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Novel In Vitro and In Silico Approaches to Study Developmental Neurotoxicity

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 15428

Special Issue Editor

Dr. David Pamies

E-Mail Website
Guest Editor
Department of Biomedical Sciences, University of Lausanne, CH-1005 Lausanne, Switzerland
Interests: neurology; neurotoxicology; developmental neurotoxicology; organoids; in vitro brain models; glioblastoma

Special Issue Information

Dear Colleagues,

There are sufficient shreds of evidence that increased exposure to environmental contaminants plays a substantial role in the increase in developmental diseases. Due to the complexity of the brain, this organ ishighly vulnerable to toxic insult. Current developmental neurotoxicity (DNT) testing guidelines present high cost and are very time consuming, generating a lack of information and knowledge concerning  new chemicals reaching the market. DNT experts have suggested changing/updating current testing guidelines with a comprehensive in vitro DNT strategy, consisting of a test battery that recapitulates key events during brain development. A DNT screening program has been developed under EFSA, the JRC, the US EPA, and the OECD to develop a complete DNT testing battery that could replace the actual guidelines OECD TG 426 or OECD TG 443.

The special issue aims to cover original research and reviews focused on new advances in in vitro and in silico neurotoxicity testing strategies and models which in the future could be used or further adapt for developmental neurotoxicology studies.

Dr. David Pamies
Guest Editor

Manuscript Submission Information

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Keywords

  • neurotoxicity
  • developmental neurotoxicity
  • in vitro assay
  • alternatives to animal teting

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Published Papers (3 papers)

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Research

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21 pages, 2335 KiB  
Article
Profiling of Human Neural Crest Chemoattractant Activity as a Replacement of Fetal Bovine Serum for In Vitro Chemotaxis Assays
by Xenia Dolde, Christiaan Karreman, Marianne Wiechers, Stefan Schildknecht and Marcel Leist
Int. J. Mol. Sci. 2021, 22(18), 10079; https://doi.org/10.3390/ijms221810079 - 18 Sep 2021
Cited by 6 | Viewed by 3602
Abstract
Fetal bovine serum (FBS) is the only known stimulus for the migration of human neural crest cells (NCCs). Non-animal chemoattractants are desirable for the optimization of chemotaxis as-says to be incorporated in a test battery for reproductive and developmental toxicity. We con-firmed here [...] Read more.
Fetal bovine serum (FBS) is the only known stimulus for the migration of human neural crest cells (NCCs). Non-animal chemoattractants are desirable for the optimization of chemotaxis as-says to be incorporated in a test battery for reproductive and developmental toxicity. We con-firmed here in an optimized transwell assay that FBS triggers directed migration along a con-centration gradient. The responsible factor was found to be a protein in the 30–100 kDa size range. In a targeted approach, we tested a large panel of serum constituents known to be chem-otactic for NCCs in animal models (e.g., VEGF, PDGF, FGF, SDF-1/CXCL12, ephrins, endothelin, Wnt, BMPs). None of the corresponding human proteins showed any effect in our chemotaxis assays based on human NCCs. We then examined, whether human cells would produce any fac-tor able to trigger NCC migration in a broad screening approach. We found that HepG2 hepa-toma cells produced chemotaxis-triggering activity (CTA). Using chromatographic methods and by employing the NCC chemotaxis test as bioassay, the responsible protein was enriched by up to 5000-fold. We also explored human serum and platelets as a direct source, independent of any cell culture manipulations. A CTA was enriched from platelet lysates several thousand-fold. Its temperature and protease sensitivity suggested also a protein component. The capacity of this factor to trigger chemotaxis was confirmed by single-cell video-tracking analysis of migrating NCCs. The human CTA characterized here may be employed in the future for the setup of assays testing for the disturbance of directed NCC migration by toxicants. Full article
(This article belongs to the Special Issue Novel In Vitro and In Silico Approaches to Study Developmental Neurotoxicity)
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20 pages, 48587 KiB  
Article
Human IPSC-Derived Model to Study Myelin Disruption
by Megan Chesnut, Hélène Paschoud, Cendrine Repond, Lena Smirnova, Thomas Hartung, Marie-Gabrielle Zurich, Helena T. Hogberg and David Pamies
Int. J. Mol. Sci. 2021, 22(17), 9473; https://doi.org/10.3390/ijms22179473 - 31 Aug 2021
Cited by 32 | Viewed by 5706
Abstract
Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human [...] Read more.
Myelin is of vital importance to the central nervous system and its disruption is related to a large number of both neurodevelopmental and neurodegenerative diseases. The differences observed between human and rodent oligodendrocytes make animals inadequate for modeling these diseases. Although developing human in vitro models for oligodendrocytes and myelinated axons has been a great challenge, 3D cell cultures derived from iPSC are now available and able to partially reproduce the myelination process. We have previously developed a human iPSC-derived 3D brain organoid model (also called BrainSpheres) that contains a high percentage of myelinated axons and is highly reproducible. Here, we have further refined this technology by applying multiple readouts to study myelination disruption. Myelin was assessed by quantifying immunostaining/confocal microscopy of co-localized myelin basic protein (MBP) with neurofilament proteins as well as proteolipid protein 1 (PLP1). Levels of PLP1 were also assessed by Western blot. We identified compounds capable of inducing developmental neurotoxicity by disrupting myelin in a systematic review to evaluate the relevance of our BrainSphere model for the study of the myelination/demyelination processes. Results demonstrated that the positive reference compound (cuprizone) and two of the three potential myelin disruptors tested (Bisphenol A, Tris(1,3-dichloro-2-propyl) phosphate, but not methyl mercury) decreased myelination, while ibuprofen (negative control) had no effect. Here, we define a methodology that allows quantification of myelin disruption and provides reference compounds for chemical-induced myelin disruption. Full article
(This article belongs to the Special Issue Novel In Vitro and In Silico Approaches to Study Developmental Neurotoxicity)
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Review

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21 pages, 1443 KiB  
Review
Human Oligodendrocytes and Myelin In Vitro to Evaluate Developmental Neurotoxicity
by Megan Chesnut, Thomas Hartung, Helena Hogberg and David Pamies
Int. J. Mol. Sci. 2021, 22(15), 7929; https://doi.org/10.3390/ijms22157929 - 25 Jul 2021
Cited by 18 | Viewed by 5022
Abstract
Neurodevelopment is uniquely sensitive to toxic insults and there are concerns that environmental chemicals are contributing to widespread subclinical developmental neurotoxicity (DNT). Increased DNT evaluation is needed due to the lack of such information for most chemicals in common use, but in vivo [...] Read more.
Neurodevelopment is uniquely sensitive to toxic insults and there are concerns that environmental chemicals are contributing to widespread subclinical developmental neurotoxicity (DNT). Increased DNT evaluation is needed due to the lack of such information for most chemicals in common use, but in vivo studies recommended in regulatory guidelines are not practical for the large-scale screening of potential DNT chemicals. It is widely acknowledged that developmental neurotoxicity is a consequence of disruptions to basic processes in neurodevelopment and that testing strategies using human cell-based in vitro systems that mimic these processes could aid in prioritizing chemicals with DNT potential. Myelination is a fundamental process in neurodevelopment that should be included in a DNT testing strategy, but there are very few in vitro models of myelination. Thus, there is a need to establish an in vitro myelination assay for DNT. Here, we summarize the routes of myelin toxicity and the known models to study this particular endpoint. Full article
(This article belongs to the Special Issue Novel In Vitro and In Silico Approaches to Study Developmental Neurotoxicity)
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