Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

Aschner, Michael

doi:10.14573/altex.1604201s

Cited by 11 publications

(11 citation statements)

References 91 publications

(117 reference statements)

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“…Finally, ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), was selected as a negative reference compound for assay development, based on the recommendations given in a recent review on reference compounds for alternative DNT test methods [92]. This is a particularly relevant compound for our study as it crosses the BBB [93], has not been demonstrated to elicit DNT, and is a drug accepted during pregnancy and for children [92]. Ibuprofen has also been used as a negative reference compound in a recent in vitro toxicity study on neural cells derived from human embryonic stem cells [94].…”

Section: Selection Of Test Chemicals From Literature Reviewmentioning

confidence: 99%

Human IPSC-Derived Model to Study Myelin Disruption

Chesnut

Paschoud

Repond

et al. 2021

IJMS

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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.

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Section: Selection Of Test Chemicals From Literature Reviewmentioning

confidence: 99%

Human IPSC-Derived Model to Study Myelin Disruption

Chesnut

Paschoud

Repond

et al. 2021

IJMS

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“…In particular, there is an ongoing search for alternative approaches to evaluate developmental neurotoxicity to replace traditional developmental neurotoxicity testing guidelines involving whole animals (e.g., refs and ). There are several alternative approaches being considered and many include, either explicitly or implicitly, an adverse outcome pathway-like approach. , Among the key events of neurodevelopment identified in AOP approaches are proliferation, migration, differentiation, neurite outgrowth, synaptogenesis, network formation and network function, synaptic pruning, and apoptosis. , These frameworks for evaluating developmental neurotoxicity of chemicals are also relevant for assessing nanoparticles.…”

Section: Adverse Outcome Pathwaymentioning

confidence: 99%

“…155,156 Among the key events of neurodevelopment identified in AOP approaches are proliferation, migration, differentiation, neurite outgrowth, synaptogenesis, network formation and network function, synaptic pruning, and apoptosis. 157,158 These frameworks for evaluating developmental neurotoxicity of chemicals are also relevant for assessing nanoparticles.…”

Section: Molecular Initiating Event (Mie)mentioning

confidence: 99%

Neurotoxicology of Nanomaterials

Boyes

Thriel

2020

Chem. Res. Toxicol.

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The remarkable advances coming about through nanotechnology promise to revolutionize many aspects of modern life; however, these advances come with a responsibility for due diligence to ensure that they are not accompanied by adverse consequences for human health or the environment. Many novel nanomaterials (having at least one dimension <100 nm) could be highly mobile if released into the environment and are also very reactive, which has raised concerns for potential adverse impacts including, among others, the potential for neurotoxicity. Several lines of evidence led to concerns for neurotoxicity, but perhaps none more than observations that inhaled nanoparticles impinging on the mucosal surface of the nasal epithelium could be internalized into olfactory receptor neurons and transported by axoplasmic transport into the olfactory bulbs without crossing the blood−brain barrier. From the olfactory bulb, there is concern that nanomaterials may be transported deeper into the brain and affect other brain structures. Of course, people will not be exposed to only engineered nanomaterials, but rather such exposures will occur in a complex mixture of environmental materials, some of which are incidentally generated particles of a similar inhalable size range to engineered nanomaterials. To date, most experimental studies of potential neurotoxicity of nanomaterials have not considered the potential exposure sources and pathways that could lead to exposure, and most studies of nanomaterial exposure have not considered potential neurotoxicity. Here, we present a review of potential sources of exposures to nanoparticles, along with a review of the literature on potential neurotoxicity of nanomaterials. We employ the linked concepts of an aggregate exposure pathway (AEP) and an adverse outcome pathway (AOP) to organize and present the material. The AEP includes a sequence of key events progressing from material sources, release to environmental media, external exposure, internal exposure, and distribution to the target site. The AOP begins with toxicant at the target site causing a molecular initiating event and, like the AEP, progress sequentially to actions at the level of the cell, organ, individual, and population. Reports of nanomaterial actions are described at every key event along the AEP and AOP, except for changes in exposed populations that have not yet been observed. At this last stage, however, there is ample evidence of population level effects from exposure to ambient air particles that may act similarly to engineered nanomaterials. The data give an overall impression that current exposure levels may be considerably lower than those reported experimentally to be neurotoxic. This impression, however, is tempered by the absence of long-term exposure studies with realistic routes and levels of exposure to address concerns for chronic accumulation of materials or damage. Further, missing across the board are "key event relationships", which are quantitative expressions linking the key events of either the AEP or ...

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“…The key events of brain development covered by the in vitro methods used in ENDpoiNTs have been chosen according to the available mechanistic insights pertaining to DNT (see Figure 2) [42][43][44][45]. The experimental models employed are summarized in Table 3.…”

Section: Relevant Models and Endpoints To Test Ed-induced Dntmentioning

confidence: 99%

The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

Lupu

Andersson

Bornehag

et al. 2020

IJMS

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Ubiquitous exposure to endocrine-disrupting chemicals (EDCs) has caused serious concerns about the ability of these chemicals to affect neurodevelopment, among others. Since endocrine disruption (ED)-induced developmental neurotoxicity (DNT) is hardly covered by the chemical testing tools that are currently in regulatory use, the Horizon 2020 research and innovation action ENDpoiNTs has been launched to fill the scientific and methodological gaps related to the assessment of this type of chemical toxicity. The ENDpoiNTs project will generate new knowledge about ED-induced DNT and aims to develop and improve in vitro, in vivo, and in silico models pertaining to ED-linked DNT outcomes for chemical testing. This will be achieved by establishing correlative and causal links between known and novel neurodevelopmental endpoints and endocrine pathways through integration of molecular, cellular, and organismal data from in vitro and in vivo models. Based on this knowledge, the project aims to provide adverse outcome pathways (AOPs) for ED-induced DNT and to develop and integrate new testing tools with high relevance for human health into European and international regulatory frameworks.

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Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

Cited by 11 publications

References 91 publications

Human IPSC-Derived Model to Study Myelin Disruption

Human IPSC-Derived Model to Study Myelin Disruption

Neurotoxicology of Nanomaterials

The ENDpoiNTs Project: Novel Testing Strategies for Endocrine Disruptors Linked to Developmental Neurotoxicity

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