Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(5), P. 1271 - 1295

Published: March 13, 2024

Abstract Adult neurotoxicity (ANT) and developmental (DNT) assessments aim to understand the adverse effects underlying mechanisms of toxicants on human nervous system. In recent years, there has been an increasing focus so-called new approach methodologies (NAMs). The Organization for Economic Co-operation Development (OECD), together with European American regulatory agencies, promote use validated alternative test systems, but date, guidelines DNT ANT assessment rely primarily classical animal testing. Alternative methods include both non-animal approaches systems non-vertebrates (e.g., nematodes) or non-mammals fish). Therefore, this review summarizes advances NAMs focusing highlights potential current critical issues full implementation these in future. status vitro battery (DNT IVB) is also reviewed as a first step context. Critical such (i) need batteries method integration (from silico vivo alternatives, e.g., zebrafish, C. elegans ) requiring interdisciplinarity manage complexity, (ii) interlaboratory transferability, (iii) urgent validation are discussed.

Language: Английский

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Comprehensive mapping of the AOP-Wiki database: identifying biological and disease gaps

Frontiers in Toxicology, Journal Year: 2024, Volume and Issue: 6

Published: March 8, 2024

Introduction: The Adverse Outcome Pathway (AOP) concept facilitates rapid hazard assessment for human health risks. AOPs are constantly evolving, their number is growing, and they referenced in the AOP-Wiki database, which supported by OECD. Here, we present a study that aims at identifying well-defined biological areas, as well gaps within future research needs. It does not intend to provide systematic comprehensive summary of available literature on but summarizes maps knowledge diseases represented already developed (with OECD endorsed status or under validation). Methods: Knowledge from database were extracted prepared analysis using multi-step procedure. An automatic mapping existing information (i.e., genes/proteins diseases) was performed bioinformatics tools overrepresentation Gene Ontology DisGeNET), allowing both classification development AOP networks (AOPN). Results: related genitourinary system, neoplasms developmental anomalies most frequently investigated AOP-Wiki. evaluation three priority cases immunotoxicity non-genotoxic carcinogenesis, endocrine metabolic disruption, adult neurotoxicity) EU-funded PARC project (Partnership Risk Assessment Chemicals) presented. These used highlight under- over-represented adverse outcomes identify prioritize further research. Discussion: results contribute more understanding effects associated with molecular events AOPs, aid refining risk stressors mitigation strategies. Moreover, FAIRness data meets principles findability, accessibility, interoperability, reusability (FAIR)) appears be an important consideration development.

Language: Английский

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Oligodendrogenesis and myelination tracing in a CRISPR/Cas9-engineered brain microphysiological system

Frontiers in Cellular Neuroscience, Journal Year: 2023, Volume and Issue: 16

Published: Jan. 19, 2023

Introduction Oligodendrocytes (OLs) are the myelin-forming cells of central nervous system (CNS). Although OLs can be differentiated from human-induced pluripotent stem (hiPSCs), in vitro modeling axon myelination human remains challenging. Brain microphysiological systems (bMPS, e.g. organoids) complex three-dimensional (3D) cultures that offer an ideal to study this process as differentiate a more vivo -like environment; surrounded by neurons and astrocytes, which support axons. Methods Here, we take advantage CRISPR/Cas9 technology generate hiPSC line proteolipid protein 1 (PLP1), marker, is tagged with super-fold GFP (sfGFP). While generating PLP1-sfGFP reporter, used reverse transfection obtained higher Knock-In (KI) efficiency compared forward (61–72 vs. 46%). Results After validation KI quality control line, selected clones were into bMPS, fidelity, specificity, function PLP verified model. We tracked different stages oligodendrogenesis lines based on + cells’ morphology, presence surrounding axons during bMPS’ differentiation. Finally, challenged bMPS cuprizone quantified changes both percentage expressing intensity expression. Discussion This work demonstrates efficient method for description new 3D model OL differentiation, migration, maturation neurodevelopment well response environmental chemicals or disease-associated stressors.

Language: Английский

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Revolutionizing developmental neurotoxicity testing – a journey from animal models to advanced in vitro systems

ALTEX, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Developmental neurotoxicity (DNT) testing has seen enormous progress over the last two decades. Preceding even publication of animal-based OECD test guideline for DNT in 2007, a series non-animal technology workshops and conferences (starting 2005) shaped community that delivered comprehensive battery vitro methods (IVB). Its data interpretation is covered by very recent guidance (No. 377). Here, we aim to overview field, focusing on evolution strategies, role emerging technologies, impact guidelines testing. In particular, this an example targeted development animal-free approach one most complex hazards chemicals human health. These developments started literally from blank slate, with no proposed alternative available. Over decades, cutting-edge science enabled design spares animals enables throughput challenging hazard. While it evident field needs regulation, massive economic decreased cognitive capacity caused chemical exposure should be prioritized more highly. Beyond this, claim fame scientific brought understanding brain, its development, how can perturbed. Plain language summaryDevelopmental predicts hazard brain development. Comprehensive advanced strategies using now replace approaches assess large numbers accurately efficiently than approach. Recent formalized DNT, marking pivotal achievement field. The shift towards reflects both commitment animal welfare growing recognition public health impacts associated impaired function exposures. innovations ultimately contribute safer management better protection health, especially during vulnerable stages

Language: Английский

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Microenvironments Matter: Advances in Brain-on-Chip

Biosensors, Journal Year: 2023, Volume and Issue: 13(5), P. 551 - 551

Published: May 16, 2023

To highlight the particular needs with respect to modeling unique and complex organization of human brain structure, we reviewed state-of-the-art in devising models engineered instructive microenvironments. acquire a better perspective on brain’s working mechanisms, first summarize importance regional stiffness gradients tissue, varying per layer cellular diversities layers. Through this, one can an understanding essential parameters emulating vitro. In addition organizational architecture, addressed also how mechanical properties have impact neuronal cell responses. this respect, advanced vitro platforms emerged profoundly changed methods efforts from past, mainly focusing animal or line research. The main challenges imitating features dish are regard composition functionality. neurobiological research, there now that aim cope such by self-assembly human-derived pluripotent stem cells (hPSCs), i.e., brainoids. Alternatively, these brainoids be used stand-alone conjunction Brain-on-Chip (BoC) platform technology, 3D-printed gels, other types guidance features. Currently, made giant leap forward regarding cost-effectiveness, ease-of-use, availability. We bring recent developments together into review. believe our conclusions will give novel towards advancing microenvironments for BoCs functions either healthy diseased states brain.

Language: Английский

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Navigating Neurotoxicity and Safety Assessment of Nanocarriers for Brain Delivery: Evaluation Models and Insights

Acta Biomaterialia, Journal Year: 2024, Volume and Issue: 189, P. 25 - 56

Published: Sept. 20, 2024

Language: Английский

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Microinstrumentation for Brain Organoids

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: 13(21)

Published: Jan. 13, 2024

Brain organoids are three-dimensional aggregates of self-organized differentiated stem cells that mimic the structure and function human brain regions. Organoids bridge gaps between conventional drug screening models such as planar mammalian cell culture, animal studies, clinical trials. They can revolutionize fields developmental biology, neuroscience, toxicology, computer engineering. Conventional microinstrumentation for cellular engineering, microfluidic chips; microelectrode arrays (MEAs); optical, magnetic, acoustic techniques, has limitations when applied to (3D) organoids, primarily due their limits with inherently two-dimensional geometry interfacing. Hence, there is an urgent need develop new instrumentation compatible live culture techniques scalable 3D formats relevant organoids. This review discusses approaches emerging necessary advanced organoid-machine interfaces. Specifically, this article surveys recently developed microinstrumentation, including printed curved microfluidics, fast-scan optical buckling self-folding MEAs, interfaces electrochemical measurements, spatially controllable magnetic technologies two-way information transfer highlights key challenges must be addressed robust organoid reliable spatiotemporal transfer.

Language: Английский

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Novel Strategy to Assess the Neurotoxicity of Organic Solvents Such as Glycol Ethers: Protocol for Combining In Vitro and In Silico Methods With Human-Controlled Exposure Experiments

JMIR Research Protocols, Journal Year: 2024, Volume and Issue: 13, P. e50300 - e50300

Published: Jan. 18, 2024

Chemicals are not required to be tested systematically for their neurotoxic potency, although they may contribute the development of several neurological diseases. The absence systematic testing partially explained by current Organisation Economic Co-operation and Development (OECD) Test Guidelines, which rely on animal experiments that expensive, laborious, ethically debatable. Therefore, it is important understand risks exposed workers general population domestic products. In this study, we propose a strategy test neurotoxicity solvents using commonly used glycol ethers as case study. This study aims provide can regulatory agencies industries rank according demonstrate use toxicokinetic modeling predict air concentrations below no observed adverse effect (NOAECs) human determined in vitro assays. proposed focuses complex 3D brain model (BrainSpheres) derived from human-induced pluripotent stem cells (hiPSCs). accompanied vivo, vitro, silico models blood-brain barrier (BBB) liver metabolism. data integrated into model. Internal predicted compared with results vivo human-controlled exposure validation. then reverse dosimetry concentrations, leading lower than NOAECs hiPSC-derived These predictions will protection exposures. Swiss Centre Applied Human Toxicology funded project, commencing January 2021. Ethics Committee approval was obtained November 16, 2022. Zebrafish methods started February 2021, whereas recruitment volunteers 2022 after COVID-19 pandemic-related restrictions were lifted. We anticipate able 2026 6 propylene based incorporating metabolism, BBB leakage parameters, toxicity. great interest chemical needing seeking novel solutions develop risk assessments. It protecting health deleterious effects environmental chemicals. DERR1-10.2196/50300.

Language: Английский

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Applying iPSC Technology in Drug Discovery

Published: Jan. 1, 2025

Language: Английский

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2024 International Academy of Toxicologic Pathology (IATP) Satellite Symposium: New Approach Methodologies (NAMs) for Neurotoxicity Assessment and Regulatory Perspectives

Toxicologic Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: May 15, 2025

The International Academy of Toxicologic Pathology (IATP) Satellite Symposium on “New Approach Methodologies (NAMs) for Neurotoxicity Assessment and Regulatory Perspectives,” organized in Spain, addressed the growing need improved assessment neurotoxicity. Traditional neurotoxicity using vivo animal studies are impractical testing substantial number environmental chemicals that currently lack data early detection neuro-related adverse reactions drug discovery. NAMs, including human vitro assays small model organisms, have been developed faster cost-effective neurotoxic potential. While NAMs offer practicality, utility, valuable mechanistic insights, their integration into regulatory decision-making requires robust scientific validation technical characterization. Confidence application can be supported by mapping cellular outcomes to neuropathological findings mammals, humans, through Adverse Outcome Pathway (AOP) framework, Integrated Testing (IATA). Case presented demonstrated chemical safety evaluations, focusing developmental (DNT), Parkinson’s disease, drug-induced seizures. In conjunction with toxicology studies, represent a significant step toward advancing toxicity via hazard identification screening assessments.

Language: Английский

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