RESUMO
The US EPA's Toxicity Forecaster (ToxCast) is a suite of high-throughput in vitro assays to screen environmental toxicants and predict potential toxicity of uncharacterized chemicals. This work examines the relevance of ToxCast assay intended gene targets to putative molecular initiating events (MIEs) of neurotoxicants. This effort is needed as there is growing interest in the regulatory and scientific communities about developing new approach methodologies (NAMs) to screen large numbers of chemicals for neurotoxicity and developmental neurotoxicity. Assay gene function (GeneCards, NCBI-PUBMED) was used to categorize gene target neural relevance (1 = neural, 2 = neural development, 3 = general cellular process, 3â¯A = cellular process critical during neural development, 4 = unlikely significance). Of 481 unique gene targets, 80 = category 1 (16.6â¯%); 16 = category 2 (3.3â¯%); 303 = category 3 (63.0â¯%); 97 = category 3â¯A (20.2â¯%); 82 = category 4 (17.0â¯%). A representative list of neurotoxicants (548) was researched (ex. PUBMED, PubChem) for neurotoxicity associated MIEs/Key Events (KEs). MIEs were identified for 375 compounds, whereas only KEs for 173. ToxCast gene targets associated with MIEs were primarily neurotransmitter (ex. dopaminergic, GABA)receptors and ion channels (calcium, sodium, potassium). Conversely, numerous MIEs associated with neurotoxicity were absent. Oxidative stress (OS) mechanisms were 79.1â¯% of KEs. In summary, 40â¯% of ToxCast assay gene targets are relevant to neurotoxicity mechanisms. Additional receptor and ion channel subtypes and increased OS pathway coverage are identified for potential future assay inclusion to provide more complete coverage of neural and developmental neural targets in assessing neurotoxicity.
Assuntos
Ensaios de Triagem em Larga Escala , Síndromes Neurotóxicas , Ensaios de Triagem em Larga Escala/métodos , Animais , Humanos , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade/métodos , Neurônios/efeitos dos fármacos , Neurônios/metabolismoRESUMO
It is well established that sevoflurane exposure leads to widespread neuronal cell death in the developing brain. Adenosine deaminase acting on RNA-1 (ADAR1) dependent adenosine-to-inosine (A-to-I) RNA editing is dynamically regulated throughout brain development. The current investigation is designed to interrogate the contributed role of ADAR1 in developmental sevoflurane neurotoxicity. Herein, we provide evidence to show that developmental sevoflurane priming triggers neuronal pyroptosis, apoptosis and necroptosis (PANoptosis), and elicits the release of inflammatory factors including IL-1ß, IL-18, TNF-α and IFN-γ. Additionally, ADAR1-P150, but not ADAR1-P110, depresses cellular PANoptosis and inflammatory response by competing with Z-DNA/RNA binding protein 1 (ZBP1) for binding to Z-RNA in the presence of sevoflurane. Further investigation demonstrates that ADAR1-dependent A-to-I RNA editing mitigates developmental sevoflurane-induced neuronal PANoptosis. To restore RNA editing, we utilize adeno-associated virus (AAV) to deliver engineered circular ADAR-recruiting guide RNAs (cadRNAs) into cells, which is capable of recruiting endogenous adenosine deaminases to promote cellular A-to-I RNA editing. As anticipated, AAV-cadRNAs diminishes sevoflurane-induced cellular Z-RNA production and PANoptosis, which could be abolished by ADAR1-P150 shRNA transfection. Moreover, AAV-cadRNAs delivery ameliorates developmental sevoflurane-induced spatial and emotional cognitive deficits without influence on locomotor activity. Taken together, these results illustrate that ADAR1-P150 exhibits a prominent role in preventing ZBP1-dependent PANoptosis through A-to-I RNA editing in developmental sevoflurane neurotoxicity. Application of engineered cadRNAs to rectify the compromised ADAR1-dependent A-to-I RNA editing provides an inspiring direction for possible clinical preventions and therapeutics.
Assuntos
Adenosina Desaminase , Adenosina , Edição de RNA , Proteínas de Ligação a RNA , Sevoflurano , Animais , Adenosina/metabolismo , Adenosina Desaminase/metabolismo , Adenosina Desaminase/genética , Apoptose/efeitos dos fármacos , Inosina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Piroptose/efeitos dos fármacos , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genéticaRESUMO
The underlying mechanism of the aluminum (Al) on neurotoxicity remains unclear. We explored whether the impairment of hippocampal neurons induced by developmental Al exposure was associated with the m6A RNA modification in mice. In this study, the pregnant female mice were administered 4â¯mg/mL aluminum-lactate from gestational day (GD) 6 to postnatal day (PND) 21. On PND 21, 10 offsprings per group were euthanized by exsanguination from the abdominal aorta after deep anesthetization. The other offsprings which treated with aluminum-lactate on maternal generation were divided into two groups and given 0 (PND60a) and 4â¯mg/mL (PND60b) aluminum-lactate in their drinking water until PND 60. Significant neuronal injuries of hippocampus as well as a reduction in the m6A RNA modification and the expression of methylase were observed at PND 21 and PND 60a mice. The results indicated that Al-induced developmental neurotoxicity could persist into adulthood despite no sustained Al accumulation. m6A RNA modification had a crucial role in developmental neurotoxicity induced by Al. In addition, Al exposure during the embryonic to adult stages can cause more severe nerve damage and decline of m6A RNA modification. Collectively, these results suggest that the mechanism underlying Al-induced neurotoxicity appears to involve m6A RNA modification.
Assuntos
Hipocampo , Neurônios , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Feminino , Gravidez , Camundongos , Metilação , RNA/genética , RNA/biossíntese , RNA/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Alumínio/toxicidade , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Masculino , Metiltransferases/genética , Metiltransferases/metabolismo , Metilação de RNARESUMO
Sevoflurane, as a commonly used inhaled anesthetic for pediatric patients, has been reported that multiple sevoflurane exposures are associated with a greater risk of developing neurocognitive disorder. N6-Methyladenosine (m6A), as the most common mRNA modification in eukaryotes, has emerged as a crucial regulator of brain function in processes involving synaptic plasticity, learning and memory, and neurodevelopment. Nevertheless, the relevance of m6A RNA methylation in the multiple sevoflurane exposure-induced developmental neurotoxicity remains mostly elusive. Herein, we evaluated the genome-wide m6A RNA modification and gene expression in hippocampus of mice that received with multiple sevoflurane exposures using m6A-sequencing (m6A-seq) and RNA-sequencing (RNA-seq). We discovered 19 genes with differences in the m6A methylated modification and differential expression in the hippocampus. Among these genes, we determined that a total of nine differential expressed genes may be closely associated with the occurrence of developmental neurotoxicity induced by multiple sevoflurane exposures. We further found that the alkB homolog 5 (ALKBH5), but not methyltransferase-like 3 (METTL3) and Wilms tumor 1-associated protein (WTAP), were increased in the hippocampus of mice that received with multiple sevoflurane exposures. And the IOX1, as an inhibitor of ALKBH5, significantly improved the learning and memory defects and reduced neuronal damage in the hippocampus of mice induced by multiple sevoflurane exposures. The current study revealed the role of m6A methylated modification and m6A-related regulators in sevoflurane-induced cognitive impairment, which might provide a novel insight into identifying biomarkers and therapeutic strategies for inhaled anesthetic-induced developmental neurotoxicity.
Assuntos
Adenosina , Homólogo AlkB 5 da RNA Desmetilase , Hipocampo , Síndromes Neurotóxicas , Sevoflurano , Sevoflurano/toxicidade , Animais , Camundongos , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Homólogo AlkB 5 da RNA Desmetilase/genética , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Adenosina/análogos & derivados , Adenosina/metabolismo , Anestésicos Inalatórios/toxicidade , Camundongos Endogâmicos C57BL , Metilação/efeitos dos fármacos , Metiltransferases/metabolismo , Metiltransferases/genéticaRESUMO
Bupivacaine (BUP) is an anesthetic commonly used in clinical practice that when used for spinal anesthesia, might exert neurotoxic effects. Thioredoxin-interacting protein (TXNIP) is a member of the α-arrestin protein superfamily that binds covalently to thioredoxin (TRX) to inhibit its function, leading to increased oxidative stress and activation of apoptosis. The role of TXNIP in BUP-induced oxidative stress and apoptosis remains to be elucidated. In this context, the present study aimed to explore the effects of TXNIP knockdown on BUP-induced oxidative stress and apoptosis in the spinal cord of rats and in PC12 cells through the transfection of adeno-associated virus-TXNIP short hairpin RNA (AAV-TXNIP shRNA) and siRNA-TXNIP, respectively. In vivo, a rat model of spinal neurotoxicity was established by intrathecally injecting rats with BUP. The BUP + TXNIP shRNA and the BUP + Control shRNA groups of rats were injected with an AAV carrying the TXNIP shRNA and the Control shRNA, respectively, into the subarachnoid space four weeks prior to BUP treatment. The Basso, Beattie & Bresnahan (BBB) locomotor rating score, % MPE of TFL, H&E staining, and Nissl staining analyses were conducted. In vitro, 0.8 mM BUP was determined by CCK-8 assay to establish a cytotoxicity model in PC12 cells. Transfection with siRNA-TXNIP was carried out to suppress TXNIP expression prior to exposing PC12 cells to BUP. The results revealed that BUP effectively induced neurological behavioral dysfunction and neuronal damage and death in the spinal cord of the rats. Similarly, BUP triggered cytotoxicity and apoptosis in PC12 cells. In addition, treated with BUP both in vitro and in vivo exhibited upregulated TXNIP expression and increased oxidative stress and apoptosis. Interestingly, TXNIP knockdown in the spinal cord of rats through transfection of AAV-TXNIP shRNA exerted a protective effect against BUP-induced spinal neurotoxicity by ameliorating behavioral and histological outcomes and promoting the survival of spinal cord neurons. Similarly, transfection with siRNA-TXNIP mitigated BUP-induced cytotoxicity in PC12 cells. In addition, TXNIP knockdown mitigated the upregulation of ROS, MDA, Bax, and cleaved caspase-3 and restored the downregulation of GSH, SOD, CAT, GPX4, and Bcl2 induced upon BUP exposure. These findings suggested that TXNIP knockdown protected against BUP-induced spinal neurotoxicity by suppressing oxidative stress and apoptosis. In summary, TXNIP could be a central signaling hub that positively regulates oxidative stress and apoptosis during neuronal damage, which renders TXNIP a promising target for treatment strategies against BUP-induced spinal neurotoxicity.
Assuntos
Apoptose , Bupivacaína , Proteínas de Transporte , Técnicas de Silenciamento de Genes , Síndromes Neurotóxicas , Estresse Oxidativo , RNA Interferente Pequeno , Medula Espinal , Animais , Ratos , Apoptose/efeitos dos fármacos , Bupivacaína/toxicidade , Bupivacaína/efeitos adversos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Injeções Espinhais , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Células PC12 , Ratos Sprague-Dawley , RNA Interferente Pequeno/genética , Medula Espinal/metabolismo , Medula Espinal/patologia , Medula Espinal/efeitos dos fármacos , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMO
The potential neurotoxic effects of propofol, an extensively utilized anesthetic, underline the urgency to comprehend its influence on neuronal health. Insights into the role of the retinoic acid receptor-α, small nucleolar RNA host gene 1, and brain-derived neurotrophic factor (RARα-Snhg1-Bdnf) network can offer significant advancements in minimizing these effects. The study targets the exploration of the RARα and Snhg1 regulatory network's influence on Bdnf expression in the realm of propofol-induced neurotoxicity. Harnessing the Gene Expression Omnibus (GEO) database and utilizing JASPAR and RNA-Protein Interaction Prediction (RPISeq) database for projections, the study embarks on an in-depth analysis employing both in vitro and in vivo models. The findings draw a clear link between propofol-induced neurotoxicity and the amplification of RAR signaling pathways, impacting hippocampal development and apoptosis and leading to increased RARα and Snhg1 and decreased Bdnf. Propofol is inferred to accentuate neurotoxicity by heightening RARα and Snhg1 interactions, culminating in Bdnf suppression.NEW & NOTEWORTHY This study aimed to decode propofol's neurotoxic effects on the regulatory cascade, provide insights into the RARα-Snhg1-Bdnf interaction, apply extensive validation techniques, provide a detailed analysis and exploration of propofol's neurotoxicity, and offer a comprehensive approach to understanding molecular interactions.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Propofol , Receptor alfa de Ácido Retinoico , Propofol/toxicidade , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Animais , Humanos , Transdução de Sinais/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Apoptose/efeitos dos fármacos , MasculinoRESUMO
This study aimed to determine the toxic effects of vascular CCM3 gene deficiency and lead (Pb) exposure on the nervous system. Lentiviral transfection was performed to generate a stable strain of brain microvascular endothelial cells with low CCM3 expression. MTT assay assessed the survival rate of cells exposed to Pb, determining the dose and duration of Pb exposure in vitro. Proteomic analysis was performed on the differentially expressed proteins in bEnd3 and HT22 cells and flow cytometry was used to detect cell apoptosis. Finally, urine samples from pregnant and postpartum women were subjected to ICP-MS to detect Pb levels and HPLC to detect neurotransmitter metabolites. Based on the proteomic analysis of bEnd3 (CCM3-/-) cells co-cultured with HT22 cells, it was determined that HT22 cells and CCM3 genes interfered with bEnd3 cell differential proteins,2 including apoptosis and ferroptosis pathways. Electron microscopy observation, ICP-MS iron ion loading detection, and WB determination of protein GPX4 expression confirmed that HT22 cells undergo apoptosis, while bEnd3 cells undergo multiple pathways of iron death and apoptosis regulation. Furthermore, a linear regression model showed the interaction between maternal urine Pb levels, the rs9818496 site of the CCM3 SNP in peripheral blood DNA, and the concentration of the neurotransmitter metabolite 5-HIAA in maternal urine (F=4.198, P < 0.05). bEnd3 cells with CCM3 gene deficiency can induce HT22 cell apoptosis through iron death and apoptosis pathways under Pb exposure in a combined cell culture Pb exposure model, and CCM3 gene deficiency in endothelial cells and Pb exposure interacts with neural cell HT22. Epidemiological studies on maternal and newborn infants further confirmed the interaction between urine Pb levels in mothers and the SNP rs9818496 site of the CCM3 gene in peripheral blood DNA.
Assuntos
Proteínas Reguladoras de Apoptose , Apoptose , Chumbo , Chumbo/toxicidade , Chumbo/sangue , Humanos , Feminino , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Gravidez , Animais , Células Endoteliais/efeitos dos fármacos , Proteínas Proto-Oncogênicas/genética , Camundongos , Linhagem Celular , Síndromes Neurotóxicas/genética , Adulto , Proteômica , Proteínas de MembranaRESUMO
Heavy metal toxicity is a significant global health concern, with particular attention given to lead (Pb) exposure due to its adverse effects on cognitive development, especially in children exposed to low concentrations. While Pb neurotoxicity has been extensively studied, the analysis and molecular mechanisms underlying the transgenerational effects of Pb exposure-induced neurotoxicity remain poorly understood. In this study, we utilized Drosophila, a powerful developmental animal model, to investigate this phenomenon. Our findings demonstrated that Pb exposure during the developmental stage had a profound effect on the neurodevelopment of F0 fruit flies. Specifically, we observed a loss of correlation between the terminal motor area and muscle fiber area, along with an increased frequency of the ß-lobe midline crossing phenotype in mushroom bodies. Western blot analysis indicated altered expression levels of synaptic vesicle proteins, with a decrease in Synapsin (SYN) and an increase in Bruchpilot (BRP) expression, suggesting changes in synaptic vesicle release sites. These findings were corroborated by electrophysiological data, showing an increase in the amplitude of evoked excitatory junctional potential (EJP) and an increase in the frequency of spontaneous excitatory junctional potential (mEJP) following Pb exposure. Importantly, our results further confirmed that the developmental neurotoxicity resulting from grandparental Pb exposure exhibited a transgenerational effect. The F3 offspring displayed neurodevelopmental defects, synaptic function abnormalities, and repetitive behavior despite lacking direct Pb exposure. Our MeDIP-seq analysis further revealed significant alterations in DNA methylation levels in several neurodevelopmental associated genes (eagle, happyhour, neuroglian, bazooka, and spinophilin) in the F3 offspring exposed to Pb. These findings suggest that DNA methylation modifications may underlie the inheritance of acquired phenotypic traits resulting from environmental Pb exposure.
Assuntos
Drosophila melanogaster , Síndromes Neurotóxicas , Animais , Criança , Humanos , Chumbo/metabolismo , Metilação de DNA , Síndromes Neurotóxicas/genética , GenomaRESUMO
Fluoride could cause developmental neurotoxicity and significantly affect the intelligence quotient (IQ) of children. However, the systematic mechanism of neuronal damage caused by excessive fluoride administration in offspring is largely unknown. Here, we present a comprehensive integrative transcriptome and metabolome analysis to study the mechanism of developmental neurotoxicity caused by chronic fluoride exposure. Comparing the different doses of fluoride treatments in two generations revealed the exclusive signature of metabolism pathways and gene expression profiles. In particular, neuronal development and synaptic ion transport are significantly altered at the gene expression and metabolite accumulation levels for both generations, which could act as messengers and enhancers of fluoride-induced systemic neuronal injury. Choline and arachidonic acid metabolism, which highlighted in the integrative analysis, exhibited different regulatory patterns between the two generations, particularly for synaptic vesicle formation and inflammatory factor transport. It may suggest that choline and arachidonic acid metabolism play important roles in developmental neurotoxic responses for offspring mice. Our study provides comprehensive insights into the metabolomic and transcriptomic regulation of fluoride stress responses in the mechanistic explanation of fluoride-induced developmental neurotoxicity.
Assuntos
Fluoretos , Síndromes Neurotóxicas , Humanos , Criança , Camundongos , Animais , Fluoretos/toxicidade , Transcriptoma , Ácido Araquidônico , Metaboloma , Síndromes Neurotóxicas/genética , Colina , EncéfaloRESUMO
Acrylamide is an environmental electrophile that has been produced in large amounts for many years. There is concern about the adverse health effects of acrylamide exposure due to its widespread industrial use and also presence in commonly consumed foods and others. IL-1ß is a key cytokine that protects the brain from inflammatory insults, but its role in acrylamide-induced neurotoxicity remains unknown. We reported recently that deletion of IL-1ß gene exacerbates ACR-induced neurotoxicity in mice. The aim of this study was to identify genes or signaling pathway(s) involved in enhancement of ACR-induced neurotoxicity by IL-1ß gene deletion or ACR-induced neurotoxicity to generate a hypothesis mechanism explaining ACR-induced neurotoxicity. C57BL/6 J wild-type and IL-1ß KO mice were exposed to ACR at 0, 12.5, 25 mg/kg by oral gavage for 7 days/week for 4 weeks, followed by extraction of mRNA from mice cerebral cortex for RNA sequence analysis. IL-1ß deletion altered the expression of genes involved in extracellular region, including upregulation of PFN1 gene related to amyotrophic lateral sclerosis and increased the expression of the opposite strand of IL-1ß. Acrylamide exposure enhanced mitochondria oxidative phosphorylation, synapse and ribosome pathways, and activated various pathways of different neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, Huntington disease, and prion disease. Protein network analysis suggested the involvement of different proteins in related to learning and cognitive function, such as Egr1, Egr2, Fos, Nr4a1, and Btg2. Our results identified possible pathways involved in IL-1ß deletion-potentiated and ACR-induced neurotoxicity in mice.
Assuntos
Acrilamida , Síndromes Neurotóxicas , Animais , Camundongos , Acrilamida/toxicidade , Encéfalo , Córtex Cerebral , Perfilação da Expressão Gênica , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/genéticaRESUMO
Acrylamide (ACR) is a by-product of the Maillard reaction, which occurs when food reacts at high temperatures. Occupational exposure is a risk factor for chronic ACR toxicity. ACR may cause neurotoxicity and depressive symptoms with high concentration in the blood; however, the underlying mechanism remains unknown. We showed the rats developed neurotoxic symptoms after being fed with ACR for 28 days, such as reduced activity and hind limb muscle weakness. We investigated whether ACR exposure causes gene expression differences by blood RNA sequencing and analyzed the differential expression of depressive symptoms-associated genes. The result indicated that IFN-γ the key regulator of neurotoxicity and depressive symptoms was induced by ACR. ACR induced the ubiquitin-mediated proteolysis pathway and JAK/STAT pathways gene expression. ACR upregulated the expression of IFN-γ, inducing neuroinflammation and neurotoxicity. ACR also upregulated the expression of JAK2, STAT1, PI3K, AKT, IκBα, UBE2D4, NF-κB, TNF-α, and iNOS in rat brain tissues and Neuro-2a cells. Thus, IFN-γ induction by ACR may induce depressive symptoms, and the ubiquitin-mediated proteolysis pathway and JAK/STAT pathways may involve in ACR neurotoxicity and depressive symptoms.
Assuntos
Acrilamida , Síndromes Neurotóxicas , Ratos , Animais , Acrilamida/toxicidade , Depressão/induzido quimicamente , Depressão/genética , Antioxidantes/metabolismo , Síndromes Neurotóxicas/genética , Ubiquitinas , RNARESUMO
Tetrodotoxin (TTX) is an exceedingly toxic non-protein biotoxin that demonstrates remarkable selectivity and affinity for sodium channels on the excitation membrane of nerves. This property allows TTX to effectively obstruct nerve conduction, resulting in nerve paralysis and fatality. Although the mechanistic aspects of its toxicity are well understood, there is a dearth of literature addressing alterations in the neural microenvironment subsequent to TTX poisoning. In this research endeavor, we harnessed human pluripotent induced stem cells to generate cerebral organoids-an innovative model closely mirroring the structural and functional intricacies of the human brain. This model was employed to scrutinize the comprehensive transcriptomic shifts induced by TTX exposure, thereby delving into the neurotoxic properties of TTX and its potential underlying mechanisms. Our findings revealed 455 differentially expressed mRNAs (DEmRNAs), 212 differentially expressed lncRNAs (DElncRNAs), and 18 differentially expressed miRNAs (DEmiRNAs) in the TTX-exposed group when juxtaposed with the control cohort. Through meticulous Gene Ontology (GO) annotation, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) analysis, we ascertained that these differential genes predominantly participate in the regulation of voltage-gated channels and synaptic homeostasis. A comprehensive ceRNA network analysis unveiled that DEmRNAs exert control over the expression of ion channels and neurocytokines, suggesting their potential role in mediating apoptosis.
Assuntos
MicroRNAs , Síndromes Neurotóxicas , Humanos , Tetrodotoxina/farmacologia , Transcriptoma , MicroRNAs/genética , MicroRNAs/metabolismo , Perfilação da Expressão Gênica , Canais de Sódio/genética , Canais de Sódio/metabolismo , Síndromes Neurotóxicas/genética , Redes Reguladoras de GenesRESUMO
Acrylamide is a neurotoxicant in human and experimental animals. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine known as a critical component of brain reaction to any insult or neurodegenerative pathologies, though its role in electrophile-induced neurotoxicity remains elusive. The aim of this study was to investigate the role of IL-1ß in acrylamide-induced neurotoxicity in mice. Ten-week-old male wild-type and IL-1ß knock-out mice were allocated into 3 groups each and exposed to acrylamide at 0, 12.5, 25 mg/kg body weight by oral gavage for 28 days. Compared with wild-type mice, the results showed a significant increase in landing foot spread test and a significant decrease in density of cortical noradrenergic axons in IL-1ß KO mice exposed to acrylamide at 25 mg/kg body weight. Exposure to acrylamide at 25 mg/kg significantly increased cortical gene expression of Gclc, Gpx1, and Gpx4 in wild-type mice but decreased them in IL-1ß KO mice. The same exposure level significantly increased total glutathione and oxidized glutathione (GSSG) in the cerebellum of wild-type mice but neither changed total glutathione nor decreased GSSG in the cerebellum of IL-1ß KO mice. The basal level of malondialdehyde in the cerebellum was higher in IL-1ß KO mice than in wild-type mice. The results suggest that IL-1ß protects the mouse brain against acrylamide-induced neurotoxicity, probably through suppression of oxidative stress by glutathione synthesis and peroxidation. This unexpected result provides new insight on the protective role of IL-1ß in acrylamide-induced neurotoxicity.
Assuntos
Acrilamida , Síndromes Neurotóxicas , Humanos , Camundongos , Masculino , Animais , Interleucina-1beta/genética , Acrilamida/toxicidade , Dissulfeto de Glutationa/metabolismo , Estresse Oxidativo , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Glutationa/metabolismo , Peso Corporal , Camundongos KnockoutRESUMO
PURPOSE OF REVIEW: Methylmercury (MeHg) is neurotoxic at high levels and particularly affects the developing brain. One proposed mechanism of MeHg neurotoxicity is alteration of the epigenetic programming. In this review, we summarise the experimental and epidemiological literature on MeHg-associated epigenetic changes. RECENT FINDINGS: Experimental and epidemiological studies have identified changes in DNA methylation following in utero exposure to MeHg, and some of the changes appear to be persistent. A few studies have evaluated associations between MeHg-related changes in DNA methylation and neurodevelopmental outcomes. Experimental studies reveal changes in histone modifications after MeHg exposure, but we lack epidemiological studies supporting such changes in humans. Experimental and epidemiological studies have identified microRNA-related changes associated with MeHg; however, more research is needed to conclude if these changes lead to persistent and toxic effects. SUMMARY: MeHg appears to interfere with epigenetic processes, potentially leading to persistent changes. However, observed associations of mercury with epigenetic changes are as of yet of unknown relevance to neurodevelopmental outcomes.
Assuntos
Compostos de Metilmercúrio , Síndromes Neurotóxicas , Humanos , Compostos de Metilmercúrio/toxicidade , Metilação de DNA , Encéfalo , Síndromes Neurotóxicas/genética , Epigênese GenéticaRESUMO
Current guidelines for developmental neurotoxicity (DNT) evaluation are based on animal models. These have limitations so more relevant, efficient and robust approaches for DNT assessment are needed. We have used the human SH-SY5Y neuroblastoma cell model to evaluate a panel of 93 mRNA markers that are frequent in Neuronal diseases and functional annotations and also differentially expressed during retinoic acid-induced differentiation in the cell model. Rotenone, valproic acid (VPA), acrylamide (ACR) and methylmercury chloride (MeHg) were used as DNT positive compounds. Tolbutamide, D-mannitol and clofibrate were used as DNT negative compounds. To determine concentrations for exposure for gene expression analysis, we developed a pipeline for neurite outgrowth assessment by live-cell imaging. In addition, cell viability was measured by the resazurin assay. Gene expression was analyzed by RT-qPCR after 6 days of exposure during differentiation to concentrations of the DNT positive compounds that affected neurite outgrowth, but with no or minimal effect on cell viability. Methylmercury affected cell viability at lower concentrations than neurite outgrowth, hence the cells were exposed with the highest non-cytotoxic concentration. Rotenone (7.3 nM) induced 32 differentially expressed genes (DEGs), ACR (70 µM) 8 DEGs, and VPA (75 µM) 16 DEGs. No individual genes were significantly dysregulated by all 3 DNT positive compounds (p < 0.05), but 9 genes were differentially expressed by 2 of them. Methylmercury (0.8 nM) was used to validate the 9 DEGs. The expression of SEMA5A (encoding semaphorin 5A) and CHRNA7 (encoding nicotinic acetylcholine receptor subunit α7) was downregulated by all 4 DNT positive compounds. None of the DNT negative compounds dysregulated any of the 9 DEGs in common for the DNT positive compounds. We suggest that SEMA5A or CHRNA7 should be further evaluated as biomarkers for DNT studies in vitro since they also are involved in neurodevelopmental adverse outcomes in humans.
Assuntos
Compostos de Metilmercúrio , Neuroblastoma , Síndromes Neurotóxicas , Animais , Humanos , Compostos de Metilmercúrio/farmacologia , Rotenona/toxicidade , RNA Mensageiro/metabolismo , Neuroblastoma/metabolismo , Neurônios , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Diferenciação CelularRESUMO
As the manufacturing and development of new synthetic compounds increase to keep pace with the expanding global demand, adverse health effects due to these compounds are emerging as critical public health concerns. Zebrafish have become a prominent model organism to study toxicology due to their genomic similarity to humans, optical clarity, well-defined developmental stages, short generation time, and cost-effective maintenance. It also provides a shorter time frame for in vivo toxicology evaluation compared to the mammalian experimental systems. Here, we used meta-analysis to examine the alteration in genes during cardiotoxicity and neurotoxicity in zebrafish, caused by chemical exposure of any kind. First, we searched the literature comprehensively for genes that are altered during neurotoxicity and cardiotoxicity followed by meta-analysis using ConsensusPathDB. Since constant communication between the heart and the brain is an important physiological phenomenon, we also analyzed interactions among genes altered simultaneously during cardiotoxicity and neurotoxicity using induced network modules analysis in ConsensusPathDB. We observed inflammation and regeneration as the major pathways involved in cardiotoxicity and neurotoxicity. A large number of intermediate genes and input genes anchored in these pathways are molecular regulators of cell cycle progression and cell death and are implicated in tumor manifestation. We propose potential predictive biomarkers for neurotoxicity and cardiotoxicity and the major pathways potentially implicated in the manifestation of a particular toxicity phenotype.
Assuntos
Síndromes Neurotóxicas , Peixe-Zebra , Humanos , Animais , Peixe-Zebra/metabolismo , Cardiotoxicidade/metabolismo , Proteínas de Peixe-Zebra/genética , Coração , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Embrião não Mamífero/metabolismo , Mamíferos/metabolismoRESUMO
Methamphetamine (METH) is an amphetamine-type stimulant that is highly toxic to the central nervous system (CNS). Repeated intake of METH can lead to addiction, which has become a globalized problem, resulting in multiple public health and safety problems. Recently, the non-coding RNA (ncRNA) has been certified to play an essential role in METH addiction through various mechanisms. Herein, we mainly focused on three kinds of ncRNAs including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which are involved in neurotoxicity effects such as cognitive impairment, behavioral abnormalities, and psychiatric disorders due to METH abuse. In addition, differential expression (DE) ncRNAs also suggest that specific responses and sensitivity to METH neurotoxicity exist in different brain regions and cells. We summarized the relationships between the ncRNAs and METH-induced neurotoxicity and psychiatric disturbances, respectively, hoping to provide new perspectives and strategies for the prevention and treatment of METH abuse. Schematic diagram of the non-coding RNAs (ncRNAs) was involved in methamphetamine (METH)-induced neurotoxicity. The ncRNAs were involved in METH-induced blood-brain barrier disruption, neuronal, astrocyte, and microglial damage, and synaptic neurotransmission impairment. The study of ncRNAs is a hot spot in the future to further understand the neurotoxicity of METH and provide more favorable scientific support for clinical diagnosis and innovation of related treatments.
Assuntos
Comportamento Aditivo , Metanfetamina , MicroRNAs , Síndromes Neurotóxicas , Humanos , Metanfetamina/toxicidade , Anfetamina , MicroRNAs/metabolismo , Síndromes Neurotóxicas/genéticaRESUMO
Neural tube malformation is a common kind of human birth defect. High temperature is one of the most common physical teratogenic factors. Several studies have suggested that heat stress may cause neurotoxicity during brain development, but more studies are warranted to reveal the mechanism and draw consistent conclusions. The current study used a cell model of primary mouse embryonic neural stem/progenitor cells (NSPCs) subjected to heat stress of 43 °C for 20 min. Our study investigated the changes in the NSPCs transcriptome under heat stress using high-throughput mRNA-seq. The NSPCs showed remarkably altered genes associated with cell growth, proliferation, cell cycle, and survival when exposed to heat stress. Heat stress reduced cell viability, proliferation, and neurosphere formation and caused cell cycle arrest and apoptosis in cultured NSPCs. PCR arrays confirmed that the TNF receptor family plays an important role in the apoptosis of NSPCs during heat stress. The results of real-time PCR confirmed that heat stress affects the expression of critical genes. We provide transcriptomic insight into heat stress-induced developmental neurotoxic effects and the underlying mechanisms.
Assuntos
Células-Tronco Neurais , Síndromes Neurotóxicas , Animais , Camundongos , Humanos , Transcriptoma , Células Cultivadas , Células-Tronco Embrionárias , Síndromes Neurotóxicas/genética , Síndromes Neurotóxicas/metabolismo , Proliferação de Células , Resposta ao Choque TérmicoRESUMO
Arsenite is a well-documented neurotoxicant that widely exists in the environment. However, the detailed mechanisms of arsenite neurotoxicity are not fully clarified. Autophagy has been reported to be involved in many neurological problems induced by arsenite. Since beclin 1 is an essential mediator of autophagy, we herein used both adult wild-type (beclin 1+/+) and heterozygous disruption of beclin 1 (beclin 1+/-) mice for chronic administration of 50 mg/L arsenite via drinking water for 3 months. Our results demonstrated that exposure of arsenite caused the working memory deficit, anxiety-like behavior and motor coordination disorder in beclin 1+/+ mice, accompanied with pathological changes in morphology and electrophysiology in the cortical tissues. This treatment of arsenite significantly reduced the number of neuronal cells and induced microglia activation and synaptic transmission disorders in the wild-type mice as compared with vehicle controls. Intriguingly, by using beclin 1+/- mice, we found that heterozygous disruption of beclin 1 profoundly attenuated these neurotoxic effects induced by arsenite, mainly manifested by improvements in the neurobehavioral impairments, abnormal electrophysiologic alterations as well as dysregulation of synaptic transmission. These findings together indicate that regulation of autophagy via beclin 1 would be a potential strategy for treatment against arsenite neurotoxicity.
Assuntos
Arsenitos , Síndromes Neurotóxicas , Camundongos , Animais , Proteína Beclina-1/genética , Proteína Beclina-1/farmacologia , Arsenitos/toxicidade , Transmissão Sináptica , Síndromes Neurotóxicas/genética , AutofagiaRESUMO
Toxicology studies provide a reliable dose range for the use of compounds. Zebrafish show unique advantages in toxicology research. Cinnamaldehyde (Cin) is one of the main active compounds isolated from Cinnamon trees and other species of the genus Cinnamomum. In this study, we investigated the developmental neurotoxicity of cinnamaldehyde in zebrafish and preliminarily explored its underlying mechanism. Cinnamaldehyde causes developmental neurotoxicity in zebrafish, as evidenced by the damage to ventricular structures, eye malformations, shortened body length, trunk curvature, decreased neuronal fluorescence, and pericardial oedema. Moreover, it can induce abnormal behaviour and gene expression in zebrafish. After treatment with the oxidative stress inhibitor astaxanthin, the behaviour and abnormal gene expression were reversed. All of these data demonstrated that the developmental neurotoxicity of cinnamaldehyde might be attributed to oxidative stress. In addition, this study also confirmed that zebrafish is a reliable model for toxicity studies.