Neurotoxicology最新文献

{"title":"Paternal exposure to chlorpyrifos disrupts protein regulation and abolishes PKCβ signaling in learning‑related neural circuits","authors":"Issam Rimawi,&nbsp;Gadi Turgeman,&nbsp;Joseph Yanai","doi":"10.1016/j.neuro.2026.103506","DOIUrl":"10.1016/j.neuro.2026.103506","url":null,"abstract":"<div><div>Environmental exposures prior to conception are increasingly recognized as modulators of offspring neurodevelopment; however, their functional impact on specific neural circuits remains poorly understood. In the present study, we investigated whether paternal preconception exposure to the neuroteratogen chlorpyrifos induces protein-level and functional alterations in learning-related brain regions of the offspring. Using a chicken (<em>Gallus gallus domesticus</em>) model, we examined the intermediate medial mesopallium (IMM), hippocampal subregions, and lateral striatum, focusing on protein expression of markers associated with neuroplasticity and cholinergic-mediated activation/translocation of protein kinase C beta (PKCβ), a key regulator of synaptic plasticity. Structural endpoints, including neuronal cell counts and dendritic morphology, were also assessed. A pre-hatch exposure paradigm was included for comparison. Paternal exposure resulted in region- and sex-specific alterations in protein expression, including changes in GDNF, DCX, FOS, and MAP2, predominantly in the lateral striatum and IMM, without corresponding transcriptional changes. Notably, no significant alterations were observed in neuronal cell counts or dendritic structure. In contrast, a robust functional deficit was identified, as paternal exposure completely abolished cholinergic-mediated PKCβ activation/translocation, an effect also observed following pre-hatch exposure. These findings demonstrate that paternal preconception exposure is associated with selective alterations in protein expression and impaired cholinergic-mediated PKCβ signaling within learning-related neural circuits, in the absence of overt structural damage. The dissociation between transcriptional and translational outcomes indicates that regulatory processes acting beyond transcription may contribute to the observed phenotype. Further studies are required to determine the underlying mechanisms and functional consequences of these changes.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103506"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148376357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human blood-derived neural progenitor cells as a platform for developmental neurotoxicity of micro- and nanoplastics","authors":"Kinga Vojnits,&nbsp;Jad Kaj,&nbsp;Kelly Rees,&nbsp;W. Russ Algar,&nbsp;Mick Bhatia,&nbsp;Sepideh Pakpour","doi":"10.1016/j.neuro.2026.103493","DOIUrl":"10.1016/j.neuro.2026.103493","url":null,"abstract":"<div><div>Micro- and nanoplastics (MNPs) are increasingly detected in human tissues, including the placenta and brain, raising concerns about their potential impact on early neurodevelopment. However, mechanistic insight is limited by the lack of human-relevant, scalable test systems for developmental neurotoxicity (DNT). Here, we establish and apply a peripheral blood-derived human neural progenitor cell (NPC) platform as a reproducible in vitro model to evaluate MNP-induced DNT under low-dose conditions reflecting currently available estimates of human exposure. Using this system, we systematically investigated the effects of 2 µm, 100 nm, and 20 nm polystyrene particles and polyester microfibers over a 21-day neuronal differentiation paradigm. The model enables simultaneous assessment of key DNT endpoints, including neuronal differentiation, neurite outgrowth, cell cycle progression, and oxidative stress. MNP exposure impaired neuronal maturation in a size- and shape-dependent manner, reducing neurite outgrowth and βIII-tubulin (TUJ1) expression. Nanoscale particles were efficiently internalized and localized to endo-lysosomal compartments, whereas micron-sized particles remained primarily surface-associated. Mechanistically, MNP exposure induced mitochondrial oxidative stress, decreased superoxide dismutase 2 expression, and disrupted cell cycle exit, resulting in sustained progenitor proliferation. Importantly, pharmacological scavenging of reactive oxygen species with N-acetyl-<span>L</span>-cysteine rescued differentiation deficits and normalized cell cycle dynamics, demonstrating a causal role for redox imbalance. Together, these findings validate peripheral blood–derived human NPCs as a sensitive and scalable platform for DNT assessment and provide mechanistic evidence that MNPs impair early human neurodevelopment through size-dependent uptake and oxidative stress pathways.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103493"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148272227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urinary volatile organic compound metabolites and depressive symptoms among U.S. adults with cardiovascular-kidney-metabolic syndrome stages 0–3: NHANES-based associations and in silico multi-omics insights","authors":"Yulin Tian,&nbsp;Yiyun Wang,&nbsp;Hongsi Cui,&nbsp;Hongjie Wang,&nbsp;Yanping Yang,&nbsp;Yu Chang","doi":"10.1016/j.neuro.2026.103508","DOIUrl":"10.1016/j.neuro.2026.103508","url":null,"abstract":"<div><h3>Background</h3><div>Depression is a major global public health burden, and environmental pollutants are increasingly associated with depressive symptoms. Volatile organic compounds (VOCs) are ubiquitous environmental contaminants with known neurotoxic potential; however, their associations with depressive symptoms, particularly in metabolically vulnerable populations such as those with cardiovascular-kidney-metabolic (CKM) syndrome, remain insufficiently characterized.</div></div><div><h3>Methods</h3><div>We conducted a population-based study of adults with CKM stages 0–3 using data from NHANES 2011–2018, assessing associations between urinary levels of 16 VOC metabolites and PHQ-9-defined depressive symptoms using multivariable logistic regression, dose-response modeling, and mixture analyses. Machine learning identified key exposures, network toxicology revealed shared molecular targets and pathways, single-cell RNA sequencing characterized cell-type-specific expression and functional states, and molecular docking assessed interactions between prioritized mVOCs and protein targets.</div></div><div><h3>Results</h3><div>Higher urinary levels of CYMA, MHBMA3, and HMPMA were significantly associated with increased odds of depressive symptoms after full adjustment, with approximately linear or nonlinear dose-response relationships. Mixture analysis indicated that these metabolites were the main contributors to the joint VOC exposure effect. Network toxicology identified enrichment of depression-related targets in neuronal signaling, synaptic transmission, and immune regulation pathways. Exploratory analysis of public scRNA-seq datasets suggested higher PIK3R1 expression in PBMC CD8 + T cells from depression-related samples and indicated altered immune-related transcriptional programs. Molecular docking suggested plausible binding interactions between the prioritized VOCs and PIK3R1.</div></div><div><h3>Conclusions</h3><div>Higher urinary VOC metabolite levels were associated with higher odds of PHQ-9-defined depressive symptoms among adults with CKM stages 0–3. In silico multi-omics analyses suggested potential involvement of PI3K/AKT-related neuroimmune pathways.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103508"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of nicotine toxicity and addiction-like behavior in Drosophila melanogaster: The role of α7 & β2 nicotinic acetylcholine receptor subunits in sensory valence and cellular stress","authors":"Titilayomi Ayomide Otenaike,&nbsp;Oluwabukola Mary Farodoye,&nbsp;Joao Batista Teixeira Rocha,&nbsp;Amos Olalekan Abolaji,&nbsp;Elgion Lucio Silva Loreto","doi":"10.1016/j.neuro.2026.103499","DOIUrl":"10.1016/j.neuro.2026.103499","url":null,"abstract":"<div><div>Nicotine addiction and toxicity are complex neurobiological conditions that exerts both toxicological and rewarding effects through nicotinic acetylcholine receptors (nAChRs), which are conventionally treated as separable phenomena, yet the relationship and shared overlapping neurobiological effects remains incompletely understood. This study combined biochemical profiling, transcriptomics, genetics, and olfactory conditioning to examine the mechanisms underlying nicotine’s systemic toxicity, cellular stress responses, and addiction-like behavior in <em>Drosophila melanogaster</em>, with a focus on α7 and β2 nAChR subunits. Chronic dietary nicotine exposure (0.15, 0.25, and 0.35 mg/mL for 5 days) reduced survival and locomotor performance, increased reactive oxygen species levels, depleted total thiols, and suppressed acetylcholinesterase (AChE) and monoamine oxidase (MAO) enzymatic activities in control flies; these effects were attenuated innAChRα7^-/- and nAChRβ2^-/- In addition, transcriptomic re-analysis of a publicly available microarray dataset revealed a coordinated cellular stress response in nicotine-exposed flies, including the altered expression of detoxification genes, odorant-binding protein Obp56h and mechanosensory genes. Behaviorally, nicotine exposure during conditioning altered the innate odor valence and resulted in a persistent punishment-resistant odor preference, defined here as addiction-like behavior; this nicotine-induced reassignment was not observed in mutant flies. Collectively, these data suggest that α7- and β2-nAChR subunits function are mediators of nicotine's toxicological and behavioral effects, and support the use of <em>Drosophila</em> as a model the investigation of nicotinic effects, while recognizing that direct equivalence with mammalian addiction circuitry should not be assumed.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103499"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Air pollution is linked to divergent cortical thickness patterns in brain regions vulnerable to Alzheimer’s disease","authors":"Lauren E. Salminen,&nbsp;Xinhui Wang,&nbsp;Andrew J. Petkus,&nbsp;Christine Fennema-Notestine,&nbsp;Jeremy A. Elman,&nbsp;Donald J. Hagler Jr,&nbsp;Joel D. Kaufman,&nbsp;Joshua Millstein,&nbsp;Meredith N. Braskie,&nbsp;Joshua Liu,&nbsp;Hyung Jin Cho,&nbsp;Deydeep Kothapalli,&nbsp;Paul M. Thompson,&nbsp;Daniel P. Beavers,&nbsp;Mark A. Espeland,&nbsp;Margaret Gatz,&nbsp;Susan M. Resnick,&nbsp;Ira Frahmand,&nbsp;Stephen R. Rapp,&nbsp;Caleb E. Finch,&nbsp;Carol E. Franz","doi":"10.1016/j.neuro.2026.103495","DOIUrl":"10.1016/j.neuro.2026.103495","url":null,"abstract":"<div><h3>Introduction</h3><div>Ambient air pollution increases Alzheimer’s disease (AD) risk, yet exposure associations with cortical thickness (CTh) in AD-vulnerable brain regions is unclear. Here we examined the associations between PM_2.5 and NO₂ with CTh in an AD meta-region of interest (ROI), and across the cortex, in participants from the Vietnam Era Twin Study of Aging (VETSA) and Women’s Health Initiative Memory Study (WHIMS).</div></div><div><h3>Methods</h3><div>We conducted a cross-sectional study using data from 387 VETSA men (M_age=61.9 ± 2.6) and 1097 WHIMS women (M_age=77.9 ± 3.7) without dementia or stroke prior to MRI. Long-term residential exposures to PM_2.5 and NO₂ were quantified as the 3-year average of monthly estimates prior to MRI that were derived from spatiotemporal models with regionalized universal kriging. Brain MRI scans were processed using FreeSurfer-v.5.3.0 to estimate CTh in 34 bilateral regions parcellated with the Desikan-Killiany atlas. An AD meta-ROI was calculated as the surface-area weighted average of CTh in four bilateral regions (entorhinal, fusiform, inferior temporal, and middle temporal cortices) that are vulnerable to AD. Linear mixed models were conducted separately in each cohort with appropriate covariates.</div></div><div><h3>Results</h3><div>In WHIMS, exposures were negatively associated with CTh in the AD meta-ROI (<em>p</em>_PM2.5&lt;0.001; <em>p</em>_NO2=0.018) and diffusely across the cortex. In VETSA, exposures were <em>positively</em> associated with CTh in the AD meta-ROI (<em>p</em>_PM2.5=0.017; <em>p</em>_NO2=0.021) and temporal pole, but effects were age-dependent, becoming negative (though nonsignificant) after age 64.</div></div><div><h3>Discussion</h3><div>Positive associations in younger VETSA men, coupled with negative associations in older WHIMS women, may suggest nonmonotonic AD-related neurodegeneration.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103495"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148278193","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":"Reduced hepcidin expression leads to iron accumulation in the substantia nigra of rotenone-induced rat model of Parkinson's disease","authors":"Feimi Li,&nbsp;Christopher Qian,&nbsp;Qian Guo,&nbsp;Zhong-Ming Qian","doi":"10.1016/j.neuro.2026.103492","DOIUrl":"10.1016/j.neuro.2026.103492","url":null,"abstract":"<div><div>Despite years of research, it is still unclear why iron accumulates in the substantia nigra (SN) of Parkinson's disease (PD) animal models and PD patients. To address this, we investigated the changes in serum iron, iron content, transferrin receptor (TfR1), ferroportin 1 (Fpn1), hepcidin, and iron regulatory proteins (IRPs) expression in the SN, and hepcidin in serum and cerebrospinal fluid (CSF) in rotenone-induced PD rat model, as well as iron content and hepcidin in rotenone-induced PD cell models. We demonstrate that rotenone induces PD-like dyskinesia, dopaminergic neuron loss, as well as increases iron and decreases hepcidin in the SN on days 10 and 30 after injection, and also increases iron in rotenone-induced PD cell models. At 30 days after rotenone injection, TfR1 expression increased and Fpn1 decreased, while 10 days after injection, TfR1 expression decreased and Fpn1 increased in the SN. Decreased hepcidin was also found in serum and CSF of rotenone treated rats, and in rotenone-treated SH-SY5Y cells and primary mesencephalic neurons. We conclude that PD-like movement disorders in rats are closely related to the loss of dopaminergic neurons, which may be associated with increased iron in the SN of rats in vivo, suggesting that hepcidin reduction may be one of the causes of iron accumulation in the SN, affecting the expression of cellular iron transport proteins at the late stage (30 days) after rotenone injection.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103492"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258987","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":"PM2.5-bound organophosphate esters and childhood attention-deficit hyperactivity disorder symptoms: A population-based study from China","authors":"Chu Chu,&nbsp;Xuan Liu,&nbsp;Yan-Xu Chen,&nbsp;Jia-Xiang Dong,&nbsp;Yun-Ting Zhang,&nbsp;Wan-Ting He,&nbsp;Jing-Wen Huang,&nbsp;Li-Xia Liang,&nbsp;Yang Zhou,&nbsp;Muhammad Amjad,&nbsp;Yan Yang","doi":"10.1016/j.neuro.2026.103509","DOIUrl":"10.1016/j.neuro.2026.103509","url":null,"abstract":"<div><div>The association between childhood exposure to PM_2.5-bound organophosphate esters (OPEs) and attention deficit hyperactivity disorder (ADHD) remains poorly understood. In this large population-based study of 131,412 children aged 6–18 years attending schools in the Pearl River Delta, China, we collected ambient fine particulate matter (PM_2.5) samples from schools to quantify OPEs levels, and screened for ADHD symptoms using parent-reported ADHD/Diagnostic and Statistical Manual of Mental Disorders (DSM-Ⅳ) Scales. We employed elastic net regression for variable selection, generalized linear mixed models (GLMMs) for association estimates, and weighted quantile sum regression to evaluate mixture effects. Odds ratios (ORs) are expressed as the change in odds of ADHD symptoms per interquartile range (IQR) increase in OPE levels. Elevated PM_2.5-bound OPE exposure was associated with higher odds of ADHD symptoms in children, especially for triphenyl phosphate (TPHP) (OR = 1.75, 95% CI: 1.70–1.79), tris(2-ethylhexyl) phosphate (TEHP) (OR = 1.73, 95% CI: 1.69–1.77), tris(1,3-dichloroisopropyl) phosphate (TDCIPP) (OR = 1.71, 95% CI: 1.67–1.75), and tris(3,4-dimethylphenyl) phosphate (T34DMPP) (OR = 1.45, 95% CI: 1.41–1.49). Similar associations were observed across different ADHD subtypes. Stratified analyses indicated heterogeneous associations across age, sex, and breastfeeding subgroups, with no consistent pattern of effect modification across all OPE exposures. These findings suggest that inhalation of OPE mixtures may be associated with adverse neurodevelopmental outcomes in children, highlighting a potential developmental window of susceptibility and raising public health concerns about airborne contaminants.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103509"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148382430","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 role of mTORC2 in the in vitro neurotoxicity of Parkinsonian mimetics 6-OHDA and MPP+","authors":"Marija Jeremic,&nbsp;Maja Jovanovic-Tucovic,&nbsp;Tamara Martinovic,&nbsp;Tamara Kravic-Stevovic,&nbsp;Danijela Stevanovic,&nbsp;Sanja Blagojevic,&nbsp;Ivanka Markovic,&nbsp;Vladimir Trajkovic","doi":"10.1016/j.neuro.2026.103497","DOIUrl":"10.1016/j.neuro.2026.103497","url":null,"abstract":"<div><div>The mechanistic target of rapamycin complex 2 (mTORC2), a key regulator of cellular metabolism, growth, and survival, remains poorly characterized in the context of dopaminergic neurotoxicity. In this study, we investigated the role of mTORC2 signaling in the survival of SH-SY5Y neuroblastoma cells exposed to the Parkinsonian neurotoxins 1-methyl-4-phenylpyridinium (MPP⁺) and 6-hydroxydopamine (6-OHDA), and examined its interplay with oxidative stress and major stress-responsive signaling pathways. Both neurotoxins induced oxidative stress and mitochondrial damage, accompanied by PINK1 accumulation and culminating in caspase-3 activation, PARP1 cleavage, and apoptotic cell death. These effects were associated with reactive oxygen species (ROS)-dependent phosphorylation of the mTORC2 components Rictor and SIN1, as well as the downstream mTORC2 target Akt (Ser473), indicating activation of mTORC2 signaling in response to neurotoxic insult. RNA interference-mediated depletion of the mTORC2 subunits Rictor, SIN1, or mLST8 reduced Akt phosphorylation and potentiated 6-OHDA-induced cytotoxicity by exacerbating oxidative stress, mitochondrial damage, PINK1 accumulation, and the apoptotic cleavage of caspase-3 and PARP1. In contrast, only Rictor depletion, but not SIN1 or mLST8 knockdown, increased the susceptibility of SH-SY5Y cells to MPP⁺-induced toxicity. Genetic inactivation of mTORC2 reduced basal phosphorylation of the cellular energy sensor AMP-activated protein kinase (AMPK), but did not alter neurotoxin-induced phosphorylation of AMPK or the mitogen-activated protein kinases ERK and JNK. Together, these findings demonstrate a protective role of mTORC2 components against 6-OHDA-induced, and to a lesser extent, MPP⁺-induced, mitochondrial damage and apoptotic cell death.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103497"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283754","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":"A multiparametric 3D cortical neurosphere NAM for developmental neurotoxicity: Chlorpyrifos and a biomonitoring-anchored PFAS mixture","authors":"Narimane Kebieche,&nbsp;Claude Lambert,&nbsp;Seugnae Yim,&nbsp;Rachid Soulimani","doi":"10.1016/j.neuro.2026.103501","DOIUrl":"10.1016/j.neuro.2026.103501","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Developmental neurotoxicity (DNT) arises from disruption of key neurodevelopmental processes—including neural stem cell proliferation, neuronal and glial differentiation, radial migration, and synaptogenesis—that collectively shape corticogenesis. Traditional in vivo guideline studies are costly, low-throughput, and provide limited mechanistic insight, prompting OECD and EFSA to promote new approach methodologies (NAMs) such as the neurosphere assay (NSA).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We refined and characterized a mouse cortical NSA over a three-week differentiation period using a multiparametric endpoint battery encompassing proliferation, neuronal and astrocytic differentiation, radial migration, synaptogenesis, and astrocytic maturation. Baseline differentiation was defined by flow cytometry, confocal immunofluorescence, and qPCR. Two chronic exposure scenarios were implemented: (i) during the 7-day proliferation phase, and (ii) from the onset of differentiation and migration throughout the three-week maturation period. Chlorpyrifos (CPF) was used as a DNT-positive reference compound, and a biomonitoring-informed PFAS mixture of PFOS, PFOA and PFUnDA was designed using French Esteban data to reflect low-nM, environmentally relevant exposure levels; due to availability constraints, PFHxS was not included and 4:2 fluorotelomer sulfonic acid (4:2 FTSA) was used as the short-chain sulfonate component.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Baseline analyses showed progressive acquisition of neuronal (TUBB3, MAP2, SATB2) and astrocytic (GFAP) phenotypes, emergence of SYP⁺/PSD95⁺ synaptic structures, and dependence on mitogenic signaling, consistent with key features of mid-gestational corticogenesis. CPF exerted biphasic effects, with early neurosphere enlargement followed by growth arrest and impaired radial migration; at 250 µM, CPF induced overt cytotoxicity and was associated with reduced GFAP expression. In contrast, PFAS mixture produced only modest effects on bulk viability yet consistently reduced radial migration and significantly downregulated &lt;em&gt;Gfap&lt;/em&gt; and &lt;em&gt;Syp&lt;/em&gt; at low-nM concentrations, in line with epidemiological and experimental evidence implicating PFAS in neurodevelopmental disorders. Within this proof-of-concept dataset, radial migration emerged as a more sensitive endpoint than bulk viability, revealing functional impairments below overt toxicity thresholds.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;div&gt;The cortical NSA captures key cellular and functional features of mid-gestational corticogenesis and discriminates compound-specific DNT liabilities, with CPF linked to reduced &lt;em&gt;Gfap&lt;/em&gt; expression under overtly toxic conditions and PFAS mixture disrupting astrocytic and synaptic programs at biomonitoring-relevant levels. By integrating complementary endpoints under chronic, developmentally targeted exposures, this work advances the NSA as a mechanistic, regulatory-relevant NAM and a s","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103501"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PM2.5 exposure exacerbates cerebral infarction via HPG axis downregulation and pituitary lipid metabolism dysregulation in mice","authors":"Xin lv,&nbsp;Guanhui Pei,&nbsp;Lijuan Liu,&nbsp;Zhou zhou,&nbsp;Yicong Zhou,&nbsp;Binbin Wang,&nbsp;Chaoyue Meng,&nbsp;Ruomeng Chen,&nbsp;Qiang Yao,&nbsp;Ge Bai,&nbsp;Xuelin Wang,&nbsp;Minghan Zhao,&nbsp;Rong Zhang,&nbsp;Henan Pan,&nbsp;Dongjing Yao,&nbsp;Yan Yan,&nbsp;Xiaoyun Liu","doi":"10.1016/j.neuro.2026.103502","DOIUrl":"10.1016/j.neuro.2026.103502","url":null,"abstract":"<div><div>Epidemiological studies have consistently associated ambient fine particulate matter (PM_2.5) with poor post-stroke prognosis. Growing evidence identifies endocrine dysregulation as a critical driver of stroke severity. Nevertheless, the influence of chronic PM_2.5 exposure on the pituitary gland, the core endocrine organ, remains unclear. Male C57BL/6 mice were randomized into 6 groups: filtered air (FA), concentrated PM_2.5 air (CA), FA + sham, CA + sham, FA + distal middle cerebral artery occlusion (dMCAO), and CA + dMCAO. All mice received whole-body inhalation of FA or CA for 12 weeks. After 12 weeks, mice in FA and CA groups were euthanized to collect serum and pituitary. For the other groups, ischemic stroke was induced by dMCAO. Infarct volume was measured at 24 h post-dMCAO, and neurological recovery was assessed at 1, 3, and 7 days post-dMCAO. Chronic PM_2.5 enlarged infarct volume, worsened sensory deficits and delayed motor recovery. It raised fasting glucose, LDL and lowered HDL. Serum LH and testosterone levels were significantly reduced following PM_2.5 exposure, and a positive correlation was observed between LH and testosterone. Multi-omics analysis of the pituitary gland revealed disturbances in lipid metabolism and significant downregulation of Jun expression. Our findings indicate that PM_2.5 exacerbates cerebral infarction, potentially through pituitary lipid metabolic dysfunction and impairment of hypothalamic–pituitary–gonadal (HPG) axis function. The observed downregulation of Jun suggests that Jun may be involved in these pathological processes.</div></div>","PeriodicalId":19189,"journal":{"name":"Neurotoxicology","volume":"115 ","pages":"Article 103502"},"PeriodicalIF":3.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}