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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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Acrylamide is a well-known neurotoxic and potentially carcinogenic compound formed during high-temperature (>120 °C) food processing via the Maillard reaction between reducing sugars and the amino acid asparagine. Emerging evidence from vertebrate and invertebrate models indicates that dietary acrylamide disrupts circadian rhythmicity-a fundamental biological process governing metabolic and behavioral homeostasis. This review introduces the concept of a "chronotoxin," defined as a toxicant that disrupts circadian regulation and produces circadian-related toxic effects, and proposes acrylamide as a relevant candidate. We summarize mechanistic insights into acrylamide-driven circadian disruption, focusing on oxidative stress, mitochondrial dysfunction, kinase signaling pathways (ERK/CREB/BDNF), and interactions with melatonin and serotonin systems. Furthermore, we highlight the translational relevance of circadian biomarkers in dietary neurotoxicology and public health monitoring, particularly under chronic, low-dose exposure. In this context, circadian endpoints may be informative for extrapolating findings to dietary exposure scenarios, while acknowledging inherent differences between experimental and dietary conditions. This review advances the concept of chronotoxicity by identifying acrylamide as a model compound for studying circadian disruption, with implications for biomarker development, dietary risk assessment, and public health monitoring, and provides a framework for evaluating circadian aspects of neurotoxicity linked to food-borne chemicals.
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.
Changing global wildfire landscapes necessitate exploration of the effects of exposure to wildfire smoke on health and disease. Exposure to this toxicant is not only associated with acute cardiopulmonary dysfunction, but is increasingly recognized as a serious risk factor for neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, the cellular and molecular mechanisms which underlie this association are not well understood. One potential mechanism linking neurotoxic environmental exposures with neurodegeneration is glial-mediated neuroinflammation, which may be influenced by innate immune signaling through the cGAS-STING pathway in response to damaged or mislocalized DNA. To address this hypothesis, we here exposed primary astrocyte-enriched mixed glial cultures to laboratory generated wildfire smoke particulate matter extract and subsequently examined their reactivity and inflammatory signaling by applying cutting-edge techniques in high content microscopy, deep learning-based image analysis, and transcriptomics. We found that wildfire smoke exposure elicits DNA damage and results in STING signal transduction in astrocytes, including the production and release of inflammatory cytokines, as well as STING-dependent neurotoxicity. To better understand the mechanisms underlying this phenomenon, we integrated transcriptomic data from in vitro and in vivo wildfire smoke exposures studies, which revealed central hubs for functional enrichment surrounding interferon signaling. Together, these data strongly identify STING signaling as a central modulator of astrocyte-mediated inflammation resulting from wildfire smoke exposure.
In this article, we describe how a conventional prescription may be usefully enhanced by the addition of special instructions and by the provision of information relevant to the patient's treatment plan. Content that we recommend for addition includes instructions for administration of drugs that are dosed in a special way, instructions for preparation for investigations, information about what each drug in the prescription does, documentation of discussions of medicolegal importance, and more. We provide examples for each suggestion, such as explaining how iron and thyroxine need to be taken, documenting discussions about benefits and risks of taking medicines during pregnancy, specifying the duration of weekly blood monitoring in patients prescribed clozapine, stating why higher than usual doses are prescribed, and warning about suicide risk. Medical professionals may choose what they wish to implement, based on need and context. The personalized enhancements that we suggest are easily implemented in digital prescriptions integrated with electronic health records; however, they can also be incorporated in handwritten prescriptions to the extent required. We believe that such an enhanced prescription will empower patients and caregivers and improve treatment adherence through better understanding of treatment advice.
Air pollution, with particulate matter (PM) as one of its most critical environmental contaminants, represents a major global health threat and a leading cause of premature mortality. PM can reach the central nervous system (CNS) and has been implicated in both neurodevelopmental and neurodegenerative disorders. Individual susceptibility to PM-induced neurotoxicity is shaped by genetic background. Apolipoprotein E (APOE), the major CNS apolipoprotein, plays a key role in brain homeostasis and neurodevelopment, and its isoforms may differentially modulate vulnerability to environmental insults. However, the interaction between APOE genotype and PM exposure during early development remains poorly understood. We aimed to investigate the developmental effects of early postnatal PM exposure in humanized apoE3 and apoE4 transgenic mice. From postnatal day (PND) 4-14, pups underwent daily whole-body inhalation exposure to Fine Atmospheric PM (SRM 2787, NIST), with a nominal theoretical chamber concentration of 3789 µg/m3. Physical milestones, neuromotor performance, and sexual maturation were monitored until PND42. Forebrain and cerebellum samples were analyzed for genes involved in neurotransmission, neurotrophic signaling, and neuroinflammation. Postnatal PM exposure reduced weight gain in females and impaired neuromotor performance. Furthermore, it accelerated eye and vaginal opening in apoE3 mice. The effects of PM exposure on gene expression were more pronounced in apoE4 mice, including alterations in GABAergic (Nkcc1), glutamatergic (Grin2b), serotonergic (5ht2c), and neurodevelopmental (Reln) markers. These findings indicate that early postnatal PM exposure disrupts neurodevelopment through sex- and genotype-specific mechanisms and support APOE genotype as a modifier of vulnerability to PM-induced developmental neurotoxicity.
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.
The rubber antioxidant N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its quinone derivative (6PPD-Q) are coexisting environmental contaminants with documented neurobehavioral effects. However, the neurotoxic consequences arising from their combined exposure remain unclear. In this study, adult zebrafish and SH-SY5Y cells were used to investigate the neurotoxic effects associated with co-exposure to 6PPD and 6PPD-Q. In zebrafish, 100 μg/L 6PPD+100 μg/L 6PPD-Q increased time spent and distance traveled in the non-reward area of the T-maze after 28 d exposure, accompanied by pathological damage in brain tissue, including reduced neuronal density, decreased Nissl bodies, and apoptosis. 6PPD-Q exacerbated oxidative damage and the decreased levels of neurotransmitters induced by 6PPD. Metabolomics implicated disruptions in neuroactive ligand-receptor interaction and citrate cycle. Transcriptomic analysis further identified dysregulation in oxidative stress, cell death, and nervous system processes related pathways, such as Peroxisome, Axon guidance, and PI3K-Akt pathway. In SH-SY5Y cells, co-exposure reduced cell viability and produced predominantly synergistic effects across concentration combinations tested. 6PPD-Q aggravated mitochondrial damage and enhanced the protein expression levels related to apoptosis induced by 6PPD, including caspase-3 and bax/bcl-2. Moreover, co-exposure inhibited the PI3K-AKT pathway, which might exacerbate neurotransmitter disturbance and apoptosis. The findings enrich the understanding of neurological health risks linked to 6PPD and 6PPD-Q, highlighting the importance of preventive strategies to mitigate the exposure risks.
Wildfire events are increasing in frequency and intensity, and aging individuals demonstrate heightened biological susceptibility to air pollution exposures including increased risk of neurological sequelae. Declining ovarian hormones levels that occur with aging in females along with associated systemic physiological and inflammatory changes may contribute to increased cerebral vulnerability to air pollution, representing a potential but underexplored mechanism. Menopause and the menopausal transition represent a period of profound physiological change that affects cardiovascular, neurological, and immune health. We tested whether peri-menopausal-like hormonal status amplifies hippocampal responses to acute wood smoke (WS) using an ovary-intact, 4-vinylcyclohexene diepoxide (VCD) model of moderate accelerated ovarian failure (AOF) in female C57BL/6 mice. Animals were exposed to HEPA-filtered air (FA) or WS for 4 h/day over 2 consecutive days (∼0.5 mg/m³). Exposure characterization confirmed a complex mixture of combustion products with significant levels of both trace metals and gas release during WS exposure. Spatial transcriptomics (10x Visium; n = 4 sections/group) with automated cell-type annotation identified astrocytes, GABAergic and glutamatergic neurons, oligodendrocytes, revealed cell type-specific transcriptional alterations following WS exposure. Distinct transcriptional patterns were observed across all identified neuronal and glial cell populations. Together, these findings define a cell-type specific transcriptomic framework describing how WS exposure and ovarian hormone decline interact to influence hippocampal responses and identify potential cellular pathways relevant to hippocampal vulnerability.
Parkinson's disease (PD) is the second most common neurodegenerative disorder with cognitive impairment as a prime non-motor symptom. Biomarkers can assist in detecting cognitive impairment, which normally follows movement dysfunction, and also assist in the differentiation of PD patients with and without cognitive dysfunction, facilitating the early diagnosis and disease management while also allowing for timely therapeutic intervention. Here, we have reviewed the biomarkers of Parkinson's disease from different sources i.e., body fluids (CSF, blood, salivary, urine and tear) and tissues (gut and skin), along with the techniques used for the detection of these biomarkers. We further discuss the importance of biomarker validation and the significance of cohort studies in biomarker discoveries. The chapter is aimed at updating the knowhow of the disease biomarkers that may assist differentiation of these overlapping entities.
Manganese (Mn) is an essential heavy metal, required for the normal development of many organ systems and is crucial to brain growth and development. At high exposure concentrations, Mn is a neurotoxicant. Mn exposure has been associated with motor, behavioral and cognitive impairment. Few studies have assessed the association between Mn exposure and cognitive function using NHANES data. This study re-explored the association between blood manganese concentrations and cognitive function through a re-analysis of NHANES 2011-2014 data using a larger combined sample and composite cognitive z-score methodology. A representative survey of the US population (60-80 years of age) completed objective cognitive function assessments and metal biomonitoring (n = 2,439). We created a composite cognitive z-score by using the average of the standardized scores of the six cognitive tests (three trials of CERAD Word List Learning Test, CERAD delayed recall, Animal fluency test and DSST) and compared to adjusted blood Mn. Linear regression was performed by constructing three models (univariate model, a model with all covariates and a model with only significant covariates). Confounding by gender, age, race/ethnicity, education level, total number of people in the family, smoking history and income (family monthly poverty level category) are included in the models. Median Mn was 8.71 µg/L with an IQR of 6.94-11.16. There was a statistically significant association between quartiles of blood Mn and composite z-score, only in the univariate model. However, in linear regression analyses, adjusting for potential confounders, blood Mn as a continuous variable was not statistically associated with the composite cognitive z-score (µg/L, β = 0.0038, 95% CI -0.004 to 0.012). The mean of composite z-score in the first quartile is the lowest compared to the mean of the second, third and fourth, with statistical significance. While the mean of the third quartile is the highest, followed by the fourth and then the second (0.022, 0.012 and 0.007, respectively). Our findings suggest that associations between blood manganese concentrations and cognitive performance at low environmental exposure levels are modest and attenuate after adjustment for demographic and socioeconomic confounders. Unlike some previous NHANES analyses that reported impaired cognition primarily among individuals with higher manganese exposure, we did not observe a consistent independent dose-response association across the broader population exposure range.
Carbon monoxide (CO) poisoning is a leading cause of environmental poisoning in the United States and can impair cellular metabolism through both hypoxia and direct mitochondrial toxicity, particularly via inhibition of cytochrome c oxidase (Complex IV, CIV). In this study, we performed a comprehensive assessment of the cerebral metabolic response to CO exposure in a swine model. Twenty-nine swine (∼10 kg) were assigned to three groups: Sham (n = 10), CO 1000 ppm (n = 8), and CO 2000 ppm (n = 11). Animals in the CO groups were exposed to CO for 120 min followed by 30 min of room air. Cerebral metabolism was assessed using invasive cerebral microdialysis and continuous non-invasive diffuse optical monitoring of cerebral blood flow, oxygenation, and CIV redox state. Following the exposure period, brain tissue was harvested for mitochondrial respiration analysis and western blotting. Severe CO exposure (2000 ppm) produced significant cerebral metabolic impairment, demonstrated by decreased oxidation of cytochrome-c-oxidase, reduced oxygen metabolism, and increased microdialysis markers of metabolic stress including lactate-to-pyruvate ratio and glycerol. In contrast, moderate CO exposure (1000 ppm) resulted in minimal metabolic changes despite elevated carboxyhemoglobin levels. Ex-vivo mitochondrial respirometry also demonstrated impaired mitochondrial respiration in CO-exposed animals. These findings demonstrate greater cerebral metabolic dysfunction with higher CO exposure and suggest that carboxyhemoglobin levels alone may not accurately reflect the degree of cerebral metabolic injury.
Ozone (also known as triatomic oxygen [O₃]) is an allotropic form of oxygen commonly found in the atmosphere. Growing epidemiological and experimental evidence indicates that chronic exposure to environmental ozone (as a pollutant) may worsen systemic disorders, including neurodegenerative processes. Prolonged exposure to atmospheric uncontrolled ozone increases pulmonary production of reactive oxygen and nitrogen species, triggering oxidative damage and a sustained inflammatory state locally and systemically, and leading to multiple alterations, including blood-brain barrier breakdown and microglial dysfunction, mechanisms strongly implicated in neurodegenerative processes. Interestingly, ozone therapy (controlled and non-inhaled) has been used in medicine for its multiple health benefits, including antimicrobial, anti-inflammatory, and antioxidant effects. Thus, it is plausible to consider ozone as a hormetin with potential neuroprotective effects. Additionally, experimental evidence showing its effects in nerve regeneration, including improved structural and functional recovery following facial or sciatic nerve injury, further strengthens the potential of ozone therapy. However, further studies are required to define optimal dosing strategies and administration protocols. Given these findings, the scope of this review is to critically examine and integrate all available evidence on ozone's dual role in neurological and neurodegenerative conditions. By combining mechanistic insights, preclinical and clinical data, this review aims to clarify the complex, bidirectional relationship among ozone exposure, redox biology, neuroinflammation, and neurodegeneration.
Di-(2-ethylhexyl) phthalate (DEHP) is a widespread environmental contaminant linked to endocrine disruption, neurotoxicity, and cognitive aging. However, its effects on hippocampal function in aging populations remain unclear. In this study, 22-month-old male C57BL/6J mice were orally exposed to DEHP (0.2, 20, or 200  mg/kg/day) for 5 weeks to model environmentally relevant and toxicological exposure scenarios. Cognitive performance was evaluated using the Morris water maze and novel object recognition tests, while hippocampal alterations were assessed through histology, immunofluorescence, and molecular analyses. DEHP exposure at higher doses impaired spatial learning and memory, whereas the lowest dose induced subtle molecular changes. Mechanistically, DEHP reduced oligodendrocyte maturation and myelin integrity, inhibited oligodendrocyte precursor cell (OPC) differentiation, and induced local thyroid hormone disruption and neuroinflammation. Notably, DEHP activated the Nogo-A/S1PR2 pathway and its downstream RhoA/ROCK2 signaling, contributing to synaptic deficits marked by decreased PSD95 expression. In summary, subacute DEHP exposure disrupts hippocampal homeostasis in aged male mice by impairing myelin integrity, glial function, and synaptic stability. Activation of the Nogo-A/S1PR2 axis represents a key mechanistic link underlying these effects, providing insight into how environmental phthalates may accelerate age-related cognitive decline.
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.
Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pathophysiology of these disorders. This study aimed to investigate the association between indicators of glial activation (glial fibrillary acidic protein; GFAP) and axonal injury (neurofilament light chain; NfL) in plasma with functional brain connectivity, and externalizing psychopathology (EXT) in a neurodevelopmental cohort. Towards this, a cross-sectional study was conducted with 144 participants selected from the Indian cVEDA cohort and balanced into EXT and healthy control (HC) groups using Mahalanobis distance matching. Plasma GFAP and NfL were quantified using Simoa technology. Resting-state fMRI data were used to generate between-network connectivity deviation scores via normative modelling. We used Gamma General Linear Models (Gamma GLMs) to test for an age-by-EXT interaction on GFAP/ NfL levels and sparse partial least squares (sPLS) regression to identify connectivity features that correlated with them. We found a significant age-by-EXT interaction for GFAP (p = 0.002), where EXT was associated with higher GFAP levels only in younger participants (<14 years). No significant effects were found for NfL. The sPLS analysis identified a significant five-feature brain connectivity signature that correlated with GFAP levels. This pattern was characterized by atypically strong connectivity between sensorimotor-limbic and attention-default mode networks, and weaker-than-expected connectivity within the default mode network. In conclusion, our findings identify a strong association between plasma GFAP and EXT in youth in an age dependent manner, suggesting a key role for glial activation in the early pathophysiology of these disorders. This process is linked to a specific, multivariate pattern of brain dysconnectivity, providing a potential neurobiological signature that warrants further investigation.
Sleep is an important biological function. This article considers practical matters related to the prescription of sedative-hypnotic drugs to patients with insomnia. This article also presents practical suggestions for the management of excessive sedation in patients who need pharmacologic treatments with sedating adverse effects when dose reduction is not an option. Issues examined include the choice of drug for sleep-onset insomnia and for sleep-maintenance insomnia; the choice of drug for insomnia in patients with psychiatric disorders; sedative-hypnotic dosing in contexts such as perturbation of multiple neurotransmitter systems; metabolic drug interactions with sedative-hypnotic drugs; gastrointestinal absorption of hypnotic drugs and time to onset of drowsiness; the effect of food on absorption and time to onset of drowsiness; the effect of glucagon-like peptide-1 receptor agonist (GLP-1RA) drugs on absorption and time to onset of drowsiness; the importance of half-life for the duration of action of the sedative-hypnotic drug; strategies to address oversedation with sedating psychotropic drugs; treating insomnia with classical monoamine oxidase inhibitors, especially tranylcypromine; optimization of sedative-hypnotic therapy; provision of patient guidance; and related matters. Readers are also reminded that sleep hygiene and cognitive-behavioral approaches should routinely be combined with sedative-hypnotic drug therapy to optimize insomnia care and improve treatment outcomes.