Establishment of a human cell-based in vitro battery to assess developmental neurotoxicity hazard of chemicals

Chemosphere, Journal Year: 2022, Volume and Issue: 311, P. 137035 - 137035

Published: Oct. 31, 2022

Developmental neurotoxicity (DNT) is a major safety concern for all chemicals of the human exposome. However, DNT data from animal studies are available only small percentage manufactured compounds. Test methods with higher throughput than current regulatory guideline methods, and improved relevance urgently needed. We therefore explored feasibility hazard assessment based on new approach (NAMs). An in vitro battery (IVB) was assembled ten individual NAMs that had been developed during past years to probe effects various fundamental neurodevelopmental processes. All assays used neural cells at different developmental stages. This allowed us assess disturbances of: (i) proliferation progenitor (NPC); (ii) migration crest cells, radial glia neurons oligodendrocytes; (iii) differentiation NPC into (iv) neurite outgrowth peripheral central neurons. In parallel, cytotoxicity measures were obtained. The concentration-dependent screening reliable biostatistical processing complex multi-dimensional set 120 test compounds, containing subsets pre-defined positive negative provided alerts (hit or borderline) 24 28 known toxicants (82% sensitivity), none 17 controls. Based results this screen project, strategies how IVB may be context risk scenarios employing integrated approaches testing (IATA).

Language: Английский

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New approach methods to assess developmental and adult neurotoxicity for regulatory use: a PARC work package 5 project

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

Published: April 26, 2024

In the European regulatory context, rodent in vivo studies are predominant source of neurotoxicity information. Although they form a cornerstone neurotoxicological assessments, costly and topic ethical debate. While public expects chemicals products to be safe for developing mature nervous systems, considerable numbers commerce have not, or only limited extent, been assessed their potential cause neurotoxicity. As such, there is societal push toward replacement animal models with vitro alternative methods. New approach methods (NAMs) can contribute knowledge base, increase chemical safety, modernize hazard risk assessment. Provided reach an acceptable level relevance reliability, NAMs may considered as replacements specific studies. The Partnership Assessment Risks from Chemicals (PARC) addresses challenges development implementation collaboration agencies, Project 5.2.1e (Neurotoxicity) aims develop evaluate developmental (DNT) adult (ANT) understand applicability domain detection endocrine disruption epigenetic perturbation. To speed up assay time reduce costs, we identify early indicators later-onset effects. Ultimately, will assemble second-generation first-generation test batteries, both which aim provide assessors industry stakeholders robust, speedy, lower-cost, informative next-generation assessment tools.

Language: Английский

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Nuclear hormone receptors control fundamental processes of human fetal neurodevelopment: Basis for endocrine disruption assessment

Environment International, Journal Year: 2025, Volume and Issue: 198, P. 109400 - 109400

Published: March 21, 2025

Despite growing awareness of endocrine disrupting chemicals (EDCs), knowledge gaps remain regarding their effects on human brain development. EDC risk assessment focuses primarily EATS modalities (estrogens, androgens, thyroid hormones, and steroidogenesis), overlooking the broader range hormone receptors expressed in developing brain. This limits evaluation for potential to cause disruption-mediated developmental neurotoxicity (ED-DNT). The Neurosphere Assay, an vitro test method (DNT) evaluation, is integral component DNT testing battery, which has been used screen a broad domain environmental chemicals. Here, we define endocrine-related applicability Assay by assessing impact specificity 14 seven key neurodevelopmental processes (KNDPs), neural progenitor cell (NPC) proliferation, migration radial glia, neurons, oligodendrocytes, neurite outgrowth, differentiation neurons oligodendrocytes. Comparative analyses rat NPCs both sexes revealed species- sex-specific responses. Mechanistic insights were obtained through RNA sequencing agonist/antagonist co-exposures. Most receptor agonists modulated KNDPs at concentrations physiologically relevant concentrations. Phenotypic induced glucocorticoid (GR), liver X (LXR), peroxisome proliferator-activated beta/delta (PPARβδ), retinoic acid (RAR) retinoid (RXR) activation counteracted antagonists, confirming specificity. Transcriptomics highlighted crosstalk involvement conserved pathways (e.g. Notch Wnt). Species comparisons identified limited concordance receptor-regulated between NPCs. study presents novel findings cellular molecular actions fetal NPCs, highlights major species differences, illustrates Assay's relevance detecting MoAs, supporting its application human-based ED-DNT assessment.

Language: Английский

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Bridging imaging-based in vitro methods from biomedical research to regulatory toxicology

Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Language: Английский

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Developmental Neurotoxicity as a Case Example for a Six-Step Framework for the Sustainable Regulatory Implementation of NAMs

Current Opinion in Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 100528 - 100528

Published: April 1, 2025

Language: Английский

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A human iPSC-based in vitro neural network formation assay to investigate neurodevelopmental toxicity of pesticides

ALTEX, Journal Year: 2023, Volume and Issue: unknown, P. 452 - 470

Published: Jan. 1, 2023

Proper brain development is based on the orchestration of key neurodevelopmental processes (KNDP), including for­mation and function neural networks. If at least one KNDP affected by a chemical, an adverse outcome expected. To enable higher testing throughput than guideline animal experiments, developmental neurotoxicity (DNT) in vitro battery (DNT IVB) comprising variety assays that model several KNDPs was set up. Gap analysis revealed need for human-based assay to assess network formation (NNF). Therefore, we established human NNF (hNNF) assay. A co-culture comprised induced pluripotent stem cell (hiPSC)-derived excitatory inhibitory neurons as well primary astroglia differentiated 35 days microelectrode arrays (MEA), spontaneous electrical activity, together with cytotoxicity, assessed weekly basis after washout compounds 24 h prior measurements. In addition characterization test system, challenged 28 com­pounds, mainly pesticides, identifying their DNT potential evaluating specific spike-, burst-, parameters. This approach confirmed suitability screening environmental chemicals. Comparison benchmark con­centrations (BMC) (rNNF) rat cortical cells differences sensitivity. Together successful implementation hNNF data into postulated stressor-specific pathway (AOP) associated plausible molecular initiating event deltamethrin, this study suggests useful complement IVB.

Language: Английский

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Nanoparticles Dysregulate the Human Placental Secretome with Consequences on Angiogenesis and Vascularization

Advanced Science, Journal Year: 2024, Volume and Issue: 11(28)

Published: May 20, 2024

Exposure to nanoparticles (NPs) in pregnancy is increasingly linked adverse effects on embryo-fetal development and health later life. However, the developmental toxicity mechanisms of NPs are largely unknown, particular potential placental secretome, which orchestrates many processes pivotal for success. This study demonstrates extensive material- stage-specific deregulation signaling from a single exposure human explants physiologically relevant concentrations engineered (silica (SiO

Language: Английский

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Molecular and Functional Characterization of Different BrainSphere Models for Use in Neurotoxicity Testing on Microelectrode Arrays

Cells, Journal Year: 2023, Volume and Issue: 12(9), P. 1270 - 1270

Published: April 27, 2023

The currently accepted methods for neurotoxicity (NT) testing rely on animal studies. However, high costs and low throughput hinder their application large numbers of chemicals. To overcome these limitations, in vitro are being developed based human-induced pluripotent stem cells (hiPSC) that allow higher at lower costs. We applied six different protocols to generate 3D BrainSphere models acute NT evaluation. These include three media 2D neural induction two subsequent differentiation resulting self-organized, organotypic neuron/astrocyte microtissues. All yielded nearly 100% NESTIN-positive hiPSC-derived progenitor (hiNPCs), though with gene expression profiles concerning regional patterning. Moreover, immunocytochemistry analyses revealed the choice determines patterns. On functional level, BrainSpheres exhibited levels electrical activity microelectrode arrays (MEA). Spike sorting allowed characterization mixed cultures consisting GABAergic, glutamatergic, dopaminergic, serotonergic, cholinergic neurons. A test method testing, human multi-neurotransmitter receptor (hMNR) assay, was proposed apply such MEA-based spike sorting. promising tools not only toxicology but also drug development disease modeling.

Language: Английский

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Advancing Endocrine Disruptors via In Vitro Evaluation: Recognizing the Significance of the Organization for Economic Co-Operation and Development and United States Environmental Protection Agency Guidelines, Embracing New Assessment Methods, and the Urgent Need for a Comprehensive Battery of Tests

Toxics, Journal Year: 2024, Volume and Issue: 12(3), P. 183 - 183

Published: Feb. 28, 2024

Efforts are being made globally to improve the evaluation and understanding of endocrine-disrupting chemicals. Recognition their impact on human health environment has stimulated attention research in this field. Various stakeholders, including scientists, regulatory agencies, policymakers, industry representatives, collaborating develop robust methodologies guidelines for assessing these disruptors. A key aspect efforts is development standardized testing protocols that aim provide consistent reliable methods identifying characterizing endocrine When evaluating potential activity chemicals, no single test capable detecting all relevant agents. The battery approach designed reduce risk false negative results compounds with toxic potential. weight-of-evidence therefore necessary disruptor evaluation. This considers various types data from multiple sources, overall strength, consistency, reliability evidence. OECD highly regarded scientific rigor, transparency, consensus-based process. It crucial explore new can effectively evaluate risks associated Integrating into a comprehensive framework will enhance assessments facilitate informed decisions regarding regulation management substances, ensuring protection adverse effects.

Language: Английский

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Optimal Production of 3D Neuronal Lineage Population by Morphological Classification

Tissue Engineering and Regenerative Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: May 13, 2025

Language: Английский

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