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Novel In Vitro and In Silico Approaches to Study Developmental Neurotoxicity

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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 12894

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Special Issue Editor

Dr. David Pamies

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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

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

neurotoxicity
developmental neurotoxicity
in vitro assay
alternatives to animal teting

Published Papers (3 papers)

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Research

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21 pages, 2335 KiB

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms221810079 - 18 Sep 2021

Cited by 5 | Viewed by 2998

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 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

Open AccessArticle

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179473 - 31 Aug 2021

Cited by 26 | Viewed by 4607

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 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

Jump to: Research

21 pages, 1443 KiB

Open AccessReview

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://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157929 - 25 Jul 2021

Cited by 15 | Viewed by 4315

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 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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