CNS Neuroscience & Therapeutics
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2022
·Vol. 29
·期 1
·306-316
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IF 7.035
Ayang Zhao,Hongjiang Jin,Guibo Fan,Yan Li,Chenglong Li,Qi Li,Xiaofei Ma,Tianyang Zhao,Siqi Sun,Shuai Liu,Yueyue Gao,Sihua Qi
Background Exposure to anesthesia leads to extensive neurodegeneration and long-term cognitive deficits in the developing brain. Caenorhabditis elegans also shows persistent behavioral changes during development after exposure to anesthetics. Clinical and rodent studies have confirmed that altered expression of the regulators of G protein signaling (RGS) in the nervous system is a factor contributing to neurodegenerative and psychological diseases. Evidence from preclinical studies has suggested that RGS controls drug-induced plasticity, including morphine tolerance and addiction. This study aimed to observe the effect of propofol exposure in the neurodevelopmental stage on learning and memory in the L4 stage and to study whether this effect is related to changes in rgs-3 expression. Methods Caenorhabditis elegans were exposed to propofol at the L1 stage, and learning and memory abilities were observed at the L4 stage. The expression of rgs-3 and the nuclear distribution of EGL-4 were determined to study the relevant mechanisms. Finally, RNA interference was performed on rgs-3 -expressing cells after propofol exposure. Then, we observed their learning and memory abilities. Results Propofol time- and dose-dependently impaired the learning capacity. Propofol induced a decline in non-associative and associative long-term memory, rgs-3 upregulation, and a failure of nuclear accumulation of EGL-4/PKG in AWC neurons. Inhibition of rgs-3 could alleviate the propofol-induced changes. Conclusion Inhibition of the expression of rgs-3 alleviated propofol-induced learning and memory deficits in Caenorhabditis elegans .
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
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2024
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IF 2.7
Boyang Xu,Jun Yan,Yangtao Zhou,Feng Zhang,Binjie Wang,Jiye Wang,Yuanzhao Wu,Yu Xu
As global regulations on synthetic cannabinoids tighten, illicit vendors increasingly turn to new structures of synthetic cannabinoids to evade legal scrutiny. MDA-19, a novel synthetic cannabinoid, exhibited significant agonistic effects on type 2 cannabinoid receptors in vivo and showed emerging trends of abuse in illicit markets. However, research on the toxicological effects of MDA-19 remains scarce. In this study, we examined the effects of MDA-19 on neurodevelopment, behavior, oxidative stress, and metabolomics by exposing zebrafish embryos to MDA-19 solutions with concentrations of 1, 10, and 20 mg/L over 5 days. Results revealed that exposure to 10 and 20 mg/L of MDA-19 accelerated hatching in zebrafish embryos but led to reduced body length without affecting mortality or malformation. Furthermore, exposure to all concentrations of MDA-19 resulted in diminished swimming ability and reduced activity time in zebrafish. Transgenic zebrafish ( hb9 -GFP) exposed to MDA-19 exhibited impaired development of spinal motor neurons. Notably, exposure to 20 mg/L MDA-19 increased the levels of reactive oxygen species (ROS) in zebrafish and elevated the activity of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), while the levels of the lipid oxidation product malondialdehyde (MDA) remained unaffected. Nontargeted metabolomics analyses showed that MDA-19 interfered with multiple metabolic pathways affecting energy metabolism, such as alanine, aspartate, and glutamate metabolism; the citric acid cycle (TCA cycle), pantothenate, and coenzyme A biosynthesis; and purine metabolism. In conclusion, the present study provided the essential evidence for the neurotoxic effects of MDA-19, which was associated with impaired neurodevelopment, dysregulation of oxidative stress homeostasis, and altered energy metabolism.
研究领域:
毒理学
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神经生物学
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代谢组学
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DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
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2025
·
IF 3.6
Liu Kan,Tao Tao,Li Ranhong,Wang Huanping,Wang Li,Wu Haiying
Arsenic exposure is well-established to cause neurotoxicity, but its underlying molecular mechanisms remain unclear. This study investigates the effects of early-life arsenic exposure on the nervous system of offspring. Female mice were exposed to NaAsO₂, and alterations in learning, memory, and hippocampal lesions in offspring were assessed. Transcriptome analysis, protein interaction studies, and cellular experiments were integrated to identify key regulatory factors in arsenic-induced neurotoxicity. Arsenic interacts with HUWE1, significantly downregulating its protein expression. HUWE1 inhibition enhances GPX8 stability by reducing its ubiquitination. GPX8 disrupts histone epigenetic modifications by promoting GSH synthesis and arsenic methylation, leading to elevated H3K9 levels. HUWE1 also interacts with KDM3A, and its inhibition reduces KDM3A-mediated H3K9me1/me2 demethylation, amplifying H3K9me2-mediated transcriptional repression of LARS2 and triggering PANoptosis. This study provides novel molecular insights into arsenic-induced neurotoxicity and highlights potential therapeutic targets to mitigate arsenic-related nervous system damage.
研究领域:
毒理学
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神经生物学
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表观遗传学
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分子毒理学
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发育神经科学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2024
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IF 7.6
Rui Huang,Zijun Liu,Yunrui Pan,Zheng Ma,Huili Wang,Bin Wan,Jianzhong Li,Jing Chang
Pyrifluquinazon (PFQ), a novel insecticide containing a heptafluoroisopropyl moiety, has seen increasing use. However, limited research has been conducted on the toxicological effects and mechanisms of PFQ in aquatic organisms. To investigate the toxicity and underlying mechanisms of PFQ and its primary metabolite dPFQ in aquatic organisms, morphological, behavioral, hormonal, multi-omics analyses, and molecular docking studies were conducted on zebrafish larvae after exposure. The results showed that both PFQ and dPFQ induced developmental abnormalities, behavioral impairment, hormonal disruptions, and alterations in neurologically related metabolites and gene expression in early-stage zebrafish. Notably, delayed retinal vascular development was observed, which is also likely linked to the neurodevelopmental toxicity. Subsequently, identification and relative quantification of PFQ metabolites suggested that its toxicity might be primarily attributed to dPFQ. Finally, an Adverse Outcome Pathway (AOP) was proposed, initiating with the binding of dPFQ to the TRPV4 protein and ultimately leading to neurodevelopmental toxicity. This study delineated the neurodevelopmental toxicity of PFQ and its toxicological mechanisms in zebrafish, emphasizing the hazards posed by pesticide metabolites to non-target organisms and highlighting inherent limitations of extrapolating in vitro toxicity experiments.
研究领域:
毒理学
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环境科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2023
·
IF 6.8
Jie Wang,Chunyan Wu,Xing Zhang,Yuanyuan Song,Binquan Wang,Ke Zhang,Mingkuan Sun
As a result of the ban on bisphenol A (BPA), a hormone disruptor with developmental neurotoxicity, several BPA derivatives (BPs) have been widely used in industrial production. However, there are no effective methods for assessing the neurodevelopmental toxic effects of BPs. To address this, a Drosophila exposure model was established, and W 1118 was reared in food containing these BPs. Results showed that each BPs displayed different semi-lethal doses ranging from 1.76 to 19.43 mM. Exposure to BPs delayed larval development and affected axonal growth, resulting in the abnormal crossing of the midline of axons in the β lobules of mushroom bodies, but the damage caused by BPE and BPF was relatively minor. BPC, BPAF, and BPAP have the most significant effects on locomotor behavior, whereas BPC exhibited the most affected social interactions. Furthermore, exposure to high-dose BPA, BPC, BPS, BPAF, and BPAP also significantly increased the expression of Drosophila estrogen-related receptors. These demonstrated that different kinds of BPs had different levels of neurodevelopmental toxicity, and the severity was BPZ > BPC and BPAF > BPB > BPS > BPAP ≈ BPAl ≈ BPF > BPE. Therefore, BPZ, BPC, BPS, BPAF, and BPAP should be evaluated as potential alternatives to BPA.
研究领域:
毒理学
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神经生物学
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2025
·Vol. 26
·期 1
·349
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IF 4.9
Hongying Zhang,Yulong Liu,Yukun Huang,Kaiwen Zhao,Tingting Yu,Youjuan Wu,Zijia Yin,Meifeng Li,Dongming Li,Lihua Fan,Xiaowen Xu,Chengyu Hu,Shanghong Wang
Abamectin is an insecticide, miticide and nematicide that has been extensively used in agriculture for many years. The excessive use of abamectin inevitably pollutes water and soil and might even cause adverse effects on aquatic biota. However, it is currently unclear how abamectin exposure causes neurotoxicity in aquatic organisms. Herein, the early neural system development was assessed in zebrafish embryos following abamectin exposure. After treatment with a concentration gradient of abamectin (0.055, 0.0825, 0.11 mg/L), the survival rate, average heart rate, pericardial edema area and yolk sac edema were all documented in zebrafish embryos (96 hpf). It was found that after abamectin exposure, embryonic brain development was impaired, and motor behaviors were also affected. The fluorescence intensity was reduced in the transgenic embryos (Eno2: GFP). The activities of acetylcholinesterase (AChE) and ATPase were decreased, and the expression of neurodevelopment-related genes, such assox10,gap43,grin1b,abat,gad1b,grin2b,nestinandglsa, were all inhibited in zebrafish embryo treatment with abamectin. Furthermore, the reactive oxygen species (ROS) were triggered upon exposure to abamectin in zebrafish embryos along with the accumulation of ROS, eventually resulting in neuroapoptosis in the developing embryonic brain. In conclusion, neurodevelopmental toxicity was caused by oxidative stress-induced apoptosis in zebrafish embryos following abamectin exposure.
研究领域:
毒理学
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环境科学
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神经生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
Qi Tang,Bixi Zhao,Siqi Cao,Shuang Wang,Yue Liu,Yangyang Bai,Jiajun Song,Chuanying Pan,Haiyu Zhao,Xianyong Lan
Disinfection of public drinking water and swimming pools is crucial for preventing waterborne diseases , but it can produce harmful disinfection by-products (DBPs), increasing the risk of various diseases for those frequently exposed to such environments. Bromoacetic acid (BAA) is a ubiquitous DBP, with toxicity studies primarily focused on its in vitro cytotoxicity, and insufficient research on its neurodevelopmental toxicity. Utilizing zebrafish as a model organism, this study comprehensively explored BAA’s toxic effects and uncovered the molecular mechanisms through neurobehavioral analysis, in vivo two-photon imaging, transcriptomic sequencing, pharmacological intervention and molecular biological detection. Results demonstrated BAA induced significant changes on various indicators in the early development of zebrafish. Furthermore, BAA disrupted behavioral patterns in zebrafish larvae across locomotion activity, light-dark stimulation, and vibration stimulation paradigms. Subsequent investigation focused on larvae revealed BAA inhibited neuronal development, activated neuroinflammatory responses, and altered vascular morphology. Transcriptomic analysis revealed BAA-stressed zebrafish exhibited downregulation of visual transduction-related genes and activation of ferroptosis and cellular apoptosis. Neurobehavioral disorders were recovered by inhibiting ferroptosis and apoptosis. This study elucidates the neurodevelopmental toxicity associated with BAA, which is crucial for understanding health risks of DBPs and for the development of more effective detection methods and regulatory strategies.
研究领域:
环境科学
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毒理学
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神经生物学
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DOI
高影响因子
COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY C-TOXICOLOGY & PHARMACOLOGY
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2023
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IF 3.9
Liwang Xu,Xiaole Yang,Ying He,Qinglian Hu,Zhengwei Fu
In aquatic environment, engineered materials may inevitably interact with the coexisted organic pollutants, which affect their bioavailability and toxicity. In this contribution, the combined impacts of tetracycline (TC) and titanium dioxide nanoparticles (TiO 2 NPs) on the neurodevelopment of zebrafish larvae were investigated, and the underlying mechanisms were further elucidated. Firstly, it was confirmed that the co-existence of TC would increase the size and decrease the zeta potential of TiO 2 NPs. Following, developmental indicators and motor behaviors were investigated. Our results indicated that co-exposure to TC and TiO 2 NPs exhibited enhanced embryonic malformation rates and abnormal nervous system development in zebrafish embryos. Meanwhile, the locomotor behavior was increased upon treatment of TC and TiO 2 NP. Further, pathway enrichment analyses of transcriptomic sequencing provided detailed information that either lipid metabolism or PPAR signaling pathway were significantly affected in the co-exposure group. Also, TC + TiO 2 NP exposure significantly changed the mRNA expression of neural development-related genes and up-regulated the expression levels of neurotransmitters like 5-hydroxytryptamine, dopamine, acetylcholinesterase , and γ-aminobutyric acid. Taken together, our results demonstrated that the co-exposure of TC and TiO 2 NPs had the potential to cause neurotoxicity in zebrafish embryos.
研究领域:
环境科学
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毒理学
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神经科学
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产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2024
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IF 6.2
Yuanyuan Song,Xing Zhang,Binquan Wang,Xiaoxiao Luo,Ke Zhang,Xiaoyan Zhang,Qian Wu,Mingkuan Sun
Bisphenol AP (BPAP), an environmental endocrine disruptor, may cause neurodevelopmental disorders affecting human health. Studies have shown that BPAP impacts hormone synthesis and metabolism, causes social behavior abnormalities, and induces anxiety-like behavioral impairments in mice. However, evidence for the neurobehavioral effects of BPAP is still lacking. Here, we examined the toxic effects of BPAP on neurodevelopment using a Drosophila model. We assessed the role of BPAP exposure in autism-like behavior and explored the underlying mechanisms. Our findings indicated that BPAP exposure reduced pupation and eclosion rates and delayed growth in Drosophila . Furthermore, BPAP exposure caused autism-like behaviors, characterized by increased grooming times and aberrant social interactions, along with abnormalities in locomotor activity, as well as learning and memory ability. Mechanistically, we found that BPAP decreases the number of neuroblasts (NBs) and mature intermediate neural progenitors (INPs) in the 3rd larval brain, impairing axon guidance in the mushroom body of the adult Drosophila brain. Additionally, our transcriptome analysis revealed that BPAP exposure alters the expression of neurodevelopment-related genes ( Nplp3 , sand , lush , and orco ) and affects the estrogen signaling pathway ( Hsp70Ab , Hsp70Bc , Hsp70Ba , and Hsp70Bb ). These changes potentially explain the BPAP-induced autism-like behavior in Drosophila .
研究领域:
神经生物学
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环境科学
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分子生物学
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DOI
PubMed
高影响因子
ARCHIVES OF TOXICOLOGY
·
2022
·Vol. 96
·期 9
·2545-2557
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IF 6.168
Ji Di,Yu Yuejin,Zhu Qicheng,Li Xianjie,Zhong Xiali,Zhang Zhuyi,Ke Weijian,Niu Congying,Wang Can,Wu Jingwei,Chen Da,Song Maoyong,Wei Yanhong
Triphenyl phosphate (TPhP) is a non-halogenated organophosphorus flame retardant, and there is a higher exposure risk in children. TPhP has been found to be neurotoxic upon developmental exposure, yet the specific mechanism remains unclear. To characterize the cellular responses underlying TPhP-induced developmental neurotoxicity, we administered TPhP (0.5, 5 or 50 mg/kg/day) to neonatal mice from postnatal day 10 (P10)–P70. A total of 17,229 cells and 26,338 genes were identified in cortical samples from control and low-dose (the internal doses of metabolite DPhP comparable to human exposure level) groups using single-cell RNA sequencing (scRNA-seq). TPhP exposure led to heterogeneous transcriptional alterations and intercellular crosstalk among neurons, neural stem/progenitor cells (NSPCs), endothelial cells, and immunocytes. Deprivation of NSPCs, loss of mature neurons, and concomitant neuroinflammation mediated by extrinsic and intrinsic immunocytes were found in TPhP-exposed cortices. In addition, we observed blood–brain barrier destruction prior to the anxiety/depression-like neurobehavioral changes. These results reveal the distinctive cellular processes in TPhP’s neurodevelopmental toxicity and uncover that the impeded neurogenesis, disrupted vascular barrier, and concomitant neuroinflammation are the sensitive responses to TPhP exposure. Our study paves the way for the application of scRNA-seq in toxicity assessments for emerging neurotoxic pollutants.
研究领域:
毒理学
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神经科学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
SCIENCE OF THE TOTAL ENVIRONMENT
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2023
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IF 9.8
Xiaoxun Lu,Jiabin Hong,Jing Zhang,Qian Liu,Ganzhong Liao,Yanwei Shi,Huanwen Tang,Xiaoshan Liu
Triphenyl phosphate (TPhP) is an organophosphate flame retardant widely distributed in the environment. The neurodevelopmental toxicity of TPhP has been observed in animals and humans. Previously, we found that prenatal TPhP exposure disturbed placental tryptophan metabolism, impaired neurodevelopment in male offspring, and induced abnormal neurobehavior; however, the underlying mechanisms are unknown. In this study, using the trophoblast cell line JEG-3, we found that TPhP altered gene and protein expression in the tryptophan metabolism pathway, inhibited the tryptophan-serotonin pathway, and activated the tryptophan-kynurenine pathway. Meanwhile, TPhP induced oxidative stress by activating monoamine oxidase A (MAOA), promoting inflammatory factors including nuclear factor kappa-B (NFκB), interleukin-6, and tumor necrosis factor α. The NFκB inhibitor sulfasalazine could alleviate the effects of TPhP on tryptophan metabolism disturbance. The MAOA inhibitor clorgyline or the antioxidant N -acetylcysteine can mitigate oxidative stress and eliminate TPhP-induced inflammatory factors and tryptophan metabolism disturbances. The data above suggest that TPhP disturbed tryptophan metabolism by activating NFκB through MAOA-mediated oxidative stress. Finally, using the mouse intrauterine exposure model, the results confirmed that TPhP induced oxidative stress, activated inflammatory factors, disturbed tryptophan metabolism, and increased the levels of the tryptophan metabolites serotonin, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid in the placenta during the second trimester of pregnancy. Overall, TPhP can disturb placental tryptophan metabolism by activating the inflammatory factor NFkB, which was induced by MAOA-induced oxidative stress. The results of this study confirm that indirect exposure to xenobiotic compounds at an early life stage can impair offspring development and provide a novel perspective on the neurodevelopmental toxicity of TPhP.
研究领域:
毒理学
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生殖生物学
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神经科学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
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2021
·
IF 9.028
Kun Zhang,Jiahui Liang,Nadja R. Brun,Yanbin Zhao,Andreas A. Werdich
Rapid and cost-effective in vivo assays to screen potential environmental neurodevelopmental toxicants are necessary to address the limitations of in vitro platforms, such as the inability to fully recapitulate the developmental and physiological processes of whole organisms. In the present study, a rapid zebrafish behavioral profiling assay was developed to characterize the neurodevelopmental effects of environmental substances by quantitatively evaluating multiple spontaneous movement features of zebrafish embryos. This video analysis-based assay automatically segmented every embryo and thus was able to accurately quantify spontaneous movement features, including frequency, duration, intensity, interval, and the number of continuous movements. When tested with eight environmental substances known to be neurodevelopmental toxicants, such as chlorpyrifos and bisphenol A, the assay successfully captured frequency alterations that were well-documented in previous studies while also providing additional information. Using an optimized procedure, we further assessed 132 potential neurotoxins that spanned a wide range of molecular targets, many of which were previously detected in environmental waterbodies. The distinct altered behavioral barcodes indicated that the spontaneous movement was impacted by diverse neuroactive substances, and the effects could be effectively evaluated with the developed assay. The web-based tool, named EMAnalysis, is further provided at http://www.envh.sjtu.edu.cn/zebrafish_contraction.jsp. Thus, this assay provides an efficient platform to accelerate the pace of neurotoxic environmental contaminant discoveries.
研究领域:
环境科学
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神经科学
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毒理学
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发育生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）