Neurotoxicology最新文献_第6页

A hyperpolarization-activated cyclic nucleotide-gated channel inhibitor mitigates brain mitochondrial oxidative stress, but does not affect other neuropathological 超极化激活的环核苷酸门控通道抑制剂减轻脑线粒体氧化应激，但不影响其他神经病理。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-10-28 DOI: 10.1016/j.neuro.2025.103341

Hiranya Pintana , Nattayaporn Apaijai , Adivitch Sripusanapan , Titikorn Chunchai , Damrongsak Jinarat , Aphisek Kongkaew , Nipon Chattipakorn , Siriporn C. Chattipakorn

Background

The effects of ivabradine, a hyperpolarization-activated cyclic nucleotide-gated channel blocker, on doxorubicin-induced chemobrain remain unclear. This study aimed to investigate whether ivabradine mitigates doxorubicin-induced chemobrain by improving cognitive function, hippocampal synaptic plasticity, and mitochondrial function, while reducing oxidative stress, inflammation, and blood-brain barrier (BBB) disruption in male rats.

Methods

Twenty-four male rats were randomly assigned to one of four groups: control-vehicle treated, control-ivabradine treated, doxorubicin-vehicle treated, and doxorubicin-ivabradine treated. Control-rats received normal saline, while doxorubicin-treated rats were given doxorubicin (3 mg/kg/day) intraperitoneally on days 0, 4, 8, 15, 22, and 29. Ivabradine (10 mg/kg) was given orally from day 0 to day 29. On day 30, cognitive function was evaluated using the novel object location (NOL) test. Following euthanasia, hippocampal synaptic plasticity, mitochondrial function, BBB integrity, brain oxidative stress and inflammation were assessed.

Results

Doxorubicin treatment led to impaired performance in the NOL test, reduced hippocampal synaptic plasticity, disruption of mitochondrial function and BBB integrity, alongside increased oxidative stress and inflammation in the brain. Ivabradine reduced the level of mitochondrial reactive oxygen species (ROS), but did not significantly improve NOL performance or synaptic plasticity in doxorubicin-treated rats. However, ivabradine partially restored hippocampal dendritic spine morphology and reduced oxidative stress and inflammation in the brain.

Conclusion

Doxorubicin-induced chemobrain resulted in cognitive impairment and brain pathologies. Ivabradine reduced mitochondrial ROS and alleviated oxidative stress and inflammation in the brain, but did not improve cognitive function or synaptic plasticity. Higher doses of ivabradine may be required for more effective neuroprotection in chemobrain.

背景：伊瓦布雷定（一种超极化激活的环核苷酸门控通道阻滞剂）对阿霉素诱导的化学脑的影响尚不清楚。本研究旨在探讨伊伐布雷定是否通过改善雄性大鼠的认知功能、海马突触可塑性和线粒体功能，同时减少氧化应激、炎症和血脑屏障（BBB）破坏，来减轻阿霉素诱导的化学脑。方法：将24只雄性大鼠随机分为4组：对照组、对照组伊瓦布雷定组、阿霉素组和阿霉素-伊瓦布雷定组。对照组大鼠给予生理盐水，阿霉素治疗组大鼠于第0、4、8、15、22、29天腹腔注射阿霉素3mg/kg/天。从第0天至第29天口服伊伐布雷定（10mg/kg）。第30天，采用新目标定位（NOL）测试评估认知功能。安乐死后，评估海马突触可塑性、线粒体功能、血脑屏障完整性、脑氧化应激和炎症。结果：阿霉素治疗导致NOL测试表现受损，海马突触可塑性降低，线粒体功能和血脑屏障完整性破坏，同时大脑氧化应激和炎症增加。伊伐布雷定降低了阿霉素处理大鼠线粒体活性氧（ROS）水平，但没有显著改善NOL性能或突触可塑性。然而，伊伐布雷定部分恢复海马树突棘形态，减少大脑氧化应激和炎症。结论：阿霉素诱导的化学脑导致认知功能障碍和脑病理。伊伐布雷定降低了线粒体ROS，减轻了大脑的氧化应激和炎症，但没有改善认知功能或突触可塑性。在化学脑中，更高剂量的伊伐布雷定可能需要更有效的神经保护。

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引用次数: 0

The role of ER/ERK/CREB pathway mediated mitophagy in bisphenol F-induced cognitive function changes in young female rats ER/ERK/CREB通路介导的线粒体自噬在双酚f诱导的年轻雌性大鼠认知功能改变中的作用

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-10-28 DOI: 10.1016/j.neuro.2025.103340

Wenhe Wang, Zeqin Peng, Xinyi Feng, Zixuan Chen, Jie Zhang, Tianwenjing Huang, Qin Zhang, Dan Wu, Qin Liu

Bisphenol F (BPF) is a widespread industrial chemical and suspected neurotoxicant, yet its effects on cognitive function and the underlying mechanisms remain unclear. This study aimed to investigate whether BPF exposure induced cognitive function changes in young female rats were associated with ER/ERK/CREB pathway and subsequent mitophagy. 4-week-old Sprague-Dawley female rats received BPF via oral gavage (25 or 250 μg/kg bw/d) for 4 weeks. Cognitive function was evaluated using the Morris water maze and novel object recognition test during the last week of exposure. Hippocampal tissue was analysed for histomorphology, ER/ERK/CREB pathway changes, mitophagy and apoptosis. In this study, spatial learning in rats was transiently impaired, whereas long-term spatial memory remained unchanged in rats following BPF exposure. The recognition capability was improved as the dose increased. At the molecular level, the protein related to ER/ERK/CREB pathway, mitophagy and apoptosis were downregulated. Moreover, the mitophagy was downregulated in hippocampal CA1 region. These findings suggested that BPF exposure affected cognitive functions in young female rats, which was associated with the alterations of mitophagy mediated by ER/ERK/CREB pathway.

双酚F （BPF）是一种广泛使用的工业化学品和疑似神经毒物，但其对认知功能的影响及其潜在机制尚不清楚。本研究旨在探讨BPF暴露诱导的年轻雌性大鼠认知功能改变是否与ER/ERK/CREB通路及其后的有丝分裂有关。4周龄Sprague-Dawley雌性大鼠灌胃BPF(25或250μg/kg bw/d) 4周。在暴露的最后一周，使用Morris水迷宫和新物体识别测试评估认知功能。分析海马组织形态学、ER/ERK/CREB通路变化、线粒体自噬和细胞凋亡情况。在本研究中，暴露于BPF后，大鼠的空间学习功能短暂受损，而长期空间记忆功能保持不变。随着剂量的增加，识别能力有所提高。在分子水平上，与ER/ERK/CREB通路、线粒体自噬和细胞凋亡相关的蛋白下调。海马CA1区有丝分裂下调。这些结果表明，BPF暴露影响了年轻雌性大鼠的认知功能，这与ER/ERK/CREB途径介导的线粒体自噬改变有关。

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引用次数: 0

DDT exposure induces microglial activation and disease-associated microglial signatures: Relevance to mechanisms of Alzheimer’s disease DDT暴露诱导小胶质细胞激活和疾病相关的小胶质细胞特征：与阿尔茨海默病的机制相关。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-11-02 DOI: 10.1016/j.neuro.2025.103343

Isha Mhatre-Winters , Aseel Eid , Nicole Blum , Yoonhee Han , Ferass M. Sammoura , Long-Jun Wu , Jason R. Richardson

Background

Alzheimer’s disease (AD) is characterized by the presence of amyloid-β plaques, neurofibrillary tangles, and neuroinflammation. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the primary metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were significantly higher in AD patients compared to age-matched controls and that DDT exposure worsened AD pathology in animal models.

Objective

Here, we investigated the effect of DDT on neuroinflammation in primary mouse microglia (PMG) and C57BL/6J mice.

Methods

DDT-induced inflammatory and disease-associated microglial (DAM) gene expression were determined in PMG by qPCR and immunocytochemistry, with and without pretreatment with the sodium channel antagonist tetrodotoxin (TTX). Furthermore, 4–5-month-old C57BL/6J mice received a single oral dose of 30 mg/kg DDT for 24 h, and the hippocampal and frontal cortical expression of proinflammatory and DAM genes was measured.

Results

PMG exposed to DDT (0.5–5.0 µM) elicited a concentration-dependent upregulation in Il-1b, Il-6, Nos2, and Tnfa mRNA levels. These effects were blocked by TTX, demonstrating the role of DDT-microglial sodium channel interactions in mediating this response. C57BL/6J mice exposed to DDT demonstrated significantly increased Nos2, Il-1b, and Il-6 mRNA in the frontal cortex (1.5–2.3-fold), and Nos2, Il-1b, and Tnfa (1.5–1.8-fold) in the hippocampus. Furthermore, microglial homeostatic genes were downregulated, while stage-1 DAM genes were upregulated both in vitro and in vivo. Notably, Apoe and Trem2 were only upregulated in the females.

Conclusion

These data indicate that DDT increases neuroinflammation, which may result from direct actions of DDT on microglia, providing a novel pathway by which DDT may contribute to AD risk.

背景：阿尔茨海默病（AD）的特点是存在淀粉样蛋白-β斑块、神经原纤维缠结和神经炎症。此前，我们报道了与年龄匹配的对照组相比，AD患者血清中农药二氯二苯三氯乙烷（DDT）的主要代谢物二氯二苯二氯乙烯（DDE）水平明显更高，并且在动物模型中，DDT暴露加重了AD病理。目的：研究DDT对小鼠原代小胶质细胞（PMG）和C57BL/6J小鼠神经炎症的影响。方法：在钠通道拮抗剂河豚毒素（TTX）预处理和不预处理的情况下，采用qPCR和免疫细胞化学方法检测ddt诱导的PMG炎症和疾病相关小胶质细胞（DAM）基因表达。此外，4-5月龄C57BL/6J小鼠单次口服滴滴涕30mg/kg，持续24h，测量海马和额叶皮质促炎和DAM基因的表达。结果：暴露于DDT（0.5-5.0µM）的PMG引起Il-1b、Il-6、Nos2和Tnfa mRNA水平的浓度依赖性上调。这些作用被TTX阻断，证明ddt -小胶质钠通道相互作用在介导这种反应中的作用。DDT暴露的C57BL/6J小鼠额叶皮质Nos2、Il-1b和Il-6 mRNA显著增加（1.5-2.3倍），海马Nos2、Il-1b和Tnfa显著增加（1.5-1.8倍）。此外，小胶质细胞内稳态基因下调，而1期DAM基因在体外和体内均上调。值得注意的是，Apoe和Trem2仅在雌性中上调。结论：这些数据表明DDT增加神经炎症，这可能是由DDT对小胶质细胞的直接作用引起的，这为DDT可能增加AD风险提供了一种新的途径。

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引用次数: 0

Association between prenatal exposures to per- and polyfluoroalkyl substances and early language development in the ECHO cohort 产前暴露于单氟烷基和多氟烷基物质与ECHO队列早期语言发育之间的关系

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-09-25 DOI: 10.1016/j.neuro.2025.103309

Patricia Cintora , Lesliam Quirós-Alcalá , Adaeze W. Nzegwu , Sudhi Upadhyaya , Megan Woodbury , Sarah Dee Geiger , Rachel Morello-Frosch , Anne L. Dunlop , Theresa M. Bastain , Anne P. Starling , Dana Dabelea , Carlos A. Camargo Jr. , Pi-I Debby Lin , Rachel S. Kelly , Assiamira Ferrara , Lisa A. Croen , Thomas G. O’Connor , June-Soo Park , Morgan Reynolds , Kurunthachalam Kannan , Susan L. Schantz

Background/Aim

The relationship between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and child neurodevelopment remains inconclusive, and few studies have investigated associations of PFAS exposure with language development. This study drew on data from seven U.S.-based Environmental influences on Child Health Outcomes (ECHO) cohorts to investigate associations between prenatal PFAS exposures and language development in early childhood.

Methods

We quantified concentrations of four PFAS in maternal plasma or serum during pregnancy. Language development was assessed using the communication scale from the Ages & Stages Questionnaires, Third Edition (ASQ®-3) in children ages 1.5–5 years (n = 1503) and the NIH Toolbox Picture Vocabulary Test (PVT) in children ages 3–5 years (n = 399). Associations between individual PFAS and language outcomes were examined in multivariable linear and logistic regression models. PFAS mixture was examined using quantile g-computation.

Results

Overall and in sex-specific analyses, we did not observe associations between individual PFAS biomarkers and language development. The PFAS mixture showed no significant associations with ASQ®-3 communication z-scores (ψ = −0.04; 95 % CI: −0.86, 0.78) or PVT t-scores (ψ = 0.35; 95 % CI: −1.14, 1.83). Sex-specific results showed a small but statistically significant negative association with ASQ®-3 communication scores in females (ψ = −0.46; 95 % CI: −0.88, −0.05; p = 0.03) and positive, albeit not statistically significant, associations with PVT t-scores in males (ψ = 0.27; 95 % CI: −1.84, 2.38) and females (ψ = 0.55; 95 % CI: −1.81, 2.92).

Conclusions

Prenatal concentrations of individual PFAS or their mixture were not associated with ASQ®-3 communication domain scores or PVT t-scores.

背景/目的：产前暴露于全氟烷基和多氟烷基物质（PFAS）与儿童神经发育之间的关系尚不明确，很少有研究调查PFAS暴露与语言发育的关系。本研究利用美国七个环境对儿童健康结果的影响（ECHO）队列的数据，调查产前PFAS暴露与儿童早期语言发展之间的关系。方法：测定妊娠期间母体血浆或血清中4种PFAS的浓度。在1.5-5岁儿童（n=1503）和3-5岁儿童（n=399）中使用《年龄与阶段问卷第三版》（ASQ®-3）中的交流量表评估语言发展。在多变量线性和逻辑回归模型中检验了单一PFAS与语言结果之间的关系。采用分位数g计算对PFAS混合物进行检测。结果：在总体和性别特异性分析中，我们没有观察到个体PFAS生物标志物与语言发育之间的关联。PFAS混合物与ASQ®-3沟通z-分数（ψ = -0.04; 95% CI: -0.86, 0.78）或PVT t-分数（ψ = 0.35; 95% CI: -1.14, 1.83）无显著相关性。性别差异结果显示，女性与ASQ®-3沟通得分呈负相关（ψ = -0.46, 95% CI: -0.88, -0.05; p = 0.03），男性与PVT t-得分呈正相关（ψ = 0.27, 95% CI: -1.84, 2.38），女性与PVT t-得分呈正相关（ψ = 0.55, 95% CI: -1.81, 2.92），但无统计学意义。结论：产前单个PFAS或其混合物浓度与ASQ®-3通信域评分或PVT t评分无关。

{"title":"Association between prenatal exposures to per- and polyfluoroalkyl substances and early language development in the ECHO cohort","authors":"Patricia Cintora , Lesliam Quirós-Alcalá , Adaeze W. Nzegwu , Sudhi Upadhyaya , Megan Woodbury , Sarah Dee Geiger , Rachel Morello-Frosch , Anne L. Dunlop , Theresa M. Bastain , Anne P. Starling , Dana Dabelea , Carlos A. Camargo Jr. , Pi-I Debby Lin , Rachel S. Kelly , Assiamira Ferrara , Lisa A. Croen , Thomas G. O’Connor , June-Soo Park , Morgan Reynolds , Kurunthachalam Kannan , Susan L. Schantz","doi":"10.1016/j.neuro.2025.103309","DOIUrl":"10.1016/j.neuro.2025.103309","url":null,"abstract":"<div><h3>Background/Aim</h3><div>The relationship between prenatal exposure to per- and polyfluoroalkyl substances (PFAS) and child neurodevelopment remains inconclusive, and few studies have investigated associations of PFAS exposure with language development. This study drew on data from seven U.S.-based Environmental influences on Child Health Outcomes (ECHO) cohorts to investigate associations between prenatal PFAS exposures and language development in early childhood.</div></div><div><h3>Methods</h3><div>We quantified concentrations of four PFAS in maternal plasma or serum during pregnancy. Language development was assessed using the communication scale from the Ages & Stages Questionnaires, Third Edition (ASQ®-3) in children ages 1.5–5 years (n = 1503) and the NIH Toolbox Picture Vocabulary Test (PVT) in children ages 3–5 years (n = 399). Associations between individual PFAS and language outcomes were examined in multivariable linear and logistic regression models. PFAS mixture was examined using quantile g-computation.</div></div><div><h3>Results</h3><div>Overall and in sex-specific analyses, we did not observe associations between individual PFAS biomarkers and language development. The PFAS mixture showed no significant associations with ASQ®-3 communication z-scores (ψ = −0.04; 95 % CI: −0.86, 0.78) or PVT t-scores (ψ = 0.35; 95 % CI: −1.14, 1.83). Sex-specific results showed a small but statistically significant negative association with ASQ®-3 communication scores in females (ψ = −0.46; 95 % CI: −0.88, −0.05; p = 0.03) and positive, albeit not statistically significant, associations with PVT t-scores in males (ψ = 0.27; 95 % CI: −1.84, 2.38) and females (ψ = 0.55; 95 % CI: −1.81, 2.92).</div></div><div><h3>Conclusions</h3><div>Prenatal concentrations of individual PFAS or their mixture were not associated with ASQ®-3 communication domain scores or PVT t-scores.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"111 ","pages":"Article 103309"},"PeriodicalIF":3.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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 : 2025-12-01 Epub 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

Long-term occupational exhaust fumes exposure and delayed cognitive impairment in older adults: A cross-sectional study in U.S 长期职业性废气暴露与老年人迟发性认知障碍：美国的一项横断面研究

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-10-18 DOI: 10.1016/j.neuro.2025.103336

Lili Liang , Perry E. Sheffield , Rose Saint Fleur-Calixte , Tianxu Xia , Spencer Xinyi Zhang , Jenny J. Lin

Background

Occupational exposure to exhaust fumes, containing neurotoxic particulate matter and polycyclic aromatic hydrocarbons (PAHs), is associated with cardiopulmonary diseases, but its cognitive effects in aging workers remain insufficiently studied. Given increasing occupational longevity, understanding these risks is critical for dementia prevention.

Methods

We analyzed data from 1110 adults aged 60 years and older in the 2011–2012 National Health and Nutrition Examination Survey (NHANES), comparing cognitive performance between exposed (24 %) and unexposed groups. Cognitive function was assessed using the Consortium to Establish a Registry for Alzheimer’s Disease Word List Learning Test (CERAD-WL), Animal Fluency Test (AFT), and Digit Symbol Substitution Test (DSST). Distributed lag nonlinear models (DLNMs) evaluated non-linear and time-lagged effects of exposure duration.

Results

Exposed workers were predominantly male (81.6 % vs. 41.8 %), had lower educational attainment (31.2 % vs. 24.4 % with less than high school education), and exhibited higher rates of smoking (65.0 % vs. 48.6 %) and excessive alcohol use (15.7 % vs. 7.0 %). Occupational exposure was associated with significant cognitive impairments in delayed memory (odds ratio [OR] = 2.55, 95 % confidence interval [CI]: 1.61–4.05), verbal fluency (OR 2.41, 1.48–3.94), and processing speed (OR 1.95, 1.19–3.18). The DLNM analyses revealed a biphasic response: minimal effects at < 20 years of exposure, but major declines after 30 years, with a 15–25-year latency period.

Conclusion

Prolonged occupational exhaust fume exposure is associated with domain-specific cognitive decline, particularly affecting memory and executive function. The dose-response relationship underscores cumulative neurotoxicity, emphasizing the need for targeted protections for high-exposure workers.

背景：职业性暴露于含有神经毒性颗粒物和多环芳烃（PAHs）的废气中与心肺疾病有关，但其对老年工人的认知影响仍未充分研究。鉴于职业寿命的延长，了解这些风险对预防痴呆症至关重要。方法：我们分析了2011-2012年全国健康与营养调查（NHANES）中1110名60岁及以上成年人的数据，比较暴露组（24%）和未暴露组的认知表现。认知功能通过建立阿尔茨海默病单词列表学习测试（CERAD-WL）、动物流畅性测试（AFT）和数字符号替代测试（DSST）进行评估。分布滞后非线性模型（DLNMs）评估了暴露时间的非线性和时滞效应。结果：暴露的工人以男性为主（81.6%对41.8%），受教育程度较低（31.2%对24.4%，低于高中学历），吸烟（65.0%对48.6%）和过度饮酒（15.7%对7.0%）的比例较高。职业暴露与延迟记忆（优势比[OR] = 2.55, 95%可信区间[CI]: 1.61-4.05）、语言流畅性（OR 2.41, 1.48-3.94）和处理速度（OR 1.95, 1.19-3.18）显著的认知障碍相关。结论：长期职业性废气暴露与特定领域的认知能力下降有关，尤其是对记忆和执行功能的影响。剂量-反应关系强调了累积性神经毒性，强调了对高暴露工人有针对性保护的必要性。

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引用次数: 0

Age-dependent effects of hyperhomocysteinemia on neural differentiation and retinal development 高同型半胱氨酸血症对神经分化和视网膜发育的年龄依赖性影响。

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-10-21 DOI: 10.1016/j.neuro.2025.103339

Manuela Sozo Cecchini, Madson Silveira de Melo , Evelise Maria Nazari

Hyperhomocysteinemia (HHcy), characterized by elevated homocysteine levels, is linked to developmental abnormalities, yet its impact on early eye development remains poorly understood. Given the well-documented neurotoxic effects of HHcy on central nervous system (CNS) development, this study aimed to investigate the age-specific effects of HHcy on eye development, focusing on retinal morphology, ultrastructure, vascular integrity, DNA integrity, apoptosis, and neural survival and differentiation. Fertilized Gallus domesticus embryos received 20 μmol homocysteine at embryonic day 2 (E2) and were analyzed at E6 and E10, key stages of eye organization and retinal layering. Although HHcy exposure did not alter retinal thickness, ultrastructural abnormalities indicating subcellular stress, such as dilated perinuclear space and rough endoplasmic reticulum cisternae, were observed. Disruptions on vascular integrity, induced by HHcy exposure were evident at both ages. DNA damage and upregulation of cell cycle regulators were noted at E6 but normalized by E10. Despite this, a reduction in cell proliferation was observed at both ages. Apoptosis increased at E10, suggesting heightened cell death during later retinal development. Neural differentiation and expression of neurotrophic factors were also impaired. Although overall retinal morphology appeared intact, HHcy induced significant molecular and structural disruptions, indicating a multifactorial, temporally dynamic mechanism of toxicity. These findings highlight the sensitivity of developing eye tissues to metabolic imbalance and suggest that even transient elevations in HHcy can interfere with critical developmental processes. This study underscores the potential role of HHcy in eye congenital anomalies and emphasizes the importance of maintaining homocysteine homeostasis during early embryogenesis.

以高同型半胱氨酸水平升高为特征的高同型半胱氨酸血症（HHcy）与发育异常有关，但其对早期眼睛发育的影响仍知之甚少。鉴于HHcy对中枢神经系统（CNS）发育的神经毒性作用已有充分文献记载，本研究旨在探讨HHcy对眼睛发育的年龄特异性影响，重点关注视网膜形态、超微结构、血管完整性、DNA完整性、细胞凋亡和神经存活和分化。在胚胎第2天（E2）接受20 μmol同型半胱氨酸，并在E6和E10（眼组织和视网膜分层的关键阶段）进行分析。虽然HHcy暴露没有改变视网膜厚度，但观察到显示亚细胞应激的超微结构异常，如核周间隙扩大和内质网池粗化。HHcy暴露引起的血管完整性破坏在两个年龄都很明显。DNA损伤和细胞周期调节因子的上调在E6中被注意到，但在E10中被正常化。尽管如此，在两个年龄段都观察到细胞增殖的减少。凋亡在E10时增加，表明在视网膜发育后期细胞死亡增加。神经分化和神经营养因子的表达也受到损害。虽然视网膜整体形态完好无损，但HHcy引起了明显的分子和结构破坏，表明毒性的多因素、时间动态机制。这些发现强调了发育中的眼组织对代谢失衡的敏感性，并表明即使是短暂的HHcy升高也会干扰关键的发育过程。本研究强调了HHcy在眼睛先天性异常中的潜在作用，并强调了在胚胎发生早期维持同型半胱氨酸稳态的重要性。

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引用次数: 0

Altered development in rodent brain cells after 900 MHz radiofrequency exposure 900 MHz射频暴露后啮齿动物脑细胞发育的改变

IF 3.9 3区医学 Q2 NEUROSCIENCES

Neurotoxicology

Pub Date : 2025-12-01 Epub Date: 2025-09-02 DOI: 10.1016/j.neuro.2025.103312

Raphaël Bodin , Lucas Godin , Camille Mougin , Anthony Lecomte , Vanessa Larrigaldie , Justyne Feat-Vetel , Sarah Méresse , Céline Montécot-Dubourg , Paulo Marcelo , Stéphane Mortaud , Anne-Sophie Villegier

Health risks related to 900 MHz 2 G frequency exposure remain inconclusive under current regulatory standards. Research into potential long-term effects is ongoing, particularly as the use of mobile networks and wireless devices increases. This study investigates the effects of non-thermal exposure levels of mobile phone 900 MHz radiofrequency electromagnetic field (RF-EMF) on rodent neurodevelopment. In vivo, the effects of pre- and post-natal 0.08 and 0.4 W/kg specific absorption rate (SAR) exposure were assessed for their impact on the proteomic profile at postnatal day 0 (PND 0). Brain-derived neurotrophic factor (BDNF), BrdU+ proliferative cells, synaptogenesis, and oxidative stress in the hippocampus and cortex of rat pups were studied at PND 8 and PND 17. Effects of the lowest SAR (0.08 W/kg) were assessed in vitro to afford mechanistic data regarding neural stem cells (NSCs) differentiation. In vivo results showed a decrease in BDNF level and BrdU+ proliferative cells with a decrease in synapse balance (excitatory synapses/inhibitory synapses). In vitro, at 0.08 W/kg there was an increase in Ki-67 + proliferative cells, apoptosis, and double-strand DNA breaks in NSCs. A lower ratio of B1 cells (primary progenitors of NSCs) among total cerebral cells and a higher ratio of oligodendrocyte progenitor cells and astrocytes were observed in the exposed NSCs. Our findings suggest that key cellular events for brain ontogenesis are likely to undergo changes with RF-EMF 900 MHz exposure during early development. These support the hypothesis that the developing central nervous system is vulnerable to RF-EMF exposures in rodents at regulatory thresholds.

与900 MHz 2 G频率接触有关的健康风险在目前的监管标准下仍然没有定论。对潜在长期影响的研究正在进行中，特别是随着移动网络和无线设备使用的增加。本研究探讨手机900 MHz射频电磁场（RF-EMF）的非热暴露水平对啮齿动物神经发育的影响。在体内，研究人员评估了产前和产后0.08和0.4 W/kg特定吸收率（SAR）暴露对出生后第0天（PND 0）蛋白质组学谱的影响。脑源性神经营养因子（BDNF）、BrdU+ 增殖细胞、突触发生和氧化应激在PND 8和PND 17大鼠幼崽的海马和皮层。体外评估最低SAR（0.08 W/kg）对神经干细胞（NSCs）分化的影响，以提供机制数据。体内实验结果显示BDNF水平和BrdU+ 增生细胞减少，突触平衡（兴奋性突触/抑制性突触）减少。在体外，0.08 W/kg时，NSCs中Ki-67 + 增殖细胞、凋亡和双链DNA断裂增加。在暴露的NSCs中，B1细胞（NSCs的原代祖细胞）占总脑细胞的比例较低，少突胶质细胞祖细胞和星形胶质细胞的比例较高。我们的研究结果表明，大脑个体发生的关键细胞事件可能在早期发育期间随着RF-EMF 900 MHz的暴露而发生变化。这些结果支持了这样一种假设，即处于调节阈值的啮齿动物中，发育中的中枢神经系统易受RF-EMF暴露的影响。

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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 : 2025-12-01 Epub 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

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 : 2025-12-01 Epub 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