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Spontaneous neocortical and cerebellar heterotopia are present in rat and mouse strains commonly used in neurotoxicology research. These malformations reflect neuronal migration defects during neocortical and cerebellar development that are inherent in these strains, yet the influence of these heterotopia are not considered in the design and interpretation of neurotoxicology research. In this review, we describe anatomical, behavioral, and physiological studies relevant to spontaneous neocortical and cerebellar heterotopia in rats and mice. This work will inform researchers in possible design and assessment approaches to account for these malformations which will likely be present in both control and exposure-treated groups.
As the implementation of 'sex as a biological variable' policies have been enacted across the world, the study of sex differences or comparisons across the sexes has steadily increased. In the field of neurotoxicology, the study of sex-dependent variability is necessary due to the plastic nature of the brain and the response to factors that influence this variability such as gonadal hormones and sex chromosomal complement. The phrase 'sex differences' is not inherently wrong, but it is an underdefined generalization that creates a distinct binary. While this binary is reductive at best, it creates the expectation of direct comparison and therefore a standard of the two groups when sex is a spectrum containing a mosaic of factors. The generalization of sex to one, often undefined, factor reduces the rigor of the research and overlooks potential variability both within and between sexes. This review provides a guide to help break down sex differences into a conglomeration of variables that can then be assessed for differences. By examining the mechanisms underlying sex difference, research can also be applied to groups and individuals who do not fit into the prescribed binary. People with chromosomal differences, cisgender atypical endocrine profiles, and transgender, nonbinary, and gender diverse (TNG) individuals should have research that can be tailored to their unique experiences and provide additional insight as to how a particular drug or toxicant can impact them in a way that may not be a predicted response based on the binary of male and female.
Selective serotonin reuptake inhibitors (SSRIs) are among the most frequently prescribed long-term neuropsychiatric medications, making any potential impact on genomic stability a clinically relevant safety question. Interpreting an SSRI “genotoxicity signal,” however, is challenging because evidence spans heterogeneous endpoints (DNA strand breaks, oxidative base lesions, micronuclei/chromosomal damage, and DNA-damage response markers) and experimental systems with widely different exposure conditions. In this translational review, we synthesize in vitro, in vivo, and human biomarker evidence to clarify what reported DNA-damage findings do—and do not—imply for chronic SSRI therapy. Across cell-based models, several SSRIs can induce oxidative stress–linked DNA-damage endpoints and DNA-damage response activation, but these effects commonly emerge at micromolar concentrations that are supratherapeutic and/or near cytotoxicity thresholds, and their magnitude can vary with metabolic competence and exposure design. Animal studies show mixed outcomes, including endpoint discordance between comet and micronucleus assays and occasional evidence of clastogenic or aneugenic effects under specific dosing regimens, limiting generalization from any single positive finding. Human biomarker studies are the most direct evidence for clinical relevance but remain limited and sensitive to confounding by indication. Available data are more consistent with an absence of a robust, clinically meaningful peripheral-blood genotoxic signal during SSRI therapy, while acknowledging scarce longitudinal follow-up, heterogeneous endpoints, and incomplete control for disease state, lifestyle, and co-medications. We propose an “interpretation ladder” to reconcile discrepancies across evidence streams and outline priorities for future research, including therapeutically relevant exposure modeling (with attention to unbound exposure), standardized reporting and quality practices, and well-controlled multi-endpoint longitudinal cohorts with transparent data sharing.
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Epidemiological data link traffic-related air pollution (TRAP) to increased risk of Alzheimer's disease (AD) and AD-related dementia (ADRD), and while experimental animal studies corroborate this association, most utilized exposure paradigms that failed to recapitulate the complexity of current, real-world TRAP exposure. Furthermore, the specific components of TRAP that promote AD pathogenesis remain unknown. This study assesses AD-relevant pathology in a transgenic rat model of AD (TgF344-AD) following chronic exposure to the gas phase vs. particulate matter (PM) components of TRAP in emissions from light-duty only (LDV) vs. combined light- and heavy-duty (LDV+HDV) vehicles. Male and female TgF344-AD rats were transported to the Caldecott Tunnel Exposure Facility (CTEF) at 1 month of age after being randomly assigned to one of six exposure groups: (1) filtered air (FA), (2) LDV+HDV gases only; (3) LDV PM only; (4) LDV+HDV PM only; (5) LDV PM and gases; and (6) LDV+HDV PM and gases. AD-relevant endpoints were quantified in 4-, 9-, 12-, and 15- month-old animals. Cortical Aβ levels at the 4, 9, and 15-month timepoints were significantly influenced by sex-by-exposure interactions. Amyloid plaque accumulation in the entorhinal cortex and hippocampus exhibited significant sex-dependent effects at 9 and 12 months so males and females were analyzed separately across all timepoints. At 9 months, females exposed to LDV+HDV PM had increased amyloid plaques in the hippocampus, and at 15 months, both females and males exposed to LDV PM and females exposed to LDV PM and gases exhibited significantly increased plaque levels in the entorhinal cortex. The rate of plaque accumulation over all four time points was accelerated in the entorhinal cortices of both sexes exposed to LDV and LDV+HDV PM alone or in combination with gases. There were no exposure effects on phosphorylated tau or Thioflavin S staining; however, the rate of neuronal cell loss with increasing age was significantly increased by exposure to LDV emissions in both females and males. Collectively, these findings demonstrate that chronic exposure to ambient TRAP in real-time promoted AD-relevant outcomes in the TgF344-AD rat with effects that varied according to age, sex, and brain region. TRAP effects occurred more prominently in groups exposed to LDV PM. Further research is needed to determine the mechanism(s) by which sex-dependent TRAP effects exacerbate AD pathogenesis so that effective interventions can be developed to improve the health of the aging brain.
The microbiota-gut-brain axis (MGBA) is a critical bidirectional communication system governing cognitive function and intestinal homeostasis. Despite growing evidence linking environmental chemicals to neurological disorders, the mechanisms underlying bisphenol A (BPA)-induced cognitive deficits remain poorly understood. Here, we demonstrate that chronic BPA exposure may induce cognitive impairment in male offspring through disruption of the MGBA, specifically via upregulation of the NLRP3 inflammasome/pyroptosis-related markers. Gravid Kunming mice received BPA (0, 2, 20, or 200µg/kg body weight/day) in drinking water until weaning; their male offspring were then orally administered identical doses for nine weeks. Behavioral tests revealed significant deficits in short- and long-term memory following high-dose (200µg/kg) BPA exposure. Mechanistically, high-dose BPA reduced hippocampal neuron density, compromised ileal barrier integrity, and induced dysbiosis characterized by decreased α-diversity (Chao1, ACE, Shannon; P < 0.05) and an elevated Firmicutes/Bacteroidota ratio. LEfSe analysis identified increased abundance of potentially pro-inflammatory genera at 200µg/kg. Crucially, high-dose BPA upregulated the expression of NLRP3, ASC, Caspase-1, GSDMD, and IL-18 in both the hippocampus and ileum, alongside elevated serum TNF-α and IL-18, indicating systemic inflammation. Correlation analyses further linked specific microbial shifts to pyroptosis markers and cognitive decline. Collectively, our findings establish that chronic BPA exposure may triffer gut dysbiosis and barrier dysfunction, leading to NLRP3 inflammasome activation and pyroptotic cell death in both the gut and brain, ultimately impairing cognition. These results underscore the neurotoxic risk posed by BPA and provide a mechanistic rationale for stricter regulatory controls on its use in food-contact materials.
The development of tacrine derivatives aims to evaluate their biological potential as inhibitors of acetylcholinesterase and butyrylcholinesterase, enzymes involved in the cholinergic system. In this study, we aimed to synthesize 1,3,4,10-tetrahydroacridin-9(2H)-one (THA), a tacrine analogue, and examined the effects of a THA-supplemented diet on behavioral and biochemical parameters in Drosophila melanogaster. Drosophila melanogaster was fed a diet supplemented with THA at different concentrations from the larval stage until the fifteenth day of adulthood. A diet containing 0.025 mM THA increased mortality after 10 days of feeding. However, larvae fed 0.1875 mM THA showed no toxic effects. Biochemical analyses revealed that ingesting 0.1875 and 0.250 mM THA elevated nitrite, hydrogen peroxide, and lactate levels in the flies' thoraces. Notably, 0.1875 and 0.250 mM THA increased citrate synthase activity in the thorax and head of the flies. However, 0.1875 mM THA showed higher acetylcholinesterase activity only in the thorax, suggesting cholinergic modulation in muscle. These findings suggest that THA supplementation supports neural and muscle health in this animal model and may be a potential treatment for chronic diseases.
Arsenic (As) is a major public health threat, with more than 200 million people at risk of consuming drinking water that exceeds World Health Organization safety guidelines. Given that inorganic arsenic (iAs) is linked to various neuropsychiatric and neurodegenerative disorders, a better understanding of its mechanisms of toxicity is warranted. Current evidence suggests that microglia are central to the pathophysiology of As-induced effects in the central nervous system. Microglia are resident immune cells in the brain that play a crucial role in surveillance, clearance of pathogens, and wound healing. They undergo distinct stages of development throughout life, and their behavior is known to be disrupted by environmental insults such as iAs. To characterize the mechanisms by which iAs alters microglial function, we examined the impact of subtoxic exposure to trivalent inorganic arsenic (As(III)) on microglial activity, both in the presence and absence of immune challenges, using a spontaneously immortalized murine cell line derived from the neonatal cerebral cortex (SIM-A9). Results indicate that iAs causes early activation of SIM-A9 cells through upregulation of toll-like receptor 4-mediated NF-κB signaling, followed by the slower onset of anti-inflammatory effects mediated through increased Nuclear Factor Erythroid 2-related Factor 2 (Nrf2) activity. This later attenuation of responses to inflammatory stimuli suggests that iAs exposure may impair neonatal microglial function and sensitize individuals to secondary challenges relevant to a range of neurological functions and disorders.
Pyrethroid insecticides, including deltamethrin and permethrin, are known for their individual toxic effects; however, evidence regarding their combined toxicity during early developmental stages remains limited. The present study aimed to investigate the neurotoxic effects of co-exposure to deltamethrin and permethrin in lactating rats, focusing on emotional and cognitive behaviors, as well as cholinergic and monoaminergic neurotransmission in their progeny at adulthood (5 months of age). Dams were orally administered deltamethrin (1.35 mg/kg/day) and permethrin (34 mg/kg/day), either individually or in combination, from postnatal day (PND) 7 to PND 21. Our results demonstrated that co-exposure of lactating females to deltamethrin and permethrin induced behavioral alterations in their offspring, including impaired locomotor activity, anxiety-like behavior, and learning and memory deficits, with sex-specific effects. Furthermore, these toxicants triggered oxidative stress in the hippocampus, as indicated by elevated levels of malondialdehyde, nitric oxide, and advanced oxidation protein products, along with impaired enzymatic and non-enzymatic antioxidant defenses. Early postnatal exposure also caused sex-dependent modifications in monoamine concentrations across multiple brain regions. Mechanistically, molecular alterations of the cholinergic system were observed in the hippocampus of both male and female rats, as evidenced by downregulation of AChE, mAChR, and nAChR gene expression. These molecular changes were further confirmed by histological analyses. In conclusion, our findings demonstrate that exposure of lactating females to deltamethrin and permethrin, individually or in combination, induces sex-dependent, deleterious, and sometimes distinct neurodevelopmental effects in their offspring at PND 150.
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 PM2.5 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). We conducted a cross-sectional study using data from 387 VETSA men (Mage=61.9±2.6) and 1097 WHIMS women (Mage=77.9±3.7) without dementia or stroke prior to MRI. Long-term residential exposures to PM2.5 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. In WHIMS, exposures were negatively associated with CTh in the AD meta-ROI (pPM2.5<0.001; pNO2=0.018) and diffusely across the cortex. In VETSA, exposures were positively associated with CTh in the AD meta-ROI (pPM2.5=0.017; pNO2=0.021) and temporal pole, but effects were age-dependent, becoming negative (though nonsignificant) after age 64. Positive associations in younger VETSA men, coupled with negative associations in older WHIMS women, may suggest nonmonotonic AD-related neurodegeneration.
Lead (Pb) is a neurotoxic environmental pollutant that causes cognitive dysfunction and metabolic disturbances in the brain. Glucose transporter 1 (GLUT1) is essential for cerebral glucose metabolism, and altered expression may impair glucose uptake and utilization, synaptic plasticity, and cognitive performance. We found that acute Pb exposure impaired learning, memory, and anxiety-related behavior of mice. Fasting blood glucose concentrations increased in Pb-exposed mice, whereas GLUT1 expression in the brain was significantly decreased. GLUT1 overexpression alleviated Pb-induced synaptic structural and functional damage in Neuro-2a cells, whereas GLUT1 knockdown exacerbated these effects. Co-treatment with Morinda officinalis oligosaccharides (MOOs) improved behavioral performance, restored GLUT1 expression, and reduced Pb-induced synaptic pathology, whereas BAY-876 aggravated neurological impairment. In conclusion, GLUT1 is a key regulator of Pb-induced neurotoxicity. These findings provide potential therapeutic strategies for preventing the neurotoxic effects of Pb.
Excessive extracellular accumulation of K+ plays a key role in the induction and propagation of seizures associated with temporal lobe epilepsy (TLE), and astrocytes are largely responsible for K+ clearance from the extracellular space. Here, we review the TLE-related changes in the content and/or activity of proteins contributing to K+ transport across the astrocytic cell membranes. Seizures, whether genetic or acquired, are linked with decreased expression and/or mislocalization of the two key astroglia-specific drivers of K+ uptake: the inward rectifying potassium channel Kir4.1 and its spatial and functional partner, the water channel aquaporin 4 (AQP4). Among neural cells of the CNS, the high K+-responsive α2 isoform of Na+/K+-ATPase is specific for astrocytes and is substantially inactivated in the brains of TLE patients and experimental animals, albeit not always in epilepsies with a genetic background. The above data consistently support the involvement of malfunctional astrocytic K+ transport as a factor facilitating seizures. By contrast, complex and variable, region-dependent dynamics of the two-pore domain potassium channels (K2P; TWIK, TASK, and TREK) were observed in astrocytes in the hippocampus, rendering their contribution to seizures difficult to interpret. Anti-seizure medication targeting metabolic processes not directly related to astrocytic K+ transport often reversed the unfavorably changed status of the astrocytic mediators of K+ buffering.
Methylmercury (MeHg) is a well-recognized environmental neurotoxicant with a marked impact on neurodevelopment. However, studies integrating stage-specific transcriptomic responses in human neuronal development remain limited. This study aimed, in an exploratory manner, to integrate and compare transcriptomic profiles induced by MeHg across distinct stages of human neuronal development, in order to evaluate shared and differential transcriptional responses among models representing early neuroepithelial differentiation, neural progenitor expansion, and mature neuronal function. MeHg-associated genes were retrieved from the Comparative Toxicogenomics Database (CTD), GeneCards, and PubChem. Three human transcriptomic datasets from GEO were analyzed, corresponding to early neuroepithelial differentiation (UKN1), neural progenitor expansion (hNPT), and mature dopaminergic neurons (LUHMES). Differentially expressed genes were identified using GEO2R. Integrated analyses included protein-protein interaction network construction, hub gene identification using centrality algorithms in Cytoscape, and functional enrichment, transcription factor, and disease ontology analyses. Integration of databases identified a set of four genes (CASP3, GPX1, MT2A, and SOD2) consistently present across all resources. Differential expression analysis across the three neuronal models revealed both shared and model-specific transcriptional responses to MeHg exposure. A conserved set of three overexpressed genes (BRD7, HSPH1, and MCM5) was identified across all models, whereas no common repressed gene signature was observed across the three systems, although partial overlaps were detected between pairs of models. Network analysis highlighted central genes associated with general stress-related processes, including apoptosis, oxidative stress, and inflammatory signaling. Functional enrichment analyses indicated activation of broad cellular stress response pathways, with additional enrichment in processes related to cell cycle regulation and genome maintenance. Disease ontology analysis showed enrichment in broad disease categories, without evidence supporting disease-specific mechanistic interpretation. This integrative transcriptomic and network-based analysis provides an exploratory framework to prioritize candidate genes and biological processes associated with methylmercury exposure across human neuronal developmental models. The results indicate consistent involvement of general stress-related processes but do not support the identification of specific mechanisms or universal regulatory patterns across models. The absence of a conserved repression signature further highlights transcriptional heterogeneity among developmental stages. Overall, these findings should be interpreted as hypothesis-generating and intended to guide future experimental validation rather than to infer defined molecular mechanisms.
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.
Modern lifestyles characterized by reduced physical activity and changing eating habits have contributed to a global rise in obesity. This research examined the effects of a diet rich in linoleic acid combined with physical exercise using a TreadWheel system in Drosophila melanogaster. The flies were fed diets with varying linoleic acid concentrations from the larval stage through to day 15 of adulthood. A diet containing 45.9 mg/mL of linoleic acid improved eclosion rates, body weight, and biochemical markers such as glycogen, cholesterol, and hydrogen peroxide levels, as well as citrate synthase and acetylcholinesterase activities in sedentary flies. Conversely, flies that consumed linoleic acid and underwent 15 days of exercise on the TreadWheel showed increased weight, lactate, glycogen, cholesterol, nitric oxide levels, and acetylcholinesterase activity. These results suggest that a 15-day regimen of linoleic acid intake combined with physical exercise on the TreadWheel enhances muscle parameters in D. melanogaster, serving as an alternative animal model for nutrition and exercise research.
Per- and polyfluoroalkyl substances (PFASs), due to their distinctive physicochemical characteristics, are emerging pollutants that are widely used as raw materials in industrial production, leading to their ubiquitous presence in the environment, plants and animals. Humans may also face health risks from exposure to PFASs. This paper reviews that the different populations are exposed to PFASs in their daily lives through diet, drinking water, indoor air, and assess the health risks to susceptible populations from various exposure pathways. Research has shown that PFASs can persist in organisms for a long time and can cross the blood-brain barrier, accumulating in the brain. Additionally, experimental studies on animals have demonstrated the occurrence of neurodevelopmental toxicity induced by PFASs, including behavioral problems, alterations to neurotransmitters, and brain tissue lesions. Epidemiological studies have demonstrated that PFASs are associated with adverse outcomes in susceptible populations, including cognitive function, learning, memory, and motor function. Finally, this paper elucidates the potential mechanisms from the perspectives of disrupted signaling pathways, synaptic plasticity, and endocrine disruption. It demonstrates that PFASs may alter neuronal synaptic structures, leading to abnormal neurotransmitter secretion and affecting intracellular calcium homeostasis and calcium signaling. It is hoped that this review will provide a reference for further research on the neurodevelopmental toxicity and health risks of PFASs.
Bodin et al. (2025) provide valuable insights into neurodevelopmental vulnerability by examining radiofrequency electromagnetic fields (RF‑EMF) exposure during early life. Their integrative design, combining whole-body exposure with endpoints such as neonatal brain proteomics, BDNF expression, synaptogenesis, and oxidative stress, offers a comprehensive framework for developmental neurotoxicology. However, interpretation of proteomic clustering relies heavily on principal component analysis (PCA), a linear technique ill-suited for high-dimensional datasets dominated by non-linear dependencies and strong inter-feature correlations. PCA plots (Fig. 3) illustrate group separation, yet variance explained (55%) and clustering stability remain underreported, raising concerns about robustness and biological interpretability, particularly given only ten differentially expressed proteins. To enhance inference, future studies should adopt biologically meaningful feature selection and advanced frameworks such as Feature Agglomeration and Highly Variable Feature Selection, alongside non-parametric correlation measures such as Spearman's rho and Kendall's tau. These strategies will improve reproducibility, uncover mechanistic patterns, and strengthen translational relevance for neurodevelopmental research.
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-L-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.
Chronic is a major neurotoxicant that disrupts hippocampal synaptic plasticity, leading to persistent cognitive deficits. This narrative review maps the adverse outcome pathways (AOPs) through which ethanol impairs synaptic function, primarily via interconnected cascades: TLR4/NF-κB-mediated neuroinflammation (triggering microglial activation and pro-inflammatory cytokines TNF-α, IL-1β), CYP2E1-driven oxidative stress (generating ROS/RNS, 4-HNE, causing protein carbonylation and mitochondrial dysfunction), and glutamate excitotoxicity (mediated by GluN2B-NMDAR subunit shifts, Ca²⁺ overload, and astrocytic EAAT2/GLT-1 downregulation). These pathways converge to suppress BDNF/TrkB signaling (via miR-206 and impaired proBDNF cleavage), leading to deficits in synaptic protein synthesis (e.g., Arc) and trafficking (e.g., GluA1 endocytosis via STEP, impaired forward trafficking). Critically, these insults potentiate neuronal apoptosis through intrinsic (ROS/mitochondrial permeabilization, caspase-9/-3) and extrinsic (TNF-α/TNF-R1, caspase-8) pathways, executing irreversible synaptic loss via caspase-3 cleavage of PSD-95, spectrin, and cytoskeletal collapse. The structural consequences-dendritic simplification, reduced mature spine density, and PSD-95 nano-domain disorganization-manifest functionally as attenuated LTP, potentiated mGluR-LTD, and impaired STDP. This synaptic decay directly underpins cognitive impairments in pattern separation, contextual memory, and cognitive flexibility. Neuroinflammation (TLR4/NF-κB) acts as a central amplifier, linking oxidative damage, excitotoxicity, and BDNF collapse to apoptotic synaptic deletion. Future research must address dose-dependency, subfield vulnerability, epigenetic regulation, and therapeutic strategies targeting TLR4, TrkB, mitochondrial antioxidants, and anti-apoptotic pathways.
Although fluoride is known to cause neurological impairment, the underlying molecular mechanisms remain unclear. Given that ferroptosis may contribute to neurotoxicity, we explored whether fluoride induces neuronal ferroptosis and sought to identify the signaling pathways involved by integrating bioinformatics analysis with experimental validation. Bioinformatics screening of 23 intersecting differentially expressed genes (DEGs) revealed significant enrichment of ferroptosis-related signaling pathways, with TP53 as the top-ranked gene. In silico analysis further predicted three potential p53 binding sites in the SLC7A11 promoter region. Experimentally, rats received 10, 50 and 100mg/L NaF, and SH-SY5Y cells were treated with 20, 40 and 60mg/L NaF. NaF-treated rats exhibited impaired performance in Morris water maze tests. Concurrently, elevated Fe2+ and total iron were detected in NaF-treated rat brains and SH-SY5Y cells. NaF treatment also impaired antioxidant capacity and induced lipid peroxidation, increasing ROS and MDA levels while decreasing GSH levels and the GSH/GSSG ratio, confirmed by immunofluorescence and biochemical analyses in vivo and in vitro. Transmission electron microscopy revealed that NaF induced mitochondrial alterations in vitro, including a loss of cristae. At the molecular level, NaF upregulated p53 (confirmed by immunofluorescence) and ACSL4 while downregulating SLC7A11 (xCT) and GPX4 expression in rat hippocampi and cells. Notably, these pathological alterations were attenuated by the ferroptosis inhibitor Ferrostatin-1 and p53 siRNA, validating the involvement of ferroptosis and the p53/xCT/GPX4 signaling pathway. In conclusion, our findings uncover that fluoride may activate the p53/xCT/GPX4 signaling pathway, inducing neuronal ferroptosis and subsequent neurological impairment, and further suggest TP53 as a potential target gene for the control of fluoride neurotoxic effects.