Mechanistic developmental neurotoxicity (DNT) research has focused predominantly on neuronal endpoints, while effects on oligodendrocytes and myelination remain less characterized. This systematic review aimed to identify mechanisms linking developmental chemical exposure to oligodendrocyte-lineage injury, impaired myelination, and associated neurodevelopmental outcomes. Eligible evidence included developmental in vitro models and in vivo exposures extending from parental preconception exposure with offspring outcomes through embryonic/fetal, neonatal, juvenile, and adolescent development. In rodents, direct exposure had to begin by postnatal day 60, and in fish and amphibians before sexual maturity; adult-only exposures without offspring developmental outcomes were excluded. PubMed, Web of Science, and Scopus were searched using an iterative strategy supported by LitSearchR, and study quality was evaluated using a modified SciRAP approach. Of 2,880 records retrieved, 1,096 remained after deduplication, 156 underwent full-text review, and 77 met the inclusion criteria for mechanistic synthesis. Disruption of oligodendrocyte-lineage development and myelination emerged as the primary outcome, associated with four recurrent mechanistic domains: hormonal and signaling dysregulation; oxidative stress, mitochondrial dysfunction, apoptosis, and cytotoxicity; astrocyte and microglia activation; and neuronal and synaptic dysfunction. Across studies, toxicant exposure impaired oligodendrocyte differentiation, maturation, and survival, with reduced or abnormal myelination and altered MBP, MAG, and CNPase. These effects were associated with thyroid-hormone and BDNF-TrkB dysregulation, oxidative-mitochondrial injury, inflammatory responses, and neuronal/synaptic alterations linked to behavioral and cognitive outcomes. These findings support oligodendrocyte and myelin endpoints as mechanistically informative components of future DNT testing and chemical risk assessment.
Environmental mycotoxins are pervasive exposures, yet how they perturb Alzheimer's disease (AD)-relevant proteostasis remains unclear. We treated SH-SY5Y cells with low-dose T-2 toxin (6 nM) for 24 h, and profiled AD-relevant protein changes alongside transcriptomic, circadian, and senescence-related readouts. We report that T‑2 toxin remodels APP and Tau homeostasis, featuring an early decrease in full‑length APP and a delayed, sustained increase in Tau phosphorylation and total Tau, accompanied by dynamic cytokine release. RNA‑seq at 12 h revealed a p53‑centered stress response and enrichment of circadian‑related pathways. Cosinor analysis indicated that CLOCK rhythmicity is preserved but reparameterized following T-2 toxin exposure, with a marked phase shift and an elevated mesor. Pharmacological disruption of CLOCK attenuated p53 induction and Tau elevation, whereas inhibition of p53 partially restored APP and reduced Tau changes while reshaping CLOCK abundance and localization, consistent with CLOCK-p53 cross‑regulation. T‑2 toxin also induced a time‑dependent senescence‑like phenotype that was attenuated by CLOCK and/or p53 inhibition. Post‑treatment with senolytic drugs dasatinib and quercetin reduced SA‑β‑gal burden, dampened p53 signaling, and improved the APP/Tau profile. Together, these data link T‑2 toxin exposure to AD‑relevant proteostasis remodeling through a CLOCK-p53-senescence axis and suggest circadian and senescence‑targeting strategies as complementary intervention points.
Ketamine presents a modern pharmacological paradox, acting as both a rapid-acting antidepressant and a drug of abuse with significant cognitive consequences. While its therapeutic potential is revolutionary, chronic exposure is increasingly associated with persistent and specific deficits in episodic and working memory. This narrative review moves beyond descriptive lists of ketamine's effects to propose a novel integrative model that delineates the coherent pathophysiological cascade through which chronic ketamine exposure induces memory dysfunction. We synthesize evidence that the initiating event-NMDA receptor antagonism, particularly on GABAergic interneurons-triggers a glutamate surge and glutamatergic dysregulation. This initial insult activates a self-reinforcing and pathological amplifying loop of neuroinflammation (e.g., microglial activation, cytokine release) and oxidative stress (e.g., mitochondrial dysfunction, ROS/RNS generation). These converging insults subsequently suppress BDNF/TrkB neurotrophic signaling and cause synaptic disintegration, impairing the plasticity mechanisms that underlie learning and memory. The cascade structurally culminates in apoptotic neuronal deletion, which permanently degrades the cellular substrate within critical memory circuits. This molecular and cellular pathology ultimately manifests as systems-level dysfunction, specifically the functional disconnection of the hippocampus-prefrontal cortex axis, explaining the core clinical memory deficits. By bridging evidence from synapse to circuit, this integrative model provides a unified framework for understanding individual vulnerability, proposes biomarkers for personalized risk assessment, and identifies targeted neuroprotective strategies to mitigate cognitive harm while preserving ketamine's therapeutic benefits.
Aluminum exposure has been implicated in neurodegenerative disorders, and aluminum-based nanoparticles exhibit greater neurotoxicity than bulk aluminum, highlighting the need to identify protective agents. Cinnamaldehyde, a major bioactive compound of cinnamon, has demonstrated neuroprotective effects in experimental models. The present study investigated whether cinnamaldehyde could attenuate cognitive deficits induced by aluminum oxide nanoparticles (ALNP) and examined the involvement of hippocampal MAPK signaling and neurotrophic pathways. Adult male Swiss mice received ALNP (10 mg/kg, oral gavage) alone or in combination with cinnamaldehyde (100, 200, or 300 mg/kg, i.p.) for five days. Novel object recognition memory was evaluated using the novel object recognition (NOR) test, and hippocampal levels of phosphorylated and total ERK and p38, as well as BDNF, were measured by western blotting. ALNP exposure impaired recognition memory and increased phosphorylation of ERK and p38 without altering total protein levels. Cinnamaldehyde improved cognitive performance in a dose-dependent manner, with significant effects observed at 300 mg/kg. Cinnamaldehyde administered alone (300 mg/kg) did not alter cognitive performance, indicating selective protection against ALNP-induced deficits. This effective dose normalized ERK and p38 phosphorylation and significantly increased hippocampal BDNF expression. Total exploration time did not differ between any groups, indicating that behavioral effects were not attributable to locomotor alterations. These findings suggest that ALNP-induced cognitive impairment is associated with stress-related activation of MAPK signaling, and that cinnamaldehyde mitigates these neurotoxic effects, possibly through restoration of kinase signaling balance and enhancement of neurotrophic support. Collectively, the results identify intracellular signaling dysregulation as a potential mechanism of nanoparticle-induced cognitive dysfunction and support cinnamaldehyde as a candidate warranting further investigation for mitigating aluminum nanoparticle neurotoxicity.
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by persistent deficits in social communication and restricted, repetitive patterns of behavior. Recent claims linking prenatal exposure to paracetamol (acetaminophen), the most commonly analgesic during pregnancy, to increased risk of ASD. This review aims to critically evaluate the validity of these associations, clarify potential biological mechanisms, and provide a balanced, evidence-based perspective to inform clinical practice. Although several observational cohort studies report statistical associations between in utero paracetamol exposure and ASD, these findings are often limited by confounding. Maternal conditions necessitating pain treatment, such as infection or fever, are themselves established risk factors for adverse neurodevelopmental outcomes. Greater emphasis here is therefore placed on robust study designs, particularly sibling-comparison analyses, which account for shared genetic and environmental influences. These epidemiological studies control for unmeasured confounders and consistently demonstrate attenuation or absence of previously reported associations, suggesting that paracetamol exposure is unlikely to be causative. This review also examines proposed mechanistic pathways, including mitochondrial dysfunction and inhibition of ribonucleotide reductase, but finds insufficient evidence to support a clinically meaningful effect in humans. Given the known risks of alternative therapies, particularly non-steroidal anti-inflammatory drugs during pregnancy, paracetamol remains the recommended first-line treatment for pain and fever. Overall, current evidence does not support a significant increase in ASD risk, and clinical guidelines should remain unchanged.
BACKGROUND:Early-life lead (Pb) exposure has been confirmed to cause long-term cognitive impairment, but the mechanisms of its programmed cell death remain incompletely elucidated. This study aims to investigate the key role of Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment in mice. METHODS:By employing both in vivo and in vitro approaches, we explored the involvement of Keap1/Nrf2-mediated ferroptosis in early-life Pb exposure-induced cognitive impairment. RESULTS:Our findings showed that early-life Pb exposure induced ferroptosis by upregulating hippocampal Keap1 expression and inhibiting the Nrf2 pathway and its downstream antioxidant proteins (GPX4, SLC7A11, and SLC3A2), and altering the expression of iron metabolism-related proteins (downregulating FTH1/FTL and upregulating DMT1). This process led to ferroptosis, as evidenced by elevated levels of the lipid peroxidation product MDA and reduced glutathione peroxidase activity. Furthermore, this process was accompanied by upregulation of the neurodegeneration-related protein APP in hippocampal tissues, which ultimately resulted in neurodegenerative lesions. CONCLUSION:This study reveals the mechanism of Keap1/Nrf2-mediated ferroptosis in cognitive dysfunction induced by early-life Pb exposure, providing a potential therapeutic strategy targeting this pathway to alleviate Pb exposure-associated neurodegenerative lesions.
Environmental nanoplastic pollution is an emerging concern for neurodevelopmental health; however, little is known about how subtle environmental modifiers influence its neurotoxic potential. In this study, we investigated whether a modest but environmentally relevant thermal elevation (0.5 °C) modulates the neurotoxic effects of 20 nm polystyrene nanoplastics (PNPs) in developing zebrafish. Embryonic exposure to PNPs induced significant anxiety-related behavioral alterations, as evidenced by changes in thigmotaxis. These behavioral disturbances were accompanied by increased oxidative stress, reflected by altered expression of antioxidant defense genes (SOD, CAT, GPx), and elevated markers of DNA damage, including γH2A.X and 8-OHdG in brain tissue. Immunofluorescence analyses further revealed disruptions in neurotrophic and neuromodulatory signaling, as indicated by altered BDNF, 5-HT4 receptor, and nNOS protein levels. Notably, even a 0.5 °C temperature increase markedly amplified these molecular and behavioral alterations. Metabolomic profiling supported these findings, demonstrating perturbations in amino acid and purine metabolism pathways associated with redox balance and neurotransmission. Together, our results indicate that subtle thermal stress enhances nanoplastic-induced neurodevelopmental toxicity through oxidative and DNA damage-mediated mechanisms, ultimately leading to functional behavioral impairment. These findings underscore the vulnerability of the developing nervous system to interacting environmental stressors.
Background Cocaine disrupts monoaminergic signaling which leads to neuroadaptive and neurotoxic changes in brain reward circuits. While its effects on mesocorticolimbic regions are well documented, its impact on the laterodorsal tegmentum (LDT), a brainstem cholinergic nucleus that is a key regulator of midbrain dopaminergic activity critical in the reinforcing properties of cocaine, remains unclear. Methods We used an organotypic culture model of LDT brain slices combined with a modified flow system enabling controlled cocaine exposure for 14 days in vitro. Slices were exposed to cocaine under continuous or daily 1-hour protocols. Cell viability, morphology, and cytotoxicity were assessed using MTT, DAPI/PI staining, and LDH release. Cholinergic neurons were identified by immunohistochemistry, and their functional responses were evaluated by electrophysiology and calcium imaging following AMPA stimulation. Results Chronic cocaine exposure induced significant, exposure-dependent reductions in cell viability and structural integrity, with more pronounced effects under continuous exposure. Cholinergic neurons showed decreased number and soma size. Cocaine exposure also altered cytotoxicity and dopamine dynamics. Functionally, cocaine-induced alterations in synaptic activity and calcium signaling were time-dependent, with increased neuronal responses observed at early stages of exposure and reduced responsiveness after prolonged exposure. Conclusion We present a novel and robust in vitro model to study long-term, drug-induced neuroadaptations and show that chronic cocaine exposure disrupts the structural and functional integrity of LDT cholinergic neurons in a time-dependent manner. Our findings suggest that actions of cocaine on altering reward processing that leads to persistence of drug-seeking behaviors likely involve degenerative effects on neurons of the LDT.
Acrylamide (ACR), a well-established neurotoxicant in humans, is commonly encountered in daily life. Previous studies have implicated cerebellar injury in ACR-induced neurotoxicity. Curcumin, a polyphenolic compound with potent neuroprotective properties, has shown protective effects in maintaining cerebellar function by suppressing oxidative stress. This study aimed to determine whether curcumin could alleviate ACR-induced motor dysfunction and cerebellar injury in rats. Administration of ACR at a dose of 10 mg/kg/day for 7 weeks induced mild gait abnormality, impaired motor coordination and balance, and significant cerebellar neuronal loss. These alterations were accompanied by oxidative stress, neurofilament accumulation and microtubule dynamic instability. ACR increased cerebellar malondialdehyde (MDA) level, reduced glutathione (GSH) level and activities of total superoxide dismutase (T-SOD) and catalase (CAT). At the molecular level, ACR exposure increased the expression of neurofilament light chain (NF-L) and reduced the levels of phosphorylated cAMP response element-binding protein (P-CREB) and brain-derived neurotrophic factor (BDNF). ACR increased tau phosphorylation and decreased acetylated α-tubulin. Curcumin intervention partially alleviated ACR-induced motor dysfunction and cerebellar cytoskeletal injury, attenuated oxidative stress, reduced NF-L accumulation, increased ERK1/2 and Akt phosphorylation, and elevated P-CREB and BDNF levels. However, curcumin had limited effects on cerebellar tau phosphorylation and microtubule instability. These results provide novel insights into the protective effects of curcumin against ACR-induced cerebellar toxicity and highlight its therapeutic potential as a protective intervention against ACR-induced neurotoxicity.
Micro- and nanoplastics (MNPs) are persistent environmental pollutants capable of crossing biological barriers, including the placenta and the blood-brain barrier, raising concerns about their impact on neurodevelopment. This systematic review synthesizes evidence from experimental rodent models, revealing morphological, molecular, and behavioral alterations associated with developmental MNPs exposure in rodent models and highlighting their potential relevance for understanding neurodevelopmental vulnerability. Following PRISMA guidelines (PROSPERO CRD420251127469), MEDLINE, EMBASE, Scopus and Web of Science were searched without date limits (last search: 18 Aug 2025). The review followed a PECO framework: population: mammalian in vivo models; exposure: MNPs during gestation, lactation, childhood, or adolescence; comparator: non-exposed or vehicle-treated controls; outcomes: behavioral, structural, or molecular central nervous system effects. Study reliability was assessed using ToxRTool. Due to heterogeneity, findings were narratively synthesized by exposure window (prenatal, postnatal, combined prenatal-early postnatal exposure). Of 542 records, 20 studies met inclusion criteria. All included studies used rodents (mice or rats) and evaluated polystyrene, polypropylene, polyethylene, or polyvinyl chloride particles delivered mainly by oral routes. Our analysis identified the central nervous system as an important target of MNPs, with convergent findings across exposure windows revealing oxidative stress and mitochondrial dysfunction, neuroinflammation (microglial/astrocytic activation), apoptosis/ferroptosis, disrupted neurogenesis and myelination, and synaptic/dendritic abnormalities. Neurochemical alterations frequently involved GABAergic and glutamatergic imbalance, with context-specific dopaminergic changes. Behaviorally, MNPs were associated with impaired learning and memory, increased anxiety-like responses, altered sociability, and repetitive/stereotyped behaviors. Several studies suggested microbiota-gut-brain interactions via intestinal barrier disruption, dysbiosis, and systemic inflammation. In rodent models, the available evidence suggests that early-life MNPs exposure may contribute to developmental neurotoxicity, which is characterized by multilevel central nervous system alterations and behavioral impairments. Standardized, environmentally relevant exposure paradigms, sex-stratified analyses, and longitudinal follow-up are needed to clarify dose-response, persistence, and human relevance.
Xylazine is a veterinary anesthetic and α2-adrenoceptor agonist found in illicit drug supplies. Injection of opioids adulterated with xylazine is correlated with necrotic tissue injury and a withdrawal syndrome including anxiety. Planarians are flatworms with a simple nervous system and no circulatory system that exhibit several characteristics, including regenerative capacity and negative phototaxis (light avoidance). Because regeneration reflects tissue repair and negative phototaxis constitutes defensive behavior, planarians provide a simple in vivo system to explore possible effects of xylazine on planarian wound repair and anxiety-like behavior. Using planarians, we investigated the effects of xylazine on cephalic regeneration and defensive responding (i.e., determined by time spent on light side of a dish divided into light and dark compartments). In decapitated planarians, chronic xylazine exposure (0.001-0.1 µM, over 2 weeks) reduced head regeneration rate. For intact worms, acute xylazine (1 µM, 5 min) caused a reduction in defensive responding (i.e., increased time in light) that was abolished by yohimbine (0.001 µM), an α2-adrenoceptor antagonist. Clonidine (0.01-1 µM), another α2-adrenoceptor agonist, mimicked xylazine's defensive responding effects. We next assessed effects of xylazine withdrawal on defensive responding. Early xylazine abstinence (0.01-1 µM, 5 and 30 min), like acute xylazine, reduced defensive responding. In contrast, during later xylazine abstinence (0.001-1 µM, 60 min), defensive responding robustly increased with no significant changes in motility. Our data show that xylazine impairs planarian regeneration and bidirectionally impacts planarian defensive behaviors with distinct acute and withdrawal-dependent effects. These results suggest that some effects of xylazine on tissue injury and anxiety-like behavior are conserved in planarians.
Neurodevelopmental disorders often share similar behavioral diagnostic criteria including socioemotional and cognitive deficits. The prairie vole is a uniquely suitable model to study these deficits because they demonstrate strong social affiliation, bi-parental care, and partner attachment. Previously, we have shown that developmental exposure to the flame-retardant mixture Firemaster 550 (FM 550) impairs socioemotional behavior in the prairie vole and alters underlying neuroanatomy and function. However, the mechanisms for impaired pair bonding in males and increased anxiety in females remain unknown, along with the specific critical window(s) of vulnerability. Herein, we exposed prairie vole dams to FM 550 during gestation or lactation, and performed bulk RNA-seq on the amygdala, a hub of socioemotional processing, in their adult offspring. Two mathematically orthogonal methods were utilized for analysis, a linear statistical method and an ensemble machine learning method, incorporating sex as a biological variable. Gene ontology (GO) pathway analysis was performed following both and results compared to identify potential mechanisms of toxicity. GO results indicated consistent expression changes in the Synapse cellular component in all conditions, and implicated glutamatergic signaling specifically. Additionally, gestational exposure (GE) altered genes underlying modulation of synaptic transmission and neural development, while lactational exposure (LE) impacted genes underlying synaptic plasticity, axon guidance, and mitophagy. Machine learning identified disruption of endocrine system development, regulation of biosynthetic processes in GE animals, and suppression of various neuroinflammatory genes across multiple groups. Finally, we performed RNA expression analysis using Nanostring and demonstrated stronger correlation with the differentially expressed genes (DEG) of interest in females than males. Overall, this study demonstrates both the intersecting and distinct impacts of FM 550 exposure on amygdalar gene expression depending on sex and timing of exposure.
Doxorubicin (DOX), an anthracycline chemotherapeutic agent, is associated with multiple adverse effects, including persistent cognitive impairment, commonly referred to as "chemobrain." This study aimed to evaluate the long-term neurotoxic effects of a clinically relevant cumulative dose of DOX in a rodent model. Three-month-old male CD-1 mice received DOX twice a week for three weeks, reaching a cumulative dose of 9.0 mg/kg. Brain tissue was analysed five months after the final administration to assess enduring neurotoxic effects. Coronal sections of the left hemisphere were evaluated for biomarkers related to apoptosis, inflammation, glial function, and neuronal integrity in the prefrontal cortex (PFC) and hippocampal formation (HF). Additionally, a significant reduction in Iba1-immunoreactive microglia and nuclei was found in the HF. Additionally, p53 levels remained elevated, while procaspase-3 levels decreased, suggesting persistent changes in apoptotic pathways. A significant reduction in brain-derived neurotrophic factor (BDNF) levels was observed in the dentate gyrus (DG), indicating impaired neurogenesis. In contrast, no substantial changes were detected in the PFC, highlighting the selective vulnerability of the HF to DOX-induced neurotoxicity. These findings underscore the enduring impact of DOX on HF and suggest potential mechanisms underlying long-term cognitive deficits observed in chemotherapy-treated patients.
Bisphenol A (BPA), a ubiquitous environmental contaminant, is increasingly recognized as a neurotoxicant. Epidemiological and experimental evidence links BPA exposure with neurodegenerative diseases and abnormal neurobehavior, implicating it as a risk factor for neuronal dysfunction and cognitive impairment. Given the critical role of microglia in maintaining brain immune homeostasis, we investigated whether BPA interfered with microglial immune reactivity, which may be one of the reasons why BPA causes neuropathological alterations. Using an in vitro BV-2 microglial model, sublethal BPA exposure, with or without lipopolysaccharide (LPS), was assessed for immunoinflammatory responses. BPA, without compromising cell viability, suppressed basal immune activity and attenuated LPS-induced responses. This was evidenced by reduced secretion of pro- and anti-inflammatory cytokines, alterations in NLRP3 inflammasome-related signaling (including caspase-1 and IL-1β processing), and dysregulated expression of antioxidants, motility-related proteins, and zinc-dependent metalloproteinases. These changes were associated with downregulation of MAPK, Akt, and NF-κB pathways, alongside ROS-dependent upregulation of the Nrf2-Keap1/heme oxygenase-1 (HO-1) axis, which interfered with both quiescent and LPS-driven Toll-like receptor 4 (TLR4) signaling. Collectively, these findings suggest that sublethal BPA interferes with TLR4-related immunoinflammatory signaling in microglia, potentially via modulation of the ROS/Nrf2-Keap1/HO-1 axis. Given that disruption of brain innate immunity may elevate the risk of developing neuropathies, this work highlights the potential impact of BPA, particularly on microglial immune function.
BACKGROUND:Evidence on the neurodevelopmental impacts of postnatal exposure to current-use pesticides (CUPs) remains fragmented. This systematic review synthesises the international epidemiological evidence linking chronic postnatal CUP exposure with neurocognitive (NC), neurobehavioural (NB), and neurological (N_) outcomes in children and adolescents. METHODS:Following PRISMA 2020 (PROSPERO-CRD42021258519), we searched PubMed, Scopus, Web of Science, Cochrane, and EBSCOhost for epidemiological studies published between January 2010 and July 2025 assessing postnatal CUP exposure and NC, NB, or N_ outcomes in individuals aged 0-21 years. Data extraction captured exposure metrics, outcome domains, study design, and methodological quality. Findings were narratively synthesised using age- and domain-organised tables and direction-of-association plots. RESULTS:Sixty-six epidemiological studies met the inclusion criteria, spanning diverse settings but with limited representation from low-income low- and middle-income countries (LMICs; n = 9), including only one study from Sub-Saharan Africa (SSA). Study designs were predominantly cross-sectional (n = 35) or longitudinal (n = 23), and exposure assessment relied largely on biomonitoring (n = 52). Across neurodevelopmental domains, 118 unique exposure-outcome findings were identified (NC n = 41; NB n = 47; N_ n = 30). Statistically significant adverse associations comprised 53.7% of NC (22/41), 57.4% of NB (27/47), and 53.3% of N_ findings (16/30). Null findings remained substantial (NC 39.0%, NB 27.7%, N_ 36.7%), while non-significant adverse associations were less frequent (5.0-13.0%). Positive associations were rare (≤2.5%). CONCLUSIONS:The evidence suggests potential associations between postnatal exposure to CUPs and adverse NC, NB, and N_ outcomes in children, although certainty is limited by methodological constraints. Future research should prioritise longitudinal designs, incorporate mixture modelling, and employ culturally and developmentally valid neurodevelopmental measures, particularly in underrepresented low-income LMICs and SSA settings.
Excitotoxicity, oxidative stress, and neuroinflammation play significant roles in the pathophysiology of neurodegenerative disorders. This study aims to examine the impact of honokiol (HNK) on antioxidant, anti-inflammatory, and anti-apoptotic mechanisms in a model of excitotoxicity induced by intracerebroventricular (icv) ouabain (OUA) in rats. Rats were allocated to five equal groups (n = 10): (I) Animals given intraperitoneal isotonic saline solution for seven days (Control); (II) animals given a single dose of 5 μl OUA solvent (artificial cerebrospinal fluid-icv) on the first day (Sham); (III) animals given a single dose of OUA (5 μl at a concentration of 10⁻³ M-icv) (OUA); (IV) Animals given HNK for seven days (HNK); (V) animals given OUA and then HNK for seven days (OUA+HNK). OUA administration caused an increase in cerebral cortex malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α) levels and a decrease in glutathione (GSH) and superoxide dismutase (SOD) levels. The OUA injection resulted in a decrease in immobility in the forced swim test, an increase in swimming and climbing activities, and a decrease in Na + /K + -ATPase enzyme activity. Significant improvements in oxidative stress markers and tissue antioxidant levels were detected with HNK treatment. Additionally, HNK treatment inhibited apoptotic processes by increasing Heat Shock Protein-70 (HSP-70) and suppressing the expression of the pro-apoptotic protein Bax. Furthermore, histopathological changes caused by OUA administration were found to improve in the HNK-treated groups. In conclusion, our findings suggest that HNK therapy, by reducing oxidative tissue damage, apoptosis, and inflammation, may be a promising adjunctive treatment for pathologies presenting with excitotoxicity.
BACKGROUND:Phthalates, particularly di(2-ethylhexyl) phthalate (DEHP), are ubiquitous environmental contaminants with well-documented neurotoxic potential. Selenium, an essential antioxidant trace element, may mitigate oxidative stress-induced neuronal damage. However, whether selenium modifies the cognitive effects of phthalate exposure remains unclear in human populations. METHODS:We analyzed cross-sectional data from adults aged ≥ 60 years in the National Health and Nutrition Examination Survey (NHANES) 2011-2014. Urinary phthalate metabolites and blood metals (lead, cadmium, mercury, manganese) were quantified. Survey-weighted linear regression with interaction terms tested whether blood selenium modified the associations between these exposures and global cognitive Z-scores. Effect modification was further evaluated using restricted cubic splines, simple slope analysis, and joint Wald tests. Oxidative stress biomarkers (alkaline phosphatase, total bilirubin, serum iron) were assessed as potential mediators. To contextualize the main NHANES findings, we performed two supplementary analyses: (i) bidirectional two-sample Mendelian randomization (MR) to test whether selenium has an independent causal effect on Alzheimer's disease (AD), and (ii) an exploratory ecological analysis using Global Burden of Disease (GBD) 2021 data to illustrate the risk of ecological fallacy when environmental co-exposures are unaccounted for. These ancillary analyses do not constitute formal triangulation, as they address selenium's main effects rather than its interaction with phthalates. RESULTS:Among 573 participants (mean age 69.7 years, 52.4% female), blood selenium significantly modified the associations of four DEHP metabolites with cognitive function, with the strongest interaction observed for MEHP (β = 0.00102, 95% CI: 0.00084-0.00121, P < 0.001). In individuals with low selenium, higher MEHP was associated with lower cognitive scores; this association was reversed in those with high selenium. In contrast, no significant interactions were found for any heavy metal (all P > 0.05). Joint Wald tests confirmed effect modification for phthalates (F = 13.34, P = 0.003) but not for metals (F = 1.03, P = 0.43). Oxidative stress biomarkers did not mediate the observed interactions. Bidirectional MR found no causal effect of selenium on AD (IVW β = -0.008, P = 0.87), ruling out reverse causation as an explanation. An exploratory ecological analysis using GBD data found a counterintuitive inverse association between dietary selenium inadequacy and dementia burden (β = -0.325, P = 0.037). This paradoxical pattern remained consistent in sensitivity analyses and likely reflects ecological confounding. It underscores that population-level nutrient-disease links can be strongly distorted by differences in diagnostic practices and unmeasured co-exposures, such as phthalates. CONCLUSIONS:Selenium reduces the cognitive harm of DEHP metabolites in older adults, with clearer and more consistent evidence for phthalates than for heavy metals. Null MR results rule out an independent causal effect of selenium on Alzheimer's disease, reinforcing that selenium's role is conditional rather than universal. A paradoxical ecological pattern, presented as a cautionary example, highlights the risk of ecological fallacy when co-exposures are unaccounted for. Together, these findings suggest that selenium's neuroprotection is context-dependent-it appears to act mainly under specific toxicant exposure rather than offering universal benefits. These findings caution against indiscriminate selenium supplementation and suggest that further longitudinal studies are needed before targeted interventions can be recommended.
Over the past 25 years, the Dutch Solvent Team project has made a substantial contribution to the diagnostic evaluation of chronic solvent-induced encephalopathy (CSE). This commentary provides a chronological overview of the project's development, highlighting advances in multidisciplinary diagnostics, retrospective exposure assessment, neuropsychological evaluation, prevention, and policy development. The project contributed to the development of national policy and international consensus guidelines, resulting in improved diagnostic consistency and a marked decline in disease incidence. The association between long-term occupational solvent exposure and CSE is supported by epidemiological, clinical, and toxicological evidence and by the substantial reduction in incidence following preventive measures. Despite these achievements, important challenges remain, including the absence of a gold-standard diagnostic test, limited understanding of individual susceptibility, and the lack of effective long-term treatment options. Future directions include further refinement of retrospective exposure assessment methods, investigation of susceptibility factors, and the development of objective diagnostic tools.
BACKGROUND:Postoperative neurocognitive disorders are common in older adults; whether prolonged volatile anesthesia causes persistent decline or amplifies preexisting vulnerability remains uncertain. We assessed whether sevoflurane exposure induces persistent cognitive impairment and hippocampal injury in young and aged rats, stratified by baseline cognitive status. METHODS:Female Wistar Hannover rats comprised young adults (10-12 weeks; n = 40) or aged (>24 months; n = 82). Aged rats were classified as cognitively intact (n = 47) or impaired (n = 35) after Morris Water Maze (MWM) pre-screening. Animals received 2% sevoflurane (SEVO+) or oxygen/air (SEVO-) for 3-h. Spatial memory was assessed by MWM probe trials (days 7, 30, and 90), with retraining. Subsets were sacrificed 24-h after exposure (n = 6/group) for histopathology and immunohistochemistry; remaining rats were evaluated after final behavioral analysis. RESULTS:SEVO caused transient memory impairment in young rats on day 7, resolving by day 30. In aged rats, effects were greater and more persistent, especially in cognitively impaired animals, with reduced target-quadrant preference, fewer crossings on days 7 and 30, and poor long-term retention. Acutely, SEVO increased hippocampal CA1 injury and elevated pro-apoptotic (Bax/Bcl-2, Cl-Cas-3) and mitochondrial/oxidative stress markers (Drp1, COX-IV, GPX1, Hsp60). Long-term, persistent CA1 pathology and elevated amyloid-β were most prominent in cognitively impaired aged rats. CONCLUSIONS:Prolonged SEVO exposure was associated with brief cognitive disruption in young female adults but led to more persistent cognitive decline and hippocampal injury in older rats with pre-existing impairment, underscoring baseline cognitive vulnerability as a modifier of long-term anesthesia-associated neurocognitive outcomes and an important consideration in surgical/anesthetic risk management.
BACKGROUND:Trace elements play essential roles in neurobiology, but evidence linking whole blood concentrations to cognitive outcomes in the general population remains limited. This study examined whether concentrations of eight trace elements: selenium, mercury, cadmium, arsenic, lead, manganese, copper, and zinc were associated with cognitive performance assessed approximately six years later in a Norwegian general population cohort from the HUNT3 Survey. METHODS:Whole blood trace element concentrations were measured using high resolution inductively coupled plasma mass spectrometry, with several strategies to minimize contamination. General cognitive performance was assessed using a validated web-based cognitive test battery capturing processing speed, motor speed, attention, and episodic and working memory. Associations were estimated using linear models with restricted cubic splines, adjusting for age, sex, and education. RESULTS:The sample included 252 participants aged 50-65 years (43% women), generally characterized by good somatic and mental health. No associations were observed for selenium, mercury, cadmium, arsenic, lead, manganese, or copper. Zinc showed a shallow U-shaped association, with slightly lower cognitive performance at mid-range concentrations, although the effect size was small. Cognitive performance declined with age and increased with educational attainment. CONCLUSIONS:In this low-exposure general population, whole blood trace elements concentrations showed no meaningful associations with cognitive performance six years later. These findings suggest that exposure levels to non-essential trace elements in this cohort are too low to exert clinically relevant effects on cognitive health. Alternatively, single time-point whole blood measurements may not reflect cumulative exposure relevant to long-term cognitive outcomes, or the study was underpowered to detect modest associations.
