Neurotoxicology最新文献

{"title":"Interactive effect of children’s copper exposure and socioeconomic status on preschoolers’ cognitive development","authors":"Hualong Zhen ,&nbsp;Linlin Zhu ,&nbsp;Xuemei Hao ,&nbsp;Jingru Lu ,&nbsp;Yufan Guo ,&nbsp;Chunmei Liang ,&nbsp;Juan Tong ,&nbsp;Fangbiao Tao ,&nbsp;Jiong Li ,&nbsp;Kun Huang","doi":"10.1016/j.neuro.2025.103377","DOIUrl":"10.1016/j.neuro.2025.103377","url":null,"abstract":"<div><h3>Purpose</h3><div>To explore the interaction effects of children's plasma copper (Cu) levels and socioeconomic status (SES) on cognitive function in preschoolers.</div></div><div><h3>Methods</h3><div>This study utilized follow-up data from the China National Birth Cohort conducted at Ma’anshan Maternal and Child Health Center between May 2017 and September 2018. Cognitive development in 3-year-old children was assessed by trained professionals using the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). Plasma Cu concentrations were measured by inductively coupled plasma mass spectrometry. Family SES was assessed as a composite index derived from a baseline parental questionnaire. Restricted cubic spline plots and Poisson regression models were applied respectively to analyze the independent and interactive effects of children’s Cu exposure and SES on preschoolers’ cognitive development.</div></div><div><h3>Results</h3><div>The median plasma Cu concentration was 1062.8 µg/L (IQR: 931.9–1229.3 µg/L). Compared to high SES, low SES was associated with an increased risk of abnormalities in cognitive function (OR=2.56, 95 % CI: 1.27–5.14), receptive communication (OR=2.87, 95 % CI: 1.22–6.80), expressive communication (OR=1.77, 95 % CI: 1.23–2.54), and fine motor (OR=2.57, 95 % CI: 1.19–5.56). A medium or high concentration of Cu was associated with an increased risk of abnormalities in cognition and expressive communication compared to a low concentration of Cu. Children with medium Cu level and low SES had an increased risk of abnormalities in cognition (OR=9.88, 95 % CI: 1.26–77.47) and expressive communication (OR=2.85, 95 % CI: 1.33–6.10) compared to low Cu/high SES. Similarly, the combination of high Cu level and low SES was associated with an increased risk of abnormalities in cognition (OR=14.35, 95 % CI: 1.81–113.52) and expressive communication (OR=3.87, 95 % CI: 1.84–8.17).</div></div><div><h3>Conclusions</h3><div>Our findings revealed that low SES and children’s high concentrations of Cu were associated with preschoolers’ cognitive development both independently and interactively.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103377"},"PeriodicalIF":3.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145885307","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}

{"title":"Linking particulate matter exposure and neurological disorders: Evidence from epidemiology, biomarkers and mechanistic studies","authors":"Saiyami Bhardwaj ,&nbsp;Abhishek Bharti ,&nbsp;Radhey Shyam Sharma ,&nbsp;Santosh Kumar Mishra ,&nbsp;Pankaj Kumar ,&nbsp;Abdul S. Ethayathulla ,&nbsp;Atinderpal Singh ,&nbsp;Vandana Mishra","doi":"10.1016/j.neuro.2025.103375","DOIUrl":"10.1016/j.neuro.2025.103375","url":null,"abstract":"<div><div>Exposure to particulate matter (PM) including fine (PM₂.₅), coarse (PM₁₀), and ultrafine particles (UFPM) has emerged as a critical environmental determinant of neurological disorders, including Alzheimer’s and Parkinson’s diseases, neurodevelopmental impairments, and cognitive decline. This review integrates evidence from 129 research articles (2002–2025) to elucidate the mechanistic, biomarker-based, and public health dimensions of PM-induced neurotoxicity. Mechanistic pathways include oxidative stress, neuroinflammation, mitochondrial dysfunction, and blood–brain barrier disruption, with documented structural and functional damage in brain regions such as the hippocampus and prefrontal cortex. PM₂.₅ serves as a carrier of neurotoxic metals (e.g., lead, cadmium, vanadium) and understudied organic toxicants (e.g., PAHs, pesticides), amplifying its pathogenic potential. Exposure occurs through the olfactory route, systemic circulation, and gut–brain axis, highlighting multiple entry points into the central nervous system. Biomarkers such as Aβ₄₂, phosphorylated tau (p-tau), and α-synuclein are elevated in experimental models, but require greater validation in human PM-exposed populations. Children and older adults represent the most vulnerable groups due to developmental sensitivity and cumulative neuroinflammatory burden, yet remain underrepresented in cohort studies. Geographic disparities further limit generalizability, with low- and middle-income countries underrepresented despite experiencing the highest PM burdens. Future research must advance longitudinal, cohort and life-course studies, multi-omics biomarker discovery, and real-world mixture toxicology to identify intervention targets. These findings call for urgent integration of air pollution control into public health strategies targeting neurological diseases, emphasizing prevention through regulation, early detection, and equity-focused research frameworks.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"113 ","pages":"Article 103375"},"PeriodicalIF":3.9,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892646","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}

{"title":"Soman-induced neurotoxicity in human iPSC-derived cerebral organoids: A whole-transcriptome analysis of ceRNA regulatory networks","authors":"Yue Wei ,&nbsp;Jingjing Shi ,&nbsp;Xuejun Chen ,&nbsp;Zhanbiao Liu ,&nbsp;Qian Jin ,&nbsp;Ruihua Zhang ,&nbsp;Tong Shi ,&nbsp;Chen Wang ,&nbsp;Liqin Li","doi":"10.1016/j.neuro.2025.103373","DOIUrl":"10.1016/j.neuro.2025.103373","url":null,"abstract":"<div><div>Traditional animal models present challenges in fully elucidating chemical-induced neurotoxicity and its underlying mechanisms in humans due to physiological and genetic differences between species. To transcend inherent species limitations, cerebral organoids were differentiated from human induced pluripotent stem cells as a human-relevant model to delineate the neurotoxic profile of soman, classified among the most potent organophosphorus nerve agents. Organoid cell diversity and architecture were assessed via immunofluorescence and single-cell RNA sequencing. A 24-hour soman exposure elicited significant nerve damage in cerebral organoids, characterized by TUNEL assay-confirmed apoptosis and Fluoro-Jade C-stained neuronal degeneration. Whole transcriptome sequencing revealed 1012 differentially expressed mRNAs, 78 differentially expressed miRNAs and 203 differentially expressed long non-coding RNAs between the soman-exposed and control groups. Bioinformatics research suggested that the differentially expressed mRNAs were linked to axon guidance, long-term potentiation, and calcium signaling pathways. Furthermore, we constructed a competive endogenous RNA network including lncRNAs, miRNAs, and mRNAs, identifying two hub lncRNAs, two hub miRNAs, and 16 key mRNAs. This regulatory network implicates soman neurotoxicity in neuroinflammation and synaptic plasticity alterations, while validating glutamate receptor dysregulation and calcium homeostasis disruption as critical pathological mediators. Concurrently, it identifies the associated lncRNAs and miRNAs as potential biomarkers and therapeutic targets for soman-induced neuronal injury. Our findings elucidate the neurotoxic effects of soman in cerebral organoids at tissue, cellular, gene expression, and regulatory network levels. This work advances our knowledge of the underlying biological processes of soman exposure by offering new insights into prospective biomarkers and treatment targets.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103373"},"PeriodicalIF":3.9,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145842154","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}

{"title":"Zebra_K+ : High-throughput analysis of acoustic startle response plasticity in zebrafish embryos and larvae in neurotoxicity testing","authors":"Niki Tagkalidou ,&nbsp;Ouwais Aljabasini ,&nbsp;Sergi Pujol ,&nbsp;Eva Prats ,&nbsp;Josep Maria Porta ,&nbsp;Carlos Barata ,&nbsp;Demetrio Raldúa","doi":"10.1016/j.neuro.2025.103372","DOIUrl":"10.1016/j.neuro.2025.103372","url":null,"abstract":"<div><div>The acoustic startle response (ASR) is a conserved sensorimotor reflex widely used to investigate neural plasticity, sensorimotor gating, and neurotoxicity. While zebrafish is an established vertebrate model for ASR analysis, most existing platforms were originally optimized for 6 dpf larvae, which constrains applications requiring reliable assessment of earlier developmental stages. Here, we introduce Zebra_K⁺, a modular extension of the previously developed Zebra_K platform, designed for high-throughput kinematic analysis of ASR in zebrafish embryos (5 days post-fertilization, dpf) and early larvae (6–7 dpf). The system enables simultaneous quantification of ASR kinematics, sensitivity, short-term habituation, and prepulse inhibition (PPI) in up to 25 individuals. Using the NMDA receptor antagonist ketamine, the dopamine receptor agonist apomorphine, and the D₂ receptor antagonist haloperidol, we validated the platform’s ability to detect pharmacologically induced and developmentally specific alterations in startle plasticity. Ketamine reduced habituation and PPI at all developmental stages, whereas apomorphine selectively impaired PPI, an effect that was reversed by haloperidol only at 7 dpf. These results demonstrate the neurodevelopmental progression of glutamatergic and dopaminergic modulation of sensorimotor gating and establish Zebra_K⁺ as a modular technological platform that supports the development of New Approach Methods (NAMs) for neurotoxicological screening and developmental neuropharmacology.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103372"},"PeriodicalIF":3.9,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145834368","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}

{"title":"Proposed key characteristics of neurotoxic chemicals","authors":"Pamela J. Lein ,&nbsp;Aaron B. Bowman ,&nbsp;Zhengyu Cao ,&nbsp;Monica Carson ,&nbsp;Brenda Eskenazi ,&nbsp;Ellen Fritsche ,&nbsp;G. Jean Harry ,&nbsp;Thomas Hartung ,&nbsp;Isaac N. Pessah ,&nbsp;William Slikker Jr. ,&nbsp;Lauren Zeise ,&nbsp;Martyn T. Smith","doi":"10.1016/j.neuro.2025.103370","DOIUrl":"10.1016/j.neuro.2025.103370","url":null,"abstract":"<div><div>A critical component of evaluating whether a chemical can cause human neurotoxicity is hazard identification, which typically involves a comprehensive literature search to identify and synthesize epidemiological, animal, and mechanistic data for the chemical of interest. The key characteristics (KCs) concept has proven to be a useful tool for searching, organizing, and evaluating mechanistic data for hazard identification. KCs are the established chemical and biological properties of known human neurotoxic agents based on understanding of their mechanisms of neurotoxicity. KCs were originally developed for carcinogens but have now also been published for endocrine- and metabolism-disruptors and various organ-selective toxic chemicals. To identify KCs associated with neurotoxic chemicals, an expert committee was convened to consider current mechanistic understanding of chemicals known to be neurotoxic in humans with the goal of identifying established molecular and cellular actions of neurotoxic chemicals. After extensive discussion, the committee reached consensus on 10 KCs. Here, we describe the 10 proposed KCs and provide chemical-related examples to support their inclusion. Several important considerations emerged from the committee’s deliberations including: (1) a mechanistic action need not be unique to neurotoxicity to be considered a KC of neurotoxic chemicals; (2) many, if not most, neurotoxic chemicals exhibit multiple KCs, and the relative importance of any specific KC and/or its causal relationship to other KCs may vary depending on life stage at the time of exposure and/or the exposure paradigm; and (3) data indicating a chemical exhibits one or more KCs of neurotoxic chemicals suggests that the chemical poses a neurotoxic hazard but does not necessarily identify the risk that the chemical presents to humans. These considerations, as well as potential applications of KCs in neurotoxicology, are discussed. The committee also strongly recommended that the list of proposed KCs of neurotoxic chemicals be viewed as a “living document” that is reviewed and revised in response to emerging insights on mechanisms of neurotoxicity, as well as lessons learned from the application of these proposed KCs, including but not limited to their use as a tool for the systemic identification and review of mechanistic data for assessment of neurotoxic hazards.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103370"},"PeriodicalIF":3.9,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827615","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}

{"title":"Understanding similarities and differences of FASD in three zebrafish populations","authors":"João Paulo Medeiros Mamede ,&nbsp;Maria Clara Galvão-Pereira ,&nbsp;Augusto Monteiro de Souza ,&nbsp;Silvia Regina Batistuzzo de Medeiros ,&nbsp;Ana Carolina Luchiari","doi":"10.1016/j.neuro.2025.103369","DOIUrl":"10.1016/j.neuro.2025.103369","url":null,"abstract":"<div><div>Alcohol consumption during pregnancy is a major public health concern, as prenatal exposure to ethanol can disrupt embryonic development and lead to Fetal Alcohol Spectrum Disorders (FASD). These disorders are characterized by a wide range of morphological, behavioral, and cognitive impairments, which variability across individuals is strongly influenced by genetic background and environmental conditions. Animal models, particularly zebrafish, offer a powerful tool to investigate how such factors modulate susceptibility to alcohol. In this study, we examined the effects of embryonic alcohol exposure in three zebrafish populations (AB, TU, and OB), assessing developmental parameters, behavior, and gene expression. Results showed that the OB population exhibited higher mortality and pronounced alterations in genes related to metabolism and neurotransmission; AB displayed reduced body and eye growth, along with increased social cohesion under alcohol exposure; while TU was more vulnerable to behavioral effects despite showing morphological resilience. Furthermore, the expression of key genes such as <em>sox2, th1, drd1b, gabra1</em><strong>,</strong> and <em>bdnf</em> varied according to both population and alcohol concentration. These findings emphasize the relevance of genetic differences in modulating alcohol’s impact and reinforce zebrafish as a valuable translational model for FASD research, paving the way for more refined diagnostic and therapeutic approaches.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103369"},"PeriodicalIF":3.9,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145799360","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}

{"title":"FTH1-mediated iron dysregulation and ferroptosis in manganese-induced neurotoxicity","authors":"Xiaoli Ma ,&nbsp;Shengtao Wei ,&nbsp;Fangfei Li ,&nbsp;Guiqiang Liang ,&nbsp;Jian Wang ,&nbsp;Yunfeng Zou","doi":"10.1016/j.neuro.2025.103367","DOIUrl":"10.1016/j.neuro.2025.103367","url":null,"abstract":"<div><div>Excessive environmental manganese (Mn) exposure has been implicated in neurological disorders, with iron homeostasis imbalance emerging as a crucial aspect in neurodegeneration diagnosis and therapy. However, the intricate mechanisms underlying Mn-induced neurotoxicity, particularly the interplay between ferroptosis and iron dysregulation, remain elusive. This study investigated the role of ferritin heavy chain 1 (FTH1)-mediated iron homeostasis disruption in manganese (Mn)-induced neurotoxicity and ferroptosis. Mn exposure was found to disrupt iron homeostasis and induce ferroptosis in neuronal cells by downregulating FTH1 expression. Elevated intracellular and mitochondrial Fe²⁺ and reactive oxygen species (ROS) levels, along with increased lipid peroxidation, were observed in Mn-treated Neuro-2a (N2a) cells. Notably, both deferoxamine (DFO) treatment and FTH1 overexpression alleviated iron imbalance and reduced ferroptotic markers. Our findings suggest that Mn triggers neuronal ferroptosis via FTH1-mediated oxidative stress and iron dysregulation, highlighting the potential of iron ion inhibitors or FTH1 modulation as therapeutic strategies. This study contributes to the understanding of Mn-induced neurotoxicity and provides insights into the mechanisms underlying ferroptosis in neuronal cells.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103367"},"PeriodicalIF":3.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781622","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}

{"title":"Formononetin protects against oxaliplatin-induced peripheral neurotoxicity via Nrf2/HO-1 antioxidant pathway without impairing anticancer efficacy","authors":"Yang-Chen Chang ,&nbsp;Wan-Hsuan Lin ,&nbsp;Horng-Huey Ko ,&nbsp;Yi-Ching Lo ,&nbsp;Hsun-Shuo Chang ,&nbsp;Hui-Ching Lin ,&nbsp;Yih-Fung Chen","doi":"10.1016/j.neuro.2025.103368","DOIUrl":"10.1016/j.neuro.2025.103368","url":null,"abstract":"<div><div>Chemotherapy-induced peripheral neuropathy (CIPN) is a common and intolerable adverse effect of oxaliplatin and paclitaxel. The intolerance to CIPN symptoms often leads to poor compliance and treatment discontinuation, jeopardizing survival outcomes. However, no Food and Drug Administration (FDA)-approved interventions exist for preventing or treating CIPN. A major challenge has been that neuroprotective candidates often diminish the effectiveness of chemotherapy, limiting their translational development. Here, we aimed to identify neuroprotective agents that maintain anticancer activity. Using ND7/23 dorsal root ganglion neurons treated with oxaliplatin and paclitaxel, we screened our compound library and identified formononetin, a natural isoflavone, as a promising candidate. Formononetin significantly protected ND7/23 DRG neurons against oxaliplatin-induced neurotoxicity by reducing oxidative stress and apoptosis via activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) antioxidant pathway and modulating protein expressions of pro-apoptotic B-cell lymphoma 2-associated X (Bax) and anti-apoptotic B-cell lymphoma 2 (BCL-2). Formononetin showed limited protection against paclitaxel-induced structural neurite damage. Importantly, unlike the ROS scavenger <em>N</em>-acetylcysteine (NAC), which decreased the anticancer effectiveness of both oxaliplatin and paclitaxel, formononetin maintained their anticancer effects in colorectal cancer HT29 cells and cervical cancer SiHa cells. Taken together, formononetin holds potential as a neuroprotectant to prevent oxaliplatin-induced neurotoxicity without compromising anticancer efficacy.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103368"},"PeriodicalIF":3.9,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145781620","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}

{"title":"Chemotherapy-induced cognitive impairment (CICI): Cisplatin’s effects on neurotransmitter regulation and oxidative stress in Drosophila melanogaster","authors":"Raifa Abdul Aziz ,&nbsp;Deepa Mugudthi Venugopal ,&nbsp;Avinash Kundadka Kudva ,&nbsp;Ramesha Hanumanthappa ,&nbsp;Mohammed S. Mustak ,&nbsp;KuramkoteShivanna Devaraju ,&nbsp;Manjeshwar Shrinath Baliga ,&nbsp;Shamprasad Varija Raghu","doi":"10.1016/j.neuro.2025.103365","DOIUrl":"10.1016/j.neuro.2025.103365","url":null,"abstract":"<div><div>Chemotherapy-induced cognitive impairment (CICI), commonly known as \"chemo brain,\" is a significant and persistent complication of cancer therapy, characterized by memory deficits and broader cognitive dysfunction. Despite its prevalence among cancer survivors, the underlying neurotoxic mechanisms remain incompletely understood. In this study, we utilized <em>Drosophila melanogaster</em> as a model organism to systematically investigate the neurobiological effects of cisplatin, a widely used platinum-based chemotherapeutic agent. Cisplatin exposure led to a marked reduction in lifespan and impaired locomotor function, indicating pronounced neurotoxicity. Biochemical analyses demonstrated dose-dependent disruptions in oxidative stress parameters - such as superoxide dismutase, catalase, glutathione, and total antioxidant capacity- alongside elevated reactive oxygen species and pro-apoptotic gene expression within neural tissues. Furthermore, cisplatin altered the synthesis and regulation of key neurotransmitters, including acetylcholine, GABA, dopamine, and serotonin. Collectively, these findings establish <em>Drosophila</em> as a robust, translationally relevant model for elucidating the molecular pathways of CICI and for high-throughput screening of neuroprotective interventions.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103365"},"PeriodicalIF":3.9,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145753743","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}

{"title":"The “route cause” of methotrexate-induced brain structure changes in a juvenile mouse model: Comparison of systemic and CNS-targeted chemotherapy","authors":"Sun Eui Choi ,&nbsp;Tiffany Ayoub ,&nbsp;Gail Lee ,&nbsp;Anne L. Wheeler ,&nbsp;Sharon L. Guger ,&nbsp;Rosanna Weksberg ,&nbsp;Shinya Ito ,&nbsp;Russell J. Schachar ,&nbsp;Johann Hitzler ,&nbsp;Brian J. Nieman","doi":"10.1016/j.neuro.2025.103363","DOIUrl":"10.1016/j.neuro.2025.103363","url":null,"abstract":"<div><div>Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and while five-year survival rates exceed 90 %, survivors display neurocognitive deficits. Magnetic resonance imaging (MRI) measurements indicate smaller volume across the brain in survivors compared to typically developing peers. Methotrexate (MTX) is the backbone of ALL chemotherapy and is delivered via various administration routes including systemic and central nervous system (CNS) targeted routes. The relative toxicities between routes have not been systematically compared. Our study aims to compare brain volume changes after systemic and CNS-targeted MTX treatment using MRI in a juvenile mouse model. MTX treatment was delivered at postnatal day 17 (P17) and P19 either via an intrathecal (IT) or intravenous (IV) injection, resulting in four total groups for the study: IV MTX (n = 14), IV saline (n = 16), IT MTX (n = 54), and IT saline (n = 51). MRI was performed pre-treatment at P14 and longitudinally after treatment at P24, P42, and P63. IT MTX was probed at a range of doses (0.5–5.0 mg/kg). Volumes of 183 segmented brain structures were compared between groups. Whole brain volume decreased after IT MTX (5.0 mg/kg) and IV MTX at P24. The number of structures significantly affected after IT MTX was highly dependent on dose. Comparison of systemic and intrathecal delivery routes revealed that systemic MTX had a wider impact on brain morphology than did IT MTX treatment, particularly at clinically relevant doses of IT MTX. This finding provides important insight into the mechanisms that likely underlie MTX-induced neurotoxicity and focuses potential interventions on systemic toxicity.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"112 ","pages":"Article 103363"},"PeriodicalIF":3.9,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145743596","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}