Advances in neurotoxicology, Journal Year: 2023, Volume and Issue: unknown, P. 197 - 237
Published: Jan. 1, 2023
Language: Английский
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
Citations
12
Archives of Toxicology, Journal Year: 2025, Volume and Issue: unknown
Published: Jan. 27, 2025
Abstract Chlorpyrifos (CPF) is an organophosphorus pesticide of concern because many in vivo animal studies have demonstrated developmental toxicity exerted by this substance; however, despite its widespread use, evidence from epidemiological still limited. In study, we collected all the information generated twenty-first century on CPF using new approach methodologies. We critically evaluated and integrated coming 70 papers considering human, rodent, avian fish models. The comparison with available adverse outcome pathways allows us to conclude that outcomes observed animals, such as memory learning impairments well reduction cognitive function, could involve several mechanisms action including inhibition acetylcholinesterase, overactivation glutamate receptors activation mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, followed both disruption neurotransmitter release increase oxidative stress apoptosis.
Language: Английский
Citations
1
Neuropsychiatric Disease and Treatment, Journal Year: 2024, Volume and Issue: Volume 20, P. 2237 - 2254
Published: Nov. 1, 2024
Organophosphates (OPs) refers to a diverse group of phosphorus-containing organic compounds; they are widely used all over the world and have had an important beneficial impact on industrial agricultural production control vector transmission. Exposure OPs different toxicities (high, moderate, slight, low toxicity) can negative consequences nervous system, such as nausea, vomiting, muscle tremors, convulsions. In severe cases, it lead respiratory failure or even death. Notably, induce neuropathy in system through specific interactions with nicotinic muscarinic receptors, phosphorylating acetylcholinesterase, neuropathic target esterases. This review summarizes possible toxicological mechanisms their interplay underlying OP pesticide poisoning, including cholinesterase inhibition non-cholinesterase mechanisms. It outlines links between poisoning neurological disorders, dementia, neurodevelopmental diseases, Parkinson's disease. Additionally, explores interactions' potential therapeutic implications that may help mitigate deleterious system.
Language: Английский
Citations
7
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
Citations
12
Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)
Published: Jan. 22, 2025
The imbalance between estrogen and androgen may be an important mechanism of BPH, but the specific remains unclear. We used mixed sustained-release pellets made testosterone estradiol (T + E2) to stimulate establishment a BPH rat model. Compared prostate hyperplasia model using only androgens, new can observed have better macroscopic pathological characteristics hyperplasia. RNA-seq bioinformatics detect differentially expressed genes (DEGs) tissue novel benign prostatic group control group, including 458 DEGs, which 336 were upregulated 122 downregulated. Then, RT-qPCR confirmed authenticity sequencing results. analysis results showed that Kif4a Mki67 top core in PPI network. Moreover, we found these two positive correlation with each other multiple cancer tissues, normal cells. DEGs mainly involved mitotic nuclear division, chromosome segregation, cytokine cell receptor interactions. also regulated by 250 miRNAs. In conclusion, built T E2-induced model, discovered potentially genes, pathways, miRNA-mRNA regulatory networks.
Language: Английский
Citations
0
Critical Reviews in Toxicology, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 17
Published: March 10, 2025
Thyroid hormone (TH) is crucial for proper neurodevelopment. Insufficient TH concentrations in early life are associated with lower IQ and delayed motor development children. Intracellular levels of modulated via the transmembrane transport intracellular deiodination, can mediate gene transcription binding to nuclear receptor. Chemical exposure disrupt homeostasis modes action targeting mechanisms, thereby potentially influencing transport, deiodination or signaling. Understanding cause effect relationships chemical hazards interfering developing brain necessary identify how chemicals might disturb result neurodevelopmental disorders. Adverse Outcome Pathways (AOPs) provide a template mapping these relationships, so far multiple AOPs have been developed adverse effects on cognition. The present review aims expand current AOP networks by (1) summarizing most important factors regulation under influence TH, (2) integrating human-based mechanistic information biological pathways which be disturbed disrupting chemicals, (3) incorporating brain-specific TH-mediated physiology, including barriers cell specificity, as well clinical knowledge. TH-specific fetal highlighted supported distinguishing type specific Molecular Initiating Events (MIEs) downstream Key (KEs) astrocytes, neurons oligodendrocytes. Two main leading outcomes (AOs) areas 'cognition' 'motor function' decreased myelination due oligodendrocyte dysfunction, synaptogenesis network formation neurons. proposed framework form basis selecting developmental neurotoxic vitro silico test systems an innovative human-focused hazard testing strategy risk assessment exposure.
Language: Английский
Citations
0
Food and Chemical Toxicology, Journal Year: 2024, Volume and Issue: 187, P. 114623 - 114623
Published: March 28, 2024
Acrylamide (ACR) is a known neurotoxicant and developmental neurotoxicant. As soft electrophile, ACR reacts with thiol groups in cysteine. One hypothesis of induced neurotoxicity (DNT) conjugation reduced glutathione (GSH) leading to GSH depletion, increased reactive oxygen species (ROS) production further oxidative stress cellular damage. In this regard, we have investigated the effect on neuronal differentiation, levels ROS human neuroblastoma SH-SY5Y cell model. After 9 days differentiation exposure, significantly impaired area neurites per at non-cytotoxic concentrations (0.33 μM 10 μM). Furthermore, dysregulated nine mRNA markers important for development, five them being associated cytoskeleton organization axonal guidance. At that attenuate did neither decrease level or total levels, nor production. addition, expression was assessed no significant altered regulation after exposure up 320 μM. Thus, ACR-induced DNT not due depletion production, cytotoxic concentrations, SH-SH5Y model during differentiation.
Language: Английский
Citations
3
Stem Cell Reviews and Reports, Journal Year: 2025, Volume and Issue: unknown
Published: April 5, 2025
Language: Английский
Citations
0
IBRO Neuroscience Reports, Journal Year: 2025, Volume and Issue: 18, P. 679 - 689
Published: April 17, 2025
Neurodevelopmental studies employing animal models encounter challenges due to interspecies differences and ethical concerns. Maturing neurons of human origin, undergoing several developmental stages, present a powerful alternative. In this study, embryonic stem cell (H9 line) was differentiated into neural cells subsequently matured over 30 days. Ion AmpliSeq™ used for transcriptomic characterization cell-derived at multiple time points. Data analysis revealed progressive increase markers associated with neuronal development astrocyte markers, indicating the establishment co-culture accommodating both glial neurons. Transcriptomic pathway enrichment also more pronounced GABAergic phenotype in neurons, signifying their specialization toward type. The findings confirm robustness these across different passages demonstrate detailed progression through stages development. model is intended neurodevelopmental applications can be adapted investigate how genetic modifications or exposure chemicals, pharmaceuticals, other environmental factors influence maturation.
Language: Английский
Citations
0
NeuroToxicology, Journal Year: 2023, Volume and Issue: 97, P. 65 - 77
Published: May 18, 2023
Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches DNT assessment needed. We used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that frequent in Neuronal diseases functional annotations also differentially expressed during retinoic acid-induced differentiation model. Rotenone, valproic acid (VPA), acrylamide (ACR) methylmercury chloride (MeHg) were as positive compounds. Tolbutamide, D-mannitol clofibrate negative To determine concentrations exposure gene expression analysis, we developed pipeline neurite outgrowth by live-cell imaging. In addition, viability was measured resazurin assay. Gene analyzed RT-qPCR after 6 days compounds affected outgrowth, but with no or minimal effect viability. Methylmercury at lower than hence cells exposed highest non-cytotoxic concentration. Rotenone (7.3 nM) induced 32 genes (DEGs), ACR (70 µM) 8 DEGs, VPA (75 16 DEGs. No individual significantly dysregulated all 3 (p < 0.05), 9 2 them. (0.8 validate The SEMA5A (encoding semaphorin 5A) CHRNA7 nicotinic acetylcholine receptor subunit α7) downregulated 4 None any DEGs common suggest should be further evaluated biomarkers studies vitro since they involved neurodevelopmental adverse outcomes humans.
Language: Английский
Citations
8