Neurotoxicology最新文献_第7页

TREM2-mediated neuroinflammatory response is involved in AgNPs-induced ferroptosis in HMC3 cells trem2介导的神经炎症反应参与了agnps诱导的HMC3细胞铁下垂。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-23 DOI: 10.1016/j.neuro.2025.103326

Haitao Yang, Menghao Guo, Shuyan Niu, Chenyu Liu, Tianshu Wu, Mengjing Cui, Yuying Xue

Silver nanoparticles (AgNPs) are widely used in industrial and biomedical applications owing to their superior physicochemical properties, especially antimicrobial activity. However, their potential health risks raise concerns. Given that the central nervous system (CNS) is a major target of AgNPs, assessing their neurotoxic effects is critical for safety evaluation. Recent studies suggest that ferroptosis may play a pivotal role in AgNPs-induced neurotoxicity, yet the underlying molecular mechanisms remain unclear. This study is the first to investigate AgNPs-triggered ferroptosis in human microglial cells (HMC3) and explore the regulatory role of triggering receptor expressed on myeloid cells 2 (TREM2)-mediated inflammatory responses. Following exposure to AgNPs (0, 50, 100, and 200 μg/mL) for 48 h, HMC3 cells exhibited dose-dependent cytotoxicity. Further analyses revealed mitochondrial ultrastructural and functional damage, intracellular Fe²⁺ overload, elevated ROS levels, GSH depletion, and increased lipid peroxidation, accompanied by dysregulated expression of ferroptosis-related proteins. Inflammatory profiling demonstrated reduced TREM2 protein levels, elevated pro-inflammatory markers, and decreased anti-inflammatory markers, indicating AgNPs-induced inflammatory responses. Treatment with the TREM2 agonist COG 1410 (5 μg/mL) significantly upregulated TREM2 expression, attenuated pro-inflammatory factors, and enhanced anti-inflammatory factors. Moreover, TREM2 activation significantly inhibited AgNPs-induced ferroptosis in HMC3 cells, indicating that TREM2-mediated inflammation may play a key role in regulating this process. These findings offer new understanding of AgNPs neurotoxicity and potential therapeutic targets for reducing CNS damage from AgNPs exposure.

银纳米粒子（AgNPs）由于其优越的物理化学性质，特别是抗菌活性，在工业和生物医学应用中得到了广泛的应用。然而，它们潜在的健康风险令人担忧。鉴于中枢神经系统（CNS）是AgNPs的主要靶点，评估其神经毒性作用对安全性评估至关重要。最近的研究表明，铁下垂可能在agnps诱导的神经毒性中起关键作用，但其潜在的分子机制尚不清楚。本研究首次研究了agnps在人小胶质细胞（HMC3）中引发的铁凋亡，并探索了触发受体表达对髓样细胞2 （TREM2）介导的炎症反应的调节作用。暴露于AgNPs(0、50、100和200μg/mL) 48小时后，HMC3细胞表现出剂量依赖性的细胞毒性。进一步的分析显示，线粒体超微结构和功能损伤、细胞内Fe 2 +过载、ROS水平升高、GSH耗竭、脂质过氧化增加，并伴有铁中毒相关蛋白的表达失调。炎症谱显示TREM2蛋白水平降低，促炎标志物升高，抗炎标志物降低，表明agnps诱导的炎症反应。TREM2激动剂COG 1410 （5μg/mL）可显著上调TREM2表达，减弱促炎因子，增强抗炎因子。此外，TREM2激活显著抑制agnps诱导的HMC3细胞铁凋亡，表明TREM2介导的炎症可能在调节这一过程中发挥关键作用。这些发现提供了对AgNPs神经毒性的新认识和减少AgNPs暴露对中枢神经系统损伤的潜在治疗靶点。

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引用次数: 0

Hexavalent chromium neurotoxicity in Caenorhabditis elegans targeted GABAergic, cholinergic, and dopaminergic neurons, and contributed to an aged phenotype 六价铬对秀丽隐杆线虫gaba能、胆碱能和多巴胺能神经元的神经毒性，并导致衰老表型。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-19 DOI: 10.1016/j.neuro.2025.103325

Samuel T. Vielee , Pan Chen , Romina Deza-Ponzio , Idoia Meaza , Shreesh Raj Sammi , Michael Aschner , John P. Wise Jr.

Hexavalent chromium [Cr(VI)] is a ubiquitous environmental pollutant and potent toxicant. Cr(VI) exposure impacts millions of people around the world, primarily through inhalation or ingestion. Such exposures are best known for contributing to cancers of the lung, sinus, and nasal passage, damage to kidneys and liver, and contact dermatitis. Growing evidence indicates exposure contributes to neurological conditions, but knowledge gaps persist regarding Cr(VI) neurotoxicity. Human studies report Cr(VI) contributes to autism spectrum disorders, motor neuron disease, olfactory dysfunction, and impaired memory. However, knowledge of specific targets for Cr(VI) in the brain is limited to reports of regional accumulation (greatest effects reported in the rodent hippocampus, hypothalamus, and pituitary gland), while cell-specific effects remain unknown. Caenorhabditis elegans is a useful high-throughput model, frequently used for metals neurotoxicity. Here, we characterize a C. elegans model to address knowledge gaps in Cr(VI) neurotoxicity. All Cr(VI) concentrations tested were sublethal, and we estimate bioaccumulation of Cr in worms was ∼1e10⁻⁸% of the administered dose after a 24-hour exposure. Cr(VI) initially targeted GABAergic neurons after a 6-hour exposure, while cholinergic, dopaminergic, and GABAergic neurons were affected following a 24-hour exposure. Impacts on behaviors were consistent with neurodegeneration. Further, Cr(VI) exacerbated gut autofluorescence in worms, indicative of accelerated biological aging. These data collectively address key knowledge gaps, identifying key neuronal targets and informing potential mechanisms of neurotoxicity.

六价铬[Cr(VI)]是一种普遍存在的环境污染物和强毒物。六价铬暴露主要通过吸入或摄入影响全世界数百万人。众所周知，这种暴露会导致肺癌、鼻窦和鼻道癌、肾脏和肝脏损伤以及接触性皮炎。越来越多的证据表明，接触会导致神经系统疾病，但关于铬（VI）神经毒性的知识差距仍然存在。人类研究报告称，Cr（VI）与自闭症谱系障碍、运动神经元疾病、嗅觉功能障碍和记忆受损有关。然而，对Cr（VI）在大脑中的特异性靶点的了解仅限于区域积累的报道（在啮齿动物的海马、下丘脑和垂体中报道了最大的作用），而细胞特异性作用仍然未知。秀丽隐杆线虫是一种有用的高通量模型，常用于金属神经毒性研究。在这里，我们描述了秀丽隐杆线虫模型，以解决Cr（VI）神经毒性的知识空白。所有测试的Cr（VI）浓度都是亚致死的，我们估计24小时暴露后，蠕虫体内Cr的生物蓄积量约为给药剂量的1e10-8%。暴露6小时后，Cr（VI）最初靶向gabaergy神经元，而暴露24小时后，胆碱能、多巴胺能和gabaergy神经元受到影响。对行为的影响与神经退行性变一致。此外，Cr（VI）加剧了蠕虫肠道自身荧光，表明生物老化加速。这些数据共同解决了关键的知识空白，确定了关键的神经元靶点，并为神经毒性的潜在机制提供了信息。

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引用次数: 0

Insights into cytotoxicity and redox modulation by the herbicide linuron and its metabolite, 3,4-dichloroaniline 除草剂Linuron及其代谢物3,4-二氯苯胺对细胞毒性和氧化还原调节的研究。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-17 DOI: 10.1016/j.neuro.2025.103324

Md. Jakaria , Jason R. Cannon

Linuron (3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea) is a phenylurea herbicide used to control the growth of grasses and weeds, thereby promoting the growth of crops such as soybeans. Both linuron and its metabolite, 3,4-dichloroaniline (DCA), have been identified as having toxic effects, including reproductive and developmental toxicity. However, the potential neurotoxic effects have not been thoroughly examined. This study investigates the toxic effects of linuron and DCA in neuronal cultures. A cell viability assay was used to evaluate cytotoxicity, while an iron and arachidonic acid-induced C11-BODIPY oxidation and ABTS assay were conducted to assess the potential redox modulatory activity of the tested compounds. Our results indicated that linuron and DCA were toxic to N27 cells (rat dopaminergic neurons) at higher concentrations, particularly above 50 μM. In contrast, these compounds did not demonstrate any considerable toxicity in HT-22 cells (mouse hippocampal neurons). We also examined whether linuron and DCA influence ferroptosis, a form of regulated cell death caused by lipid peroxidation. Our findings suggest that DCA significantly interferes with the process of ferroptosis and inhibits it due to its inherent radical-trapping antioxidant (RTA) activity. In conclusion, both linuron and its metabolite DCA showed modest cytotoxicity in N27 cells, and further experiments are needed to determine whether these agents cause neurotoxicity.

Linuron（3-（3,4-二氯苯基）-1-甲氧基-1-甲基脲）是一种苯脲类除草剂，用于控制禾草和杂草的生长，从而促进大豆等作物的生长。linuron及其代谢物3,4-二氯苯胺（DCA）已被确定具有毒性作用，包括生殖和发育毒性。然而，潜在的神经毒性作用尚未得到彻底的研究。本研究探讨了利努龙和DCA在神经元培养中的毒性作用。采用细胞活力法评估细胞毒性，采用铁和花生四烯酸诱导的C11-BODIPY氧化和ABTS法评估被试化合物的潜在氧化还原调节活性。结果表明，linuron和DCA在较高浓度下对N27细胞（大鼠多巴胺能神经元）具有毒性，特别是在50μM以上。相反，这些化合物对HT-22细胞（小鼠海马神经元）不产生毒性。我们还研究了利努龙和DCA是否影响铁下垂，这是一种由脂质过氧化引起的调节细胞死亡。我们的研究结果表明，由于其固有的自由基捕获抗氧化剂（RTA）活性，DCA显著干扰铁下垂过程并抑制它。综上所述，利努龙及其代谢物DCA对N27细胞均表现出适度的细胞毒性，尚需进一步实验确定其是否具有神经毒性。

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引用次数: 0

Early life perfluorooctanoic acid exposure induces long-lasting effects on social behaviors in adult mice 早期全氟辛酸暴露会对成年小鼠的社会行为产生长期影响。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-16 DOI: 10.1016/j.neuro.2025.103323

Yue Zhang , Na Qin , Yutong Wang , Hao Feng , Zhengxin Zhang , Chen Wang , Zihan Qin , Huiling Duo , Xi Yin , Yun Shi , Haishui Shi

Perfluorooctanoic acid (PFOA), a persistent organic pollutant widely used in the field of medicine, industry and agriculture, has been linked to various adverse health risks. However, the potential effects of early-life exposure to PFOA on social behaviors in adulthood remain unclear. ICR mice were exposed to different doses of PFOA (0, 1, 3 mg/kg) in drinking water for three weeks during the postweaning period. The open field test (OFT), social dominance test (SDT), novel object recognition (NOR) test, social interaction test (SIT) and social novelty preference (SNP) test were conducted to evaluate social behaviors. Behavioral results showed that postweaning PFOA exposure significantly decreased social dominance of both male and female mice during adulthood. PFOA exposure also reduced social interaction and improved social novelty in male mice, while impaired memory only in female mice. Results of 16S rRNA sequencing analysis showed the alpha-diversity, β-diversity and composition of gut microbiota altered after PFOA exposure. Following PFOA exposure, the abundance of beneficial bacteria such as Lactobacillus decreased specifically in female mice, whereas harmful bacteria such as Desulfovibrio increased in both male and female mice. Several pathways altered were predicted according to Kyoto Encyclopedia of Genes and Genomes (KEGG). The study reveals that postweaning exposure to PFOA has enduring effects on several social behaviors with variations dependent on sex, which may be linked to alterations in gut microbiota composition.

全氟辛酸（PFOA）是一种广泛应用于医药、工业和农业领域的持久性有机污染物，与各种不利的健康风险有关。然而，早期接触PFOA对成年后社会行为的潜在影响尚不清楚。ICR小鼠在断奶后连续3周暴露于不同剂量的PFOA（0、1、3mg/kg）饮用水中。采用开放场测验（OFT）、社会优势测验（SDT）、新物体识别测验（NOR）、社会互动测验（SIT）和社会新颖性偏好测验（SNP）对社会行为进行评价。行为学结果显示，断奶后暴露于PFOA显著降低了雄性和雌性小鼠在成年期的社会支配地位。暴露在PFOA中也会减少雄性小鼠的社交互动，提高社交新颖性，而只有雌性小鼠的记忆力受损。16S rRNA测序分析结果显示，PFOA暴露后肠道微生物群的α多样性、β多样性和组成发生了变化。在PFOA暴露后，雌性小鼠的有益细菌如乳酸杆菌的丰度明显减少，而有害细菌如Desulfovibrio在雄性和雌性小鼠中均增加。根据《京都基因与基因组百科全书》（KEGG）预测了几个通路的改变。该研究表明，断奶后接触PFOA对几种社会行为有持久的影响，这种影响取决于性别，这可能与肠道微生物群组成的改变有关。

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引用次数: 0

EphA/EphrinA5 signaling pathway involved in the abnormal synaptic remodeling and neurotoxicity caused by benzo[a]pyrene EphA/EphrinA5信号通路参与苯并[a]芘引起的突触异常重构和神经毒性。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-12 DOI: 10.1016/j.neuro.2025.103319

Xin Li , Shuang Zhou , Xiaoling Zhou , Jinfeng Zhang , Na Xia , Yangyang Li , Zhanfei Song , Hongmei Zhang

Benzo[a]pyrene (B[a]P) is recognized as a highly neurotoxic contaminant, however, the underlying mechanisms remain poorly understood. This study aimed to examine the alterations in erythropoietin-producing hepatocyte receptors (EphA4, EphA5) and their ligands (Ephrin A5) in the context of B[a]P-induced neurotoxicity, both in vivo and in vitro. A total of forty male mice were administered intraperitoneal injections of either a solvent (peanut oil) or a B[a]P solution (at doses of 0.5, 2, and 10 mg/kg) over a period of 60 days, once every other day. Following 30 exposures, the mice were subjected to exploratory behavioral assessments, transmission electron microscopy for hippocampal ultrastructural alterations, and western blotting to measure synapse-associated proteins (SYP, PSD95), as well as EphA4, EphA5, and Ephrin A5 proteins in the cerebral cortex. Parallel experiments were conducted using HT22 hippocampal neuronal cells. The results indicated that B[a]P treatment led to impairments in spatial cognitive function and spontaneous behavior, abnormal synaptic remodeling, and reduced SYP and PSD95 protein levels. Notably, compared to the control group, there was a marked increase in the protein levels of EphA4 and EphA5 in the cerebral cortex of mice following B[a]P treatment at mid and high doses, while Ephrin A5 protein level was significantly depressed at high dose. Additionally, in HT22 cells treated with B[a]P (0, 0.2, 2, and 20 μM) for 48 h, both cell viability and cell numbers exhibited a significant decline, accompanied by abnormal neuronal synaptic remodeling. In comparison to the control cells, EphA4 and EphA5 protein levels were significantly elevated in HT22 cells following B[a]P treatment, whereas Ephrin A5 protein levels were notably suppressed. These findings suggest that B[a]P may induce neurotoxicity through the disruption of synaptic remodeling via the EphA/EphrinA5 signaling pathway.

苯并[a]芘（B[a]P）被认为是一种高度神经毒性污染物，然而，其潜在机制仍知之甚少。本研究旨在体外和体内研究B[a] p诱导的神经毒性背景下产生促红细胞生成素的肝细胞受体（EphA4、EphA5）及其配体（Ephrin A5）的变化。共有40只雄性小鼠被腹腔注射溶剂（花生油）或B[A]P溶液（剂量为0.5、2和10mg/kg），为期60天，每隔一天注射一次。在30次暴露后，对小鼠进行探索性行为评估，透射电镜观察海马超微结构改变，western blotting检测突触相关蛋白（SYP, PSD95）以及大脑皮层EphA4， EphA5和Ephrin A5蛋白。采用HT22海马神经元细胞进行平行实验。结果表明，B[a]P治疗导致大鼠空间认知功能和自发性行为受损，突触重构异常，SYP和PSD95蛋白水平降低。值得注意的是，与对照组相比，B[a]P中、高剂量处理后小鼠大脑皮层EphA4、EphA5蛋白水平明显升高，而Ephrin A5蛋白水平在高剂量下明显降低。此外，B[a]P（0、0.2、2和20μM）处理HT22细胞48小时后，细胞活力和细胞数量均明显下降，并伴有异常的神经元突触重构。与对照细胞相比，B[a]P处理后，HT22细胞中EphA4和EphA5蛋白水平显著升高，而Ephrin A5蛋白水平明显降低。这些发现表明，B[a]P可能通过EphA/EphrinA5信号通路破坏突触重塑，从而诱导神经毒性。

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引用次数: 0

The nasal microbiome, inhalation exposure, and brain toxicity: A commentary 鼻微生物群，吸入暴露和脑毒性：评论。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-12 DOI: 10.1016/j.neuro.2025.103320

Christine Frieke Kuper , Eva A.J. Rennen , Wolfgang Kaufmann

The microbiome is increasingly discussed in diseases of the nervous system. The nasal microbiome is largely unexplored in neurotoxicity, while inhalation exposure to xenobiotics has been associated with neurodegenerative diseases linked to neurodegenerative diseases that are a growing health problem. The concept of a link between pathological changes of the nasal microbiome (dysbiosis) and brain neurotoxicity upon inhalation exposure is still in its early stages. In this commentary we argue that research into the nasal microbiome offers a great opportunity to obtain important information about the neurotoxicity of inhaled xenobiotics.

微生物组在神经系统疾病中被越来越多地讨论。鼻腔微生物组在神经毒性方面还未被广泛研究，而吸入暴露于异种抗生素与神经退行性疾病有关，而神经退行性疾病是一个日益严重的健康问题。鼻微生物组病理变化（生态失调）与吸入暴露后脑神经毒性之间的联系的概念仍处于早期阶段。在这篇评论中，我们认为对鼻腔微生物组的研究提供了一个很好的机会，可以获得关于吸入异种抗生素的神经毒性的重要信息。

引用次数: 0

Prenatal BPB/BPAF exposure induces depression-like behavior in male mice offspring via compound-specific transcriptional dysregulation and neurodevelopmental pathway alterations 产前BPB/BPAF暴露通过化合物特异性转录失调和神经发育通路改变诱导雄性小鼠后代抑郁样行为

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-11 DOI: 10.1016/j.neuro.2025.103322

Nannan Chen , Yuetong Liu , Yiran Zhouguo , Xueyi Cai , Xinyi Pan , Rui Guo , Wei Yan

The neurodevelopmental toxicity of bisphenol A (BPA) and its substitutes has garnered significant attention. However, the association between two widely detected environmental contaminants—BPAF and BPB—and adolescent depression, along with their underlying mechanisms, remain largely unclear. Here, we established a prenatal BPB/BPAF exposure animal model and demonstrated that such exposure induces depression- and anxiety-like behaviors in weanling male offspring. Through RNA sequencing of cortical tissues, combined with screening of depression-associated transcription factors (TFs), functional enrichment analysis of target genes, and identification of hub genes, we revealed that BPB and BPAF drive disease progression via distinct transcriptional regulatory networks and biological processes. Specifically, BPB significantly downregulate the TFs Lhx8 and Foxp1, targeting hub genes (e.g., Alb, Apoa1, Apoa2, Fga, Serpina1b, Fos, Rassf6, Rassf10, Rassf7, Moap1) to disrupt neuropeptide-, synapse-, transcription- related biological processes. In contrast, BPAF significantly upregulate the TF Neurod1, which modulate hub genes (e.g., Rpl26, Mrpl3,Rpl35, Mrpl1, Kcnd3) involved in neuronal cell body and cerebral cortex development. Molecular docking further confirmed potential binding interactions between BPB and Lhx8/ Foxp1, as well as BPAF and Neurod1, mediated by hydrogen bonding or hydrophobic interactions. These findings demonstrate that BPB and BPAF induce depression-like behavior in male offspring through compound-specific disruption of transcriptional networks, which alter neurodevelopmental pathways, potentially due to their divergent binding affinities to distinct TFs. This research offers new perspectives on the neurodevelopmental toxicity associated with BPA alternatives, offering critical implications for risk assessment and therapeutic targeting of BPAF/BPB-related neuropsychiatric disorders.

双酚A （BPA）及其替代品的神经发育毒性已经引起了人们的极大关注。然而，两种被广泛检测到的环境污染物——bpaf和bpb——与青少年抑郁症之间的关系及其潜在机制在很大程度上仍不清楚。在此，我们建立了一个产前BPB/BPAF暴露动物模型，并证明了这种暴露会导致断奶雄性后代的抑郁和焦虑样行为。通过皮质组织的RNA测序，结合抑郁相关转录因子（TFs）的筛选，靶基因的功能富集分析和枢纽基因的鉴定，我们发现BPB和BPAF通过不同的转录调控网络和生物学过程驱动疾病进展。具体而言，BPB显著下调TFs Lhx8和Foxp1，靶向中枢基因（如Alb、Apoa1、Apoa2、Fga、Serpina1b、Fos、Rassf6、Rassf10、Rassf7、Moap1），破坏神经肽、突触、转录相关的生物学过程。相比之下，BPAF显著上调TF Neurod1，其调节中枢基因（如Rpl26、Mrpl3、Rpl35、Mrpl1、Kcnd3）参与神经元细胞体和大脑皮层发育。分子对接进一步证实了BPB与Lhx8/ Foxp1、BPAF与Neurod1之间通过氢键或疏水相互作用介导的潜在结合相互作用。这些发现表明，BPB和BPAF通过对转录网络的化合物特异性破坏诱导雄性后代的抑郁样行为，从而改变神经发育途径，这可能是由于它们与不同tf的不同结合亲和力。本研究为BPA替代品相关的神经发育毒性提供了新的视角，为BPAF/ bpb相关神经精神疾病的风险评估和治疗靶向提供了重要意义。

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引用次数: 0

Ellagic acid’s dual targeting of Dmt1 uptake and Nrf2 defense counters juvenile manganese neurotoxicity 鞣花酸对Dmt1摄取和Nrf2防御的双重靶向对抗幼年锰神经毒性。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-11 DOI: 10.1016/j.neuro.2025.103321

Tolulope T. Arogundade , Oluwatomisin Idowu , George Sanyaolu , Favour E. Uware , Favour O. Akinbohun , Oluwatosin Popoola , Olutayo Arogundade , Oluwasegun D. Olatomide , Emmanuel Yawson , Olawande Bamisi , Adedamola A. Bayo-Olugbami , Habeebulahi A. Abdur-Rahman , Ezra Lambe , Rukayat Gbadamosi , Dayo R. Omotoso , Ismail Gbadamosi

Manganese (Mn) is an environmental neurotoxicant that threatens paediatric health through contaminated water. We evaluated the potential of ellagic acid (EA), a dietary polyphenol in nuts/berries, against multi-organ Mn toxicity. Juvenile male rats (n = 35) were divided into: control (distilled water), Mn (100 mg/kg MnCl₂), EA (30 mg/kg), vehicle, and Mn+EA groups. After 28 days of oral treatment, behavioral tests (OFT, EPM, ART) were conducted. Tissues were analyzed for oxidative stress (SOD, CAT, MDA), neuroinflammation (TNF-α), dopamine, AChE, gene expression (DMT1, Nrf2, Sod1), and histopathology. Mn induced locomotor deficits, anxiety-like behaviour, sensorimotor hyper-reactivity, oxidative stress (↓SOD/CAT, ↑MDA), elevated TNF-α, and reduced dopamine. EA co-treatment reversed behavioural impairments, restored antioxidant activity, normalized TNF-α/dopamine, EA suppressed Mn-induced Dmt1 upregulation, a key compensatory Mn uptake pathway in juveniles, while activating Nrf2, representing a novel dual protective mechanism. Histology confirmed EA preserved neuronal integrity and reduced hepatorenal damage. In conclusion, EA-associated downregulation of Dmt1 and downstream biochemical/histological improvements provide indirect evidence consistent with reduced Mn influx, but requires confirmation by direct brain Mn quantification.

锰（Mn）是一种环境神经毒物，通过污染的水威胁儿童健康。我们评估了鞣花酸（EA），坚果/浆果中的一种膳食多酚，对抗多器官锰毒性的潜力。将35只雄性幼年大鼠分为：对照组（蒸馏水）、Mn组（100mg/kg MnCl₂）、EA组（30mg/kg）、给药组和Mn+EA组。口服治疗28 d后进行行为学测试（OFT、EPM、ART）。组织分析氧化应激（SOD、CAT、MDA）、神经炎症（TNF-α）、多巴胺、AChE、基因表达（DMT1、Nrf2、Sod1）和组织病理学。Mn诱导运动缺陷、焦虑样行为、感觉运动高反应性、氧化应激（↓SOD/CAT，↑MDA）、TNF-α升高和多巴胺减少。EA联合治疗逆转了行为障碍，恢复了抗氧化活性，使TNF-α/多巴胺正常化，EA抑制了锰诱导的Dmt1上调（一个关键的代偿性锰摄取途径），同时激活了Nrf2，代表了一种新的双重保护机制。组织学证实EA保留了神经元的完整性，减轻了肝肾损害。总之，ea相关的Dmt1下调和下游生化/组织学改善提供了与锰流入减少一致的间接证据，但需要通过直接脑锰定量来证实。

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引用次数: 0

Chronic cisplatin treatment in young mice induces long-term complications in the peripheral nervous system in a sex-dependent manner 慢性顺铂治疗在年轻小鼠诱导周围神经系统以性别依赖的方式长期并发症。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-08 DOI: 10.1016/j.neuro.2025.103318

Laura Yanneth Ramírez-Quintanilla, Santos Adrián Pérez-Reyes, Martin de Jesus Salazar-Hernández, Héctor Fabián Torres-Rodríguez, Virginia Margarita Vargas-Muñoz, Ana Rebeca García-Araujo, Rosa Issel Acosta-González, Enriqueta Muñoz-Islas, Juan Miguel Jiménez-Andrade

Cisplatin-induced peripheral neuropathy (CIPN) is one of the most prevalent long-term complications in pediatric cancer survivors reaching adulthood. However, very few studies have evaluated the long-term effects of cisplatin administered to the young population on the peripheral nervous system and assessed whether these effects are sex-dependent. Thus, we aimed to assess baseline mechanical withdrawal thresholds (a CIPN measurement), the density of CGRP⁺ and PGP9.5⁺ axons in the glabrous skin, changes in different markers in DRG, and determine pain-like responses after intra-plantar capsaicin in female and male mice at 4 weeks after cessation of cisplatin. Four-week-old BALB/c mice were treated with cisplatin (4 mg/kg, intraperitoneally, twice weekly for 4 weeks). Four weeks after cessation of cisplatin, these mice, at 12 weeks of age, exhibited significant hindpaw mechanical hypersensitivity, which was greater in magnitude in female mice compared to male mice. At 13 weeks old, cisplatin-treated mice also had a greater density of CGRP⁺ and PGP9.5⁺ intraepidermal nerve fibers compared to saline-treated groups in female and male mice, independent of sex. The number of CGRP⁺ and ATF3⁺ neuronal profiles and CD68⁺ monocyte/macrophage in L4 DRG was higher in cisplatin-treated mice than in saline-treated mice, independent of sex. Intra-plantar capsaicin injection in adult mice resulted in greater and longer flinching and guarding behaviors in cisplatin-pretreated mice compared to saline-pretreated mice. The enhanced capsaicin-induced pain behaviors were significantly greater in female compared to male mice. These findings demonstrate long-term, partially sex-related complications in the peripheral nervous system following cisplatin treatment.

顺铂诱导的周围神经病变（CIPN）是儿童癌症幸存者成年后最常见的长期并发症之一。然而，很少有研究评估顺铂对年轻人周围神经系统的长期影响，并评估这些影响是否具有性别依赖性。因此，我们旨在评估基线机械戒断阈值（CIPN测量），无毛皮肤中CGRP+和PGP9.5+轴突的密度，DRG中不同标记物的变化，并确定顺铂停药后4周雌性和雄性小鼠脚底辣椒素后的疼痛样反应。顺铂治疗4周龄BALB/c小鼠（4mg/kg，腹腔注射，每周2次，连续4周）。停止顺铂治疗4周后，这些小鼠在12周龄时表现出明显的后爪机械过敏，雌性小鼠比雄性小鼠的程度更大。在13周龄时，顺铂处理的小鼠表皮内神经纤维的CGRP+和PGP9.5+密度也高于盐水处理的雌性和雄性小鼠，与性别无关。顺铂处理小鼠L4 DRG中CGRP+和ATF3+神经元分布和CD68+单核/巨噬细胞的数量高于盐水处理小鼠，与性别无关。成年小鼠足底内注射辣椒素导致顺铂预处理小鼠比盐水预处理小鼠退缩和守卫行为更大，时间更长。与雄性小鼠相比，雌性小鼠辣椒素诱导的疼痛行为明显增强。这些发现表明顺铂治疗后周围神经系统存在长期的、部分性相关的并发症。

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引用次数: 0

Clinical doses of gadodiamide have no damaging effects on cochlear tissue in vitro and in vivo 临床剂量加多二胺对体外和体内耳蜗组织无损伤作用。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-09-07 DOI: 10.1016/j.neuro.2025.103317

Xiong Zhang , Jingwen Zhang , Yang Tian , Yixi Xiao , Hengkang He , Jing Luo , Dalian Ding , Hai Liu , Jianhui Zhang

Gadolinium-based contrast agents (GBCAs) are widely used in systemic magnetic resonance imaging (MRI) and can be employed in otology to evaluate endolymphatic hydrops in patients with Ménière’s disease. Given the heavy metal properties of gadolinium and its tendency to deposit in tissues, it is essential to assess its ototoxic risk. We evaluated the ototoxicity of gadodiamide using in vitro and in vivo models. In vitro, cochlear explants from postnatal day 3 rats were cultured for 24 h in medium containing 0, 100 (equivalent to the concentration in perilymph after intratympanic injection), 500, or 2500 μM gadodiamide. Immunofluorescence results revealed that no significant structural damage occurred to hair cells (HCs) or spiral ganglion neuron (SGN) somata at any concentration, and that only the 2500 μM group exhibited slight thinning or disintegration of auditory nerve fibers (ANFs). In vivo, 50 μL of normal saline, 8-fold diluted, or undiluted gadodiamide was applied to the round window membrane (RWM) of adult rats via a postauricular approach. Evaluation 5 days later showed that, compared with the saline group, there were no significant changes in the compound action potential (CAP) thresholds or cochlear structures in rats treated with either 8-fold diluted or undiluted gadodiamide. The results confirmed that clinical doses of gadodiamide do not cause damage to cochlear structures; however, the neurotoxicity observed at excessively high concentrations highlights the necessity of strict adherence to dosing protocols.

钆基造影剂（gbca）广泛应用于全身磁共振成像（MRI），可用于耳科评估mims患者的内淋巴积液。鉴于钆的重金属特性及其在组织中的沉积倾向，评估其耳毒性风险是必要的。我们用体外和体内模型评估了加多二胺的耳毒性。体外，取出生第3天的大鼠耳蜗外植体，分别在含0、100（相当于鼓室内注射后淋巴周围浓度）、500、2500μM gadodiamide的培养基中培养24小时。免疫荧光结果显示，在任何浓度下，毛细胞（HCs）和螺旋神经节神经元（SGN）体均未发生明显的结构损伤，只有2500μM组听觉神经纤维（ANFs）出现轻微变薄或解体。在体内，将50μL生理盐水，经8倍稀释或未稀释的加多二胺经耳后入路涂于成年大鼠的圆窗膜。5天后评估显示，与生理盐水组相比，加多双胺8倍稀释和未稀释组大鼠的复合动作电位（CAP）阈值和耳蜗结构均无明显变化。结果证实，临床剂量的加多二胺不会对耳蜗结构造成损害；然而，在过高浓度下观察到的神经毒性突出了严格遵守给药方案的必要性。

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引用次数: 0