-352. doi:10.14573/altex.1712081
Bal-Price, A., Pistollato, F., Sachana, M. et al. (2018b). Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods. Toxicol Appl Pharmacol 354, 7-18. doi:10.1016/j.taap.2018.02.008
Basketter, D. A., Clewell, H., Kimber, I., et al. (2012). A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing. ALTEX 29, 3-89. doi:10.14573/altex.2012.1.003
Baumann, J., Gassmann, K., Masjosthusmann, S. et al. (2016). Comparative human and rat neurospheres reveal species differences in chemical effects on neurodevelopmental key events. Arch Toxicol 90, 1415-1427. doi:10.1007/s00204-015-1568-8
Bellanger, M., Demeneix, B. A., Grandjean, P. et al. (2015). Neurobehavioral deficits, diseases, and associated costs of exposure to endocrine-disrupting chemicals in the European Union. J Clin Endocrinol Metab 100, 1256-1266. doi:10.1210/jc.2014-4323
Blaauboer, B. J., Boekelheide, K., Clewell, H. J. et al. (2012). The use of biomarkers of toxicity for integrating in vitro hazard estimates into risk assessment for humans. ALTEX 29, 411-425. doi:10.14573/altex.2012.4.411
Blum, J., Masjosthusmann, S., Bartmann, K. et al. (2023). Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals. Chemosphere 311, 137035. doi:10.1016/j.chemosphere.2022.137035
Boyle, J., Yeter, D., Aschner, M. et al. (2021). Estimated IQ points and lifetime earnings lost to early childhood blood lead levels in the United States. Sci Total Environ 778, 146307. doi:10.1016/j.scitotenv.2021.146307
Butera, A., Smirnova, L., Ferrando-May, E. et al. (2023). Deconvoluting gene and environment interactions to develop “epigenetic score meter” of disease. EMBO Mol Med 15, e18208. doi:10.15252/emmm.202318208
Caloni, F., De Angelis, I. and Hartung, T. (2022). Replacement of animal testing by integrated approaches to testing and assessment (IATA): A call for in vivitrosi. Arch Toxicol 96, 1935-1950. doi:10.1007/s00204-022-03299-x
Cediel-Ulloa, A., Lupu, D. L., Johansson, Y. et al. (2022). Impact of endocrine disrupting chemicals on neurodevelopment: The need for better testing strategies for endocrine disruption-induced developmental neurotoxicity. Expert Rev Endocrinol Metab 17, 131-141. doi:10.1080/17446651.2022.2044788
Chesnut, M., Hartung, T., Hogberg, H. T. et al. (2021a). Human oligodendrocytes and myelin in vitro to evaluate developmental neurotoxicity. Int J Mol Sci 22, 7929. doi:10.3390/ijms22157929
Chesnut, M., Paschoud, H., Repond, C. et al. (2021b). Human 3D iPSC-derived brain model to study chemical-induced myelin disruption. Int J Mol Sci 22, 9473. doi:10.3390/ijms22179473
Coecke, S., Goldberg, A. M., Allen, S. et al. (2007). Workgroup report: Incorporating in vitro alternative methods for developmental neurotoxicity into international hazard and risk assessment strategies. Environ Health Perspect 115, 924-931. doi:10.1289/ehp.9427
Cohn, E. F., Clayton, B. L. L., Madhavan, M. et al. (2024). Pervasive environmental chemicals impair oligodendrocyte development. Nat Neurosci, online ahead of print. doi:10.1038/s41593-024-01599-2
Crofton, K. M., Mundy, W. R., Lein, P. J. et al. (2011). Developmental neurotoxicity testing: Recommendations for developing alternative methods for the screening and prioritization of chemicals. ALTEX 28, 9-15. doi:10.14573/altex.2011.1.009
Crofton, K., Fritsche, E., Ylikomi, T. and Bal-Price, A. (2014). International STakeholder NETwork (ISTNET) for creating a developmental neurotoxicity testing (DNT) roadmap for regulatory purposes. ALTEX 31, 223-224. doi:10.14573/altex.1402121
Crofton, K. M. and Mundy, W. R. (2021). External scientific report on the interpretation of data from the developmental neurotoxicity in vitro testing assays for use in integrated approaches for testing and assessment. EFSA Support Publ 18, 6924E. doi:10.2903/sp.efsa.2021.en-6924
Diemar, M. G., Vinken, M., Teunis, M. et al. (2024). Report of the First ONTOX stakeholder network meeting: Digging under the surface of ONTOX together with the stakeholders. Altern Lab Anim 52, 117-131. doi:10.1177/02611929231225730
Fritsche, E., Crofton, K. M., Hernandez, A. F. et al. (2017). OECD/EFSA workshop on developmental neurotoxicity (DNT): The use of non-animal test methods for regulatory purposes. ALTEX 34, 311-315. doi:10.14573/altex.1701171
Fritsche, E., Barenys, M., Klose, J. et al. (2018). Current availability of stem cell-based in vitro methods for developmental neurotoxicity (DNT) testing. Toxicol Sci 165, 21-30. doi:10.1093/toxsci/kfy178
Furxhi, I. and Murphy, F. (2020). Predicting in vitro neurotoxicity induced by nanoparticles using machine learning. Int J Mol Sci 21, 5280. doi:10.3390/ijms21155280
Gaylord, A., Osborne, G., Ghassabian, A. et al. (2020). Trends in neurodevelopmental disability burden due to early life chemical exposure in the USA from 2001 to 2016: A population-based disease burden and cost analysis. Mol Cell Endocrinol 502, 110666. doi:10.1016/j.mce.2019.110666
Grandjean, P. and Landrigan, P. J. (2006). Developmental neurotoxicity of industrial chemicals. Lancet 368, 2167-2178. doi:10.1016/S0140-6736(06)69665-7
Grandjean, P. and Landrigan, P. J. (2014). Neurobehavioural effects of developmental toxicity. Lancet Neurol 13, 330-338. doi:10.1016/S1474-4422(13)70278-3
Groot, M. W. G. M., Westerink, R. H. S. and Dingemans, M. M. L. (2013). Don’t judge a neuron only by its cover: Neuronal function in in vitro developmental neurotoxicity testing. Toxicol Sci 132, 1-7. doi:10.1093/toxsci/kfs269
Hartung, T., van Vliet, E., Jaworska, J. et al. (2012). Systems toxicology. ALTEX 29, 119-128. doi:10.14573/altex.2012.2.119
Hartung, T., Luechtefeld, T., Maertens, A. et al. (2013a). Integrated testing strategies for safety assessments. ALTEX 30, 3-18. doi:10.14573/altex.2013.1.003
Hartung, T., Stephens, M. and Hoffmann, S. (2013b). Mechanistic validation. ALTEX 30, 119-130. doi:10.14573/altex.2013.2.119
Hartung, T. and Tsatsakis, A. M. (2021). The state of the scientific revolution in toxicology. ALTEX 38, 379-386. doi:10.14573/altex.2106101
Hartung, T. (2023a). ToxAIcology – The evolving role of artificial intelligence in advancing toxicology and modernizing regulatory science. ALTEX 40, 559-570. doi:10.14573/altex.2309191
Hartung, T. (2023b). A call for a human exposome project. ALTEX 40, 4-33. doi:10.14573/altex.2301061
Hartung, T., Smirnova, L., Morales Pantoja, I. E. et al. (2023). The Baltimore declaration toward the exploration of organoid intelligence. Front Sci 1, 1017235. doi:10.3389/fsci.2023.1017235
Hartung, T., Morales Pantoja, I. E. and Smirnova, L. (2024). Brain organoids and organoid intelligence (OI) from ethical, legal, and social points of view. Front Artif Intell 6, 1307613. doi:10.3389/frai.2023.1307613
Hernández-Jerez, A. F., Adriaanse, P. I., Aldrich, A. P. et al. (2021). Development of integrated approaches to testing and assessment (IATA) case studies on developmental neurotoxicity (DNT) risk assessment. EFSA J 19, e06599. doi:10.2903/j.efsa.2021.6599
Hertz-Picciotto, I. and Delwiche, L. (2009). The rise in autism and the role of age at diagnosis. Epidemiology 20, 84-90. doi:10.1097/ede.0b013e3181902d15
Hogberg, H. T., Kinsner-Ovaskainen, A., Coecke, S. et al. (2010). mRNA expression is a relevant tool to identify developmental neurotoxicants using an in vitro approach. Toxicol Sci 113, 95-115. doi:10.1093/toxsci/kfp175
Hogberg, H. T., Sobanski, T., Novellino, A. et al. (2011). Application of micro-electrode arrays (MEAs) as an emerging technology for developmental neurotoxicity: Evaluation of domoic acid-induced effects in primary cultures of rat cortical neurons. Neurotoxicology 32, 158-168. doi:10.1016/j.neuro.2010.10.007
Hogberg, H. T., Bressler, J., Christian, K. M. et al. (2013). Toward a 3D model of human brain development for studying gene/environment interactions. Stem Cell Res Ther 4, S4. doi:10.1186/scrt365
Hogberg, H. T., de Cássia da Silveira e Sá, R., Kleensang, A. et al. (2021). Organophosphorus flame retardants are developmental neurotoxicants in a rat primary BrainSphere in vitro model. Arch Toxicol 95, 207-228. doi:10.1007/s00204-020-02903-2
Hogberg, H. T. and Smirnova, L. (2022). The future of 3D brain cultures in developmental neurotoxicity testing. Front Toxicol 4, 808620. doi:10.3389/ftox.2022.808620
Honegger, P., Lenoir, D. and Favrod, P. (1979). Growth and differentiation of aggregating fetal brain cells in a serum-free defined medium. Nature 282, 305-308. doi:10.1038/282305a0
Huang, Q., Tang, B., Romero, J. C. et al. (2022). Shell microelectrode arrays (MEAs) for brain organoids. Sci Adv 8, eabq5031. doi:10.1126/sciadv.abq5031
Ilieva, M., Fex Svenningsen, Å., Thorsen, M. et al. (2018). Psychiatry in a dish: Stem cells and brain organoids modeling autism spectrum disorders. Biol Psychiatry 83, 558-568. doi:10.1016/j.biopsych.2017.11.011
Juberg, D. R., Fox, D. A., Forcelli, P. A. et al. (2023). A perspective on in vitro developmental neurotoxicity test assay results: An expert panel review. Regul Toxicol Pharmacol 143, 105444. doi:10.1016/j.yrtph.2023.105444
Keown, C., Shih, P., Nair, A. et al. (2013). Local functional overconnectivity in posterior brain regions is associated with symptom severity in autism spectrum disorders. Cell Rep 5, 567-572. doi:10.1016/j.celrep.2013.10.003
Kilpatrick, S., Irwin, C. and Singh, K. K. (2023). Human pluripotent stem cell (hPSC) and organoid models of autism: Opportunities and limitations. Transl Psychiatry 13, 217. doi:10.1038/s41398-023-02510-6
Kleensang, A., Maertens, A., Rosenberg, M. et al. (2014). Pathways of toxicity. ALTEX 31, 53-61. doi:10.14573/altex.1309261
Kleinstreuer, N. and Hartung, T. (2024). Artificial intelligence (AI) – It’s the end of the tox as we know it (and I feel fine) – AI for predictive toxicology. Arch Toxicol 98, 735-754. doi:10.1007/s00204-023-03666-2
Knight, J., Hartung, T. and Rovida, C. (2023). 4.2 million and counting... the animal toll for REACH systemic toxicity studies. ALTEX 40, 389-407. doi:10.14573/altex.2303201
Kobolak, J., Teglasi, A., Bellak, T. et al. (2020). Human induced pluripotent stem cell-derived 3D-neurospheres are suitable for neurotoxicity screening. Cells 9, 1122. doi:10.3390/cells9051122
Krewski, D., Andersen, M., Tyshenko, M. G. et al. (2020). Toxicity testing in the 21st century: Progress in the past decade and future perspectives. Arch Toxicol 94, 1-58. doi:10.1007/s00204-019-02613-4
Krug, A. K., Kolde, R., Gaspar, J. A. et al. (2013a). Human embryonic stem cell-derived test systems for developmental neurotoxicity: A transcriptomics approach. Arch Toxicol 87, 123-143. doi:10.1007/s00204-012-0967-3
Krug, A. K., Balmer, N. V., Matt, F. et al. (2013b). Evaluation of a human neurite growth assay as specific screen for developmental neurotoxicants. Arch Toxicol 87, 2215-2231. doi:10.1007/s00204-013-1072-y
Kuehn, B. M. (2010). Increased risk of ADHD associated with early exposure to pesticides, PCBs. JAMA 304, 27-28. doi:10.1001/jama.2010.860
La Merrill, M. A., Vandenberg, L. N., Smith, M. T. et al. (2020). Consensus on the key characteristics of endocrine-disrupting chemicals as a basis for hazard identification. Nat Rev Endocrinol 16, 45-57. doi:10.1038/s41574-019-0273-8
Lancaster, M., Renner, M., Martin, C. A. et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature 501, 373-379. doi:10.1038/nature12517
Landrigan, P. J. (2010). What causes autism? Exploring the environmental contribution. Curr Opin Pediatr 22, 219-225. doi:10.1097/mop.0b013e328336eb9a
Lee, J. and Freeman, J. L. (2014). Zebrafish as a model for developmental neurotoxicity assessment: The application of the zebrafish in defining the effects of arsenic, methylmercury, or lead on early neurodevelopment. Toxics 2, 464-495. doi:10.3390/toxics2030464
Lein, P., Silbergeld, E., Locke, P. et al. (2005). In vitro and other alternative approaches to developmental neurotoxicity testing (DNT). Environ Toxicol Pharmacol 19, 735-744. doi:10.1016/j.etap.2004.12.035
Lein, P., Locke, P. and Goldberg, A. (2007). Meeting report: Alternatives for developmental neurotoxicity testing. Environ Health Perspect 115, 764-768. doi:10.1289/ehp.9841
Leist, M., Efremova, L. and Karreman, C. (2010). Food for thought ... considerations and guidelines for basic test method descriptions in toxicology. ALTEX 27, 309-317. doi:10.14573/altex.2010.4.309
Leist, M., Hasiwa, N., Daneshian, M. et al. (2012). Validation and quality control of replacement alternatives – Current status and future challenges. Toxicol Res 1, 8-22. doi:10.1039/c2tx20011b
Leist, M., Hasiwa, N., Rovida, C. et al. (2014). Consensus report on the future of animal-free systemic toxicity testing. ALTEX 31, 341-356. doi:10.14573/altex.1406091
Leist, M., Ghallab, A., Graepel, R. et al. (2017). Adverse outcome pathways: Opportunities, limitations and open questions. Arch Toxicol 91, 3477-3505. doi:10.1007/s00204-017-2045-3
Li, S. and Xia, M. (2019). Review of high-content screening applications in toxicology. Arch Toxicol 93, 3387-3396. doi:10.1007/s00204-019-02593-5
Luderer, U., Eskenazi, B., Hauser, R. et al. (2019). Proposed key characteristics of female reproductive toxicants as an approach for organizing and evaluating mechanistic data in hazard assessment. Environ Health Perspect 127, 075001. doi:10.1289/ehp4971
Maass, C., Schaller, S., Dallmann, A. et al. (2023). Considering developmental neurotoxicity in vitro data for human health risk assessment using physiologically-based kinetic modeling: Deltamethrin case study. Toxicol Sci 192, 59-70. doi:10.1093/toxsci/kfad007
Maenner, M. J., Warren, Z., Williams, A. R. et al. (2023). Prevalence and characteristics of autism spectrum disorder among children aged 8 years – Autism and developmental disabilities monitoring network, 11 Sites, United States, 2020. MMWR Surveill Summ 72, 1-14. doi:10.15585/mmwr.ss7202a1
Makris, S. L., Raffaele, K., Allen, S. et al. (2009). A retrospective performance assessment of the developmental neurotoxicity study in support of OECD test guideline 426. Environ Health Perspect 117, 17-25. doi:10.1289/ehp.11447
Marx, U., Andersson, T. B., Bahinski, A. et al. (2016). Biology-inspired microphysiological system approaches to solve the prediction dilemma of substance testing. ALTEX 33, 272-321. doi:10.14573/altex.1603161
Marx, U., Akabane, T., Andersson, T. et al. (2020). Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. ALTEX 37, 365-394. doi:10.14573/altex.2001241
Meigs, L., Smirnova, L., Rovida, C. et al. (2018). Animal testing and its alternatives – The most important omics is economics. ALTEX 35, 275-305. doi:10.14573/altex.1807041
Modafferi, S., Zhong, X., Kleensang, A. et al. (2021). Gene-environment interactions in developmental neurotoxicity: A case study of synergy between chlorpyrifos and CHD8 knockout in human BrainSpheres. Environ Health Perspect 129, 77001. doi:10.1289/ehp8580
Moore, N. P., Beekhuijzen, M., Boogaard, P. J. et al. (2016). Guidance on the selection of cohorts for the extended one-generation reproduction toxicity study (OECD test guideline 443). Regul Toxicol Pharmacol 80, 32-40. doi:10.1016/j.yrtph.2016.05.036
Morales Pantoja, I. E., Smirnova, L., Muotri, A. R. et al. (2023a). First organoid intelligence (OI) workshop to form an OI community. Front Artif Intell 6, 1116870. doi:10.3389/frai.2023.1116870
Morales Pantoja, I. E., Ding, L., Leite, P. E. C. et al. (2023b). A novel approach to increase glial cell populations in brain microphysiological systems. Adv Biol, e2300198. Online ahead of print. doi:10.1002/adbi.202300198
Mundy, W. R., Padilla, S., Breier, J. M. et al. (2015). Expanding the test set: Chemicals with potential to disrupt mammalian brain development. Neurotoxicol Teratol 52, 25-35. doi:10.1016/j.ntt.2015.10.001
Nishimura, Y., Murakami, S., Ashikawa, Y. et al. (2015). Zebrafish as a systems toxicology model for developmental neurotoxicity testing. Congenit Anom (Kyoto) 55, 1-16. doi:10.1111/cga.12079
NRC – National Research Council (2007). Toxicity Testing in the 21st Century: A Vision and a Strategy. Washington, DC, USA: The National Academies Press. doi:10.17226/11970
Nyffeler, J., Chovancova, P., Dolde, X. et al. (2018). A structure-activity relationship linking non-planar PCBs to functional deficits of neural crest cells: New roles for connexins. Arch Toxicol 92, 1225-1247. doi:10.1007/s00204-017-2125-4
OECD (2001). Test No. 416: Two-Generation Reproduction Toxicity. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris, doi:10.1787/9789264070868-en
OECD (2007). Test No. 426: Developmental Neurotoxicity Study. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264067394-en
OECD (2018). Test No. 443: Extended One-Generation Reproductive Toxicity Study. OECD Guidelines for the Testing of Chemicals, Section 4. OECD Publishing, Paris. doi:10.1787/9789264185371-en
OECD (2023). Initial Recommendations on Evaluation of Data from the Developmental Neurotoxicity (DNT) In-Vitro Testing Battery. Series on Testing and Assessment No. 377. https://one.oecd.org/document/ENV/CBC/MONO(2023)13/en/pdf
Pamies, D., Bal-Price, A., Simeonov, A. et al. (2017). Good cell culture practice for stem cells and stem-cell-derived models. ALTEX 34, 95-132. doi:10.14573/altex.1607121
Pamies, D., Block, K., Lau, P. et al. (2018). Rotenone exerts developmental neurotoxicity in a human brain spheroid model. Toxicol Appl Pharmacol 354, 101-114. doi:10.1016/j.taap.2018.02.003
Pamies. D., Leist, M., Coecke, S. et al. (2022). Guidance document on good cell and tissue culture practice 2.0 (GCCP 2.0). ALTEX 39, 30-70. doi:10.14573/altex.2111011
Persson, M. and Hornberg, J. J. (2016). Advances in predictive toxicology for discovery safety through high content screening. Chem Res Toxicol 29, 1998-2007. doi:10.1021/acs.chemrestox.6b00248
Pessah, I. N. and Lein, P. J. (2008). Evidence for environmental susceptibility in autism – What we need to know about gene x environment interactions. In A. Zimmerman (ed.), Autism: Current Theories and Evidence (409-428). Humana Press.
Pistollato, F., de Gyves, E. M., Carpi, D. et al. (2020). Assessment of developmental neurotoxicity induced by chemical mixtures using an adverse outcome pathway concept. Environ Health 19, 23. doi:10.1186/s12940-020-00578-x
Pitzer, E. M., Shafer, T. J. and Herr, D. W. (2023). Identification of neurotoxicology (NT)/developmental neurotoxicology (DNT) adverse outcome pathways and key event linkages with in vitro DNT screening assays. Neurotoxicology 99, 184-194. doi:10.1016/j.neuro.2023.10.007
Rempel, E., Hoelting, L., Waldmann, T. et al. (2015). A transcriptome-based classifier to identify developmental toxicants by stem cell testing: Design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol 89, 1599-1618. doi:10.1007/s00204-015-1573-y
Rice, D. and Barone, S. Jr. (2000). Critical periods of vulnerability for the developing nervous system: Evidence from humans and animal models. Environ Health Perspect 108, Suppl 3, 511-533. doi:10.1289/ehp.00108s3511
Rodier, P. M. (1995). Developing brain as a target of toxicity. Environ Health Perspect 103, Suppl 6, 73-76. doi:10.1289/ehp.95103s673
Romero, J. C., Berlinicke, C., Chow, S. et al. (2023). Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system. Front Cell Neurosci 16, 1094291. doi:10.3389/fncel.2022.1094291
Rossignol, D., Genuis, S. and Frye, R. (2014). Environmental toxicants and autism spectrum disorders: A systematic review. Transl Psychiatry 4, e360. doi:10.1038/tp.2014.4
Roth, A. and MPS-WS Berlin 2019 (2021). Human microphysiological systems for drug development. Science 373, 1304-1306. doi:10.1126/science.abc3734
Rovida, C., Alépée, N., Api, A. M. et al. (2015). Integrated testing strategies (ITS) for safety assessment. ALTEX 32, 25-40. doi:10.14573/altex.1411011
Rovida, C., Busquet, F., Leist, M. et al. (2023). REACH out-numbered! The future of REACH and animal numbers. ALTEX 40, 367-388. doi:10.14573/altex.2307121
Russo, F. B., Brito, A., de Freitas, A. M. et al. (2019). The use of iPSC technology for modeling autism spectrum disorders. Neurobiol Dis 130, 104483. doi:10.1016/j.nbd.2019.104483
Sachana, M., Bal-Price, A., Crofton, K. M. et al. (2019). International regulatory and scientific effort for improved developmental neurotoxicity testing. Toxicol Sci 167, 45-57. doi:10.1093/toxsci/kfy211
Sachana, M., Shafer, T. J. and Terron, A. (2021a). Toward a better testing paradigm for developmental neurotoxicity: OECD efforts and regulatory considerations. Biology 10, 86. doi:10.3390/biology10020086
Sachana, M., Willett, C., Pistollato, F. et al. (2021b). The potential of mechanistic information organised within the AOP framework to increase regulatory uptake of the developmental neurotoxicity (DNT) in vitro battery of assays. Reprod Toxicol 103, 159-170. doi:10.1016/j.reprotox.2021.06.006
Sagiv, S. K., Thurston, S. W., Bellinger, D. C. et al. (2010). Prenatal organochlorine exposure and behaviors associated with attention deficit hyperactivity disorder in school-aged children. Am J Epidemiol 171, 593-601. doi:10.1093/aje/kwp427
Santos, J. L. S., Araújo, C. A., Rocha, C. A. G. et al. (2023). Modeling autism spectrum disorders with induced pluripotent stem cell-derived brain organoids. Biomolecules 13, 260. doi:10.3390/biom13020260
Schiffelers, M. W. A., Blaauboer, B. J., Bakker, W. E. et al. (2015). Regulatory acceptance and use of the extended one generation reproductive toxicity study within Europe. Regul Toxicol Pharmacol 71, 114-124. doi:10.1016/j.yrtph.2014.10.012
Schmidt, B. Z., Lehmann, M., Gutbier, S. et al. (2016). In vitro acute and developmental neurotoxicity screening: An overview of cellular platforms and high-throughput technical possibilities. Arch Toxicol 91, 1-33. doi:10.1007/s00204-016-1805-9
Schmuck, M. R., Temme, T., Dach, K. et al. (2017). Omnisphero: A high-content image analysis (HCA) approach for phenotypic developmental neurotoxicity (DNT) screenings of organoid neurosphere cultures in vitro. Arch Toxicol 91, 2017-2028. doi:10.1007/s00204-016-1852-2
Schwartz, M. P., Hou, Z., Propson, N. E. et al. (2015). Human pluripotent stem cell-derived neural constructs for predicting neural toxicity. Proc Natl Acad Sci U S A 112, 12516-12521. doi:10.1073/pnas.1516645112
Shafer, T. J. (2019). Application of microelectrode array approaches to neurotoxicity testing and screening. Adv Neurobiol 22, 275-297. doi:10.1007/978-3-030-11135-9_12
Smirnova, L., Hogberg, H. T., Leist, M. et al. (2014). Developmental neurotoxicity – Challenges in the 21st century and in vitro opportunities. ALTEX 31, 129-156. doi:10.14573/altex.1403271
Smirnova, L., Seiler, A. E. M. and Luch, A. (2015a). microRNA profiling as tool for developmental neurotoxicity testing (DNT). Curr Protoc Toxicol 64, 20.9.1-22. doi:10.1002/0471140856.tx2009s64
Smirnova, L., Harris, G., Leist, M. et al. (2015b). Cellular resilience. ALTEX 32, 247-260. doi:10.14573/altex.1509271
Smirnova, L., Kleinstreuer, N., Corvi, R. et al. (2018). 3S – Systematic, systemic, and systems biology and toxicology. ALTEX 35, 139-162. doi:10.14573/altex.1804051
Smirnova, L., Caffo, B. S., Gracias, D. H. et al. (2023a). Organoid intelligence (OI): The new frontier in biocomputing and intelligence-in-a-dish. Front Sci 1, 1017235. doi:10.3389/fsci.2023.1017235
Smirnova, L., Morales Pantoja, I. E. and Hartung, T. (2023b). Organoid Intelligence (OI) – The ultimate functionality of a brain microphysiological system. ALTEX 40, 191-203. doi:10.14573/altex.2303261
Smirnova, L. and Hartung, T. (2024). The promise and potential of brain organoids. Adv Healthc Mater, e2302745. Online ahead of print. doi:10.1002/adhm.202302745
Spînu, N., Cronin, M. T. D., Lao, J. et al. (2022). Probabilistic modelling of developmental neurotoxicity based on a simplified adverse outcome pathway network. Comput Toxicol 21, 100206. doi:10.1016/j.comtox.2021.100206
Suciu, I., Pamies, D., Peruzzo, R. et al. (2023a). GxE interactions as a basis for toxicological uncertainty. Arch Toxicol 97, 2035-2049. doi:10.1007/s00204-023-03500-9
Suciu, I., Delp, J., Gutbier, S. et al. (2023b). Definition of the neurotoxicity-associated metabolic signature triggered by berberine and other respiratory chain inhibitors. Antioxidants 13, 49. doi:10.3390/antiox13010049
US EPA (1998). Health Effects Test Guidelines OPPTS 870.6300 Developmental Neurotoxicity Study. https://nepis.epa.gov/exe/zypdf.cgi/p100irwo.pdf?dockey=p100irwo.pdf
van Thriel, C., Westerink, R. H., Beste, C. et al. (2012). Translating neurobehavioural endpoints of developmental neurotoxicity tests into in vitro assays and readouts. Neurotoxicology 33, 911-924. doi:10.1016/j.neuro.2011.10.002
van Vliet, E., Stoppini, L., Balestrino, M. et al. (2007). Electrophysiological recording of re-aggregating brain cell cultures on multi-electrode arrays to detect acute neurotoxic effects. Neurotoxicology 28, 1136-1146. doi:10.1016/j.neuro.2007.06.004
van Vliet, E., Morath, S., Linge, J. et al. (2008). A novel in vitro metabolomics approach for neurotoxicity testing, proof of principle for methyl mercury chloride and caffeine. Neurotoxicology 29, 1-12. doi:10.1016/j.neuro.2007.09.007
van Vliet, E., Daneshian, M., Beilmann, M. et al. (2014). Current approaches and future role of high content imaging in safety sciences and drug discovery. ALTEX 31, 479-493. doi:10.14573/altex.1405271
Villa, C., Combi, R., Conconi, D. et al. (2021). Patient-derived induced pluripotent stem cells (iPSCs) and cerebral organoids for drug screening and development in autism spectrum disorder: Opportunities and challenges. Pharmaceutics 13, 280. doi:10.3390/pharmaceutics13020280
Vinken, M., Benfenati, E., Busquet, F. et al. (2021). Safer chemicals using less animals: Kick-off of the European ONTOX project. Toxicology 458, 152846. doi:10.1016/j.tox.2021.152846
Wegscheid, M. L., Anastasaki, C., Hartigan, K. A. et al. (2021). Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis. Cell Rep 36, 109315. doi:10.1016/j.celrep.2021.109315
Willett, C. E. (2018). The use of adverse outcome pathways (AOPs) to support chemical safety decisions within the context of integrated approaches to testing and assessment (IATA). In H. Kojima, T. Seidle and H. Spielmann (eds), Alternatives to Animal Testing (83-90). Singapore: Springer. doi:10.1007/978-981-13-2447-5_11
Yamada, S., Hirano, Y., Kurosawa, O. et al. (2019). Evaluation of developmental neurotoxicity using neural differentiation potency in human iPS cells. Proc Annu Meet Jpn Pharmacol Soc 92. https://www.jstage.jst.go.jp/article/jpssuppl/92/0/92_3-P-127/_pdf
Yi, Z., Gao, H., Ji, X. et al. (2021). Mapping drug-induced neuropathy through in-situ motor protein tracking and machine learning. J Am Chem Soc 143, 14907-14915. doi:10.1021/jacs.1c07312
Zablotsky, B., Black, L. I., Maenner, M. J. et al. (2019). Prevalence and trends of developmental disabilities among children in the US: 2009-2017. Pediatrics 144, e20190811. doi:10.1542/peds.2019-0811
Zhang, L., Li, M., Zhang, D. et al. (2023). Developmental neurotoxicity (DNT) QSAR combination prediction model establishment and structural characteristics interpretation. Toxicol Res 13, tfad116. doi:10.1093/toxres/tfad116
Zhong, X., Harris, G., Smirnova, L. et al. (2020). Antidepressant paroxetine exerts developmental neurotoxicity in an iPSC-derived 3D human brain model. Front Cell Neurosci 14, 25. doi:10.3389/fncel.2020.00025