Effects of all-trans and 9-cis retinoic acid on differentiating human neural stem cells in vitro

Toxicology, Journal Year: 2023, Volume and Issue: 487, P. 153461 - 153461

Published: Feb. 16, 2023

Cyanobacterial blooms are known sources of environmentally-occurring retinoid compounds, including all-trans and 9-cis retinoic acids (RAs). The developmental hazard for aquatic organisms has been described, while the implications human health assessment not yet sufficiently characterized. Here, we employ a neural stem cell model that can differentiate in vitro into mixed culture neurons glia. Cells were exposed to non-cytotoxic 8–1000 nM or RA 9–18 days (DIV13 DIV22, respectively). Impact on biomarkers was analyzed gene expression (RT-qPCR) protein level (western blot proteomics) at both time points; network patterning (immunofluorescence) DIV22. exposure significantly concentration-dependently increased acid receptors metabolizing enzyme CYP26A1, confirming chemical-specific response model. Expression thyroid hormone signaling-related genes remained mostly unchanged. Markers progenitors/stem cells (PAX6, SOX1, SOX2, NESTIN) decreased with increasing concentrations, though basal population remained. Neural markers (DCX, TUJ1, MAP2, NeuN, SYP) unchanged high concentrations (200–1000 nM). Conversely, (astro-)glial marker S100β Together, biomarker analysis indicates an RA-dependent promotion glial fates over differentiation, despite abundance during differentiation. Interestingly, induced substantial changes morphology: low resulted network-like differentiation pattern, RA) almost completely prevented such patterning. After functional confirmation function, morphological features could present proxy formation assessment, apical key event (neuro-)developmental Adverse Outcome Pathways. described application (developmental) neurotoxicity emerging environmentally-relevant retinoids contributes evidence-base use differentiating models risk assessment.

Language: Английский

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Zebrafish and nematodes as whole organism models to measure developmental neurotoxicity

Critical Reviews in Toxicology, Journal Year: 2024, Volume and Issue: 54(5), P. 330 - 343

Published: May 27, 2024

Despite the growing epidemiological evidence of an association between toxin exposure and developmental neurotoxicity (DNT), systematic testing DNT is not mandatory in international regulations for admission pharmaceuticals or industrial chemicals. However, to date around 200 compounds, ranging from pesticides, chemicals, have been tested current OECD test guidelines (TG-443 TG-426). There are calls development new approach methodologies (NAMs) DNT, which has resulted a battery using

Language: Английский

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From Pipeline to Plant Protection Products: Using New Approach Methodologies (NAMs) in Agrochemical Safety Assessment

Journal of Agricultural and Food Chemistry, Journal Year: 2024, Volume and Issue: 72(19), P. 10710 - 10724

Published: April 30, 2024

The human population will be approximately 9.7 billion by 2050, and food security has been identified as one of the key issues facing global population. Agrochemicals are an important tool available to farmers that enable high crop yields continued access healthy foods, but average new agrochemical active ingredient takes more than ten years, 350 million dollars, 20,000 animals develop register. time, monetary, animal costs incentivize use New Approach Methodologies (NAMs) in early-stage screening prioritize chemical candidates. This review outlines NAMs currently or can adapted for programs. It covers vitro screens on horizon areas regulatory concern. Overall, with enables prioritization development agrochemicals without environmental health concerns through a directed, agile, iterative program before animal-based testing is even considered.

Language: Английский

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The potential of mechanistic information organised within the AOP framework to increase regulatory uptake of the developmental neurotoxicity (DNT) in vitro battery of assays

Reproductive Toxicology, Journal Year: 2021, Volume and Issue: 103, P. 159 - 170

Published: June 17, 2021

A major challenge in regulatory developmental neurotoxicity (DNT) assessment is lack of toxicological information for many compounds. Therefore, the Test Guidelines programme Organisation Economic Cooperation and Development (OECD) took initiative to coordinate an international collaboration between diverse stakeholders consider integration alternative approaches towards improving current chemical DNT testing. During past few years, a series workshops was organized during which consensus reached that incorporation testing battery relies on vitro assays anchored key neurodevelopmental processes should be developed. These include neural progenitor cell proliferation, neuronal oligodendrocyte differentiation, migration, neurite outgrowth, synaptogenesis network formation, as well events identified existing Adverse Outcome Pathways (AOPs). AOPs deliver mechanistic causal links molecular initiating event, intermediate adverse outcome concern, providing biological context facilitate development Integrated Approaches Testing Assessment (IATA) various purposes. Developing IATA case studies, using derived from AOPs, expected increase scientific confidence use methods within IATA, thereby facilitating uptake. This manuscript summarizes state efforts enhance by focusing role informing different purposes, aiming OECD guidance document data interpretation.

Language: Английский

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The Future of 3D Brain Cultures in Developmental Neurotoxicity Testing

Frontiers in Toxicology, Journal Year: 2022, Volume and Issue: 4

Published: Jan. 27, 2022

Human brain is undoubtedly the most complex organ in body. Thus, it difficult to develop adequate and at same time human relevant test systems models cover aspects of homeostasis even more challenging address development. Animal tests for Developmental Neurotoxicity (DNT) have been devised, but because underlying mechanisms neural development, interspecies differences, there are many limitations animal-based approaches. The high costs, number animals used per technical difficulties these prohibitive routine DNT chemical screening. Therefore, potential chemicals remain unidentified. New approach methodologies (NAMs) needed change this. Experts field recommended use a battery vitro be initial prioritization high-risk environmental testing. Microphysiological (MPS) mimic vivo counterpart terms cellular composition, recapitulation regional architecture functionality. These amendable with promising features such as (i) complexity, (ii) closer response (iii) possibility multiplex assays one system, which can increase throughput predictivity health. resent progress 3D MPS research, advantages, future perspectives discussed this review.

Language: Английский

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