Chronic noise exposure is associated with cardiovascular and mental health outcomes, yet its neurobiological effects remain poorly characterized. MRI-based brain-age models estimate structural brain aging, but their sensitivity to environmental and occupational noise exposure has not been systematically evaluated. We examined associations of environmental and occupational noise exposure, separately and in combination, with brain age gap (BAG) across six MRI-based brain-age prediction models. We analyzed 108 Korean hospital workers who underwent high-resolution three-dimensional T1-weighted magnetic resonance imaging. Residential environmental noise exposure was classified as high when daytime noise was ≥60 dB or nighttime noise was ≥55 dB. Because no participant had occupational noise exposure ≥85 dBA as an 8-h time-weighted average, occupational exposure was categorized as relatively lower or higher using the cohort-specific median. BAG was calculated as predicted brain age minus chronological age using brainageR, XGBoost, ENIGMA, pyment, DenseNet, and TSAN models. Primary analyses used covariate-adjusted linear models for BAG, controlling for age, sex, and intracranial volume. Age-bias-corrected and Z-standardized brain-age advancement (BAA) was used for descriptive joint-exposure visualization and exploratory trend analysis. High environmental noise exposure was associated with a less negative BAG in the TSAN model than low environmental noise exposure (−8.1 vs. −12.1 years; p = 0.0036), indicating a relatively older-appearing brain. Daytime and nighttime environmental noise levels were positively correlated with TSAN-derived BAG (Spearman's rho = 0.253, false discovery rate-adjusted p = 0.008; rho = 0.215, false discovery rate-adjusted p = 0.025, respectively). Occupational noise exposure alone was not significantly associated with BAG in any model. No environmental-noise-by-occupational-noise interaction remained statistically significant after false discovery rate correction. In an exploratory TSAN analysis, each additional high-exposure domain was associated with a 0.27-standard-deviation increase in BAA (95% confidence interval, 0.01 to 0.59; p for trend = 0.048). Environmental noise exposure was associated with relatively older-appearing brain structure in the TSAN model, whereas occupational noise exposure alone was not consistently associated with BAG. Concurrent environmental and relatively higher occupational noise exposure showed a model-specific joint-exposure burden gradient but did not provide formal evidence of synergistic or non-additive effects. Larger longitudinal studies are needed to replicate these findings and clarify the utility of brain-age measures in environmental and occupational health research.
N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine (6PPD) is a widely used tire additive that undergoes environmental transformation to 6PPD-quinone (6PPD-Q), which is ubiquitously detected in environmental matrices. Increasing evidence demonstrates that exposure to 6PPD-Q adversely affects organisms through neurobehavioral disruption and neurotoxicity. While studies document behavioral abnormalities and molecular alterations, a comprehensive synthesis linking these outcomes remains limited. The objective of this review was to synthesize current literature reporting neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans using experimental and computational approaches. Using PRISMA guidelines, a search was conducted in PubMed and Google Scholar using several key phrases related to 6PPD-Q and neurotoxicity, capturing 1874 records. Relevant articles were assessed by full-text review for criteria eligibility, and the final review included 27 articles. In fish, exposure to 6PPD-Q can alter neurobehaviors like locomotor activity, anxiety-like responses, social and aggressive behaviors, and disturbances in circadian-regulated activities. Such behavioral outcomes correspond closely with neurotransmitter imbalance, neuroendocrine disruption, blood-brain barrier dysfunction, and transcriptome changes affecting neural signaling pathways. In rodents, repeated or chronic exposure to 6PPD-Q leads to neuronal damage, cognitive impairment, anxiety-like behavior, and memory deficits. Human biomonitoring and mechanistic studies further associate 6PPD-Q exposure with oxidative stress, mitochondrial dysfunction, and molecular responses relevant to neurological diseases. Leveraging the Comparative Toxicogenomics Database, computational analysis revealed entities associated with 6PPD-Q in the database were related to Alzheimer's disease, dopaminergic synapses, neurotrophin signaling pathways, and Parkinson's disease. Taken together, data suggests that 6PPD-Q may interfere with neuronal signaling, connectivity, and plasticity, leading to behavioral deficits. Based on predictive docking scores using fish, rodent, and human orthologs, 6PPD-Q may interact with tyrosine hydroxylase and L-dopa decarboxylase which can potentially lead to disrupted dopamine biosynthesis pathways. Given the widespread environmental presence of 6PPD-Q and its continuous introduction into aquatic ecosystems, characterizing such mechanisms is critical for improving ecological and human health risk assessments.
Developmental and adult neurotoxicity testing is an integral part of safety assessment guidelines. A key endpoint, typically performed in rodents, is the evaluation of learning and memory (L&M). Historically, a variety of equipment and testing paradigms have been developed and used across the industry. In recent years, regulatory guidance documents have become more prescriptive and stipulate specific types of tests to be used at different ages. The most common L&M tests for developmental neurotoxicity are performed using water mazes. Navigational L&M can be split into two principal types where animals use external visual cues from the surrounding environment for allocentric navigation (tested in a Morris water maze), and internal cues for egocentric navigation (tested in multiple T-mazes, such as the Biel or Cincinnati water maze, when performed in complete darkness [under infrared lighting]). With increasing degrees of light and the consequent visibility of distal cues, there is a shift towards a combination of egocentric and allocentric navigation. This paper provides methodological details of a practical screening test for L&M for juvenile, young-adult and mature rats using a modified Biel water maze under red light, which has been validated using a positive control across multiple Charles River facilities. Other available water mazes, such as Cincinnati and Morris water mazes have limited proficiency in weanling (PND 21–22) rodents. This manuscript illustrates that the modified Biel water maze can be used to screen for deficits in learning and memory in juvenile (weanling) rats, as well as at older life stages, in compliance with published regulatory guidelines for safety assessment studies.
Aim Cannabis use during pregnancy has increased, raising concerns about potential effects on offspring brain development. The objective of this systematic review was to evaluate MRI-based evidence on the association between prenatal cannabis exposure (PCE) and offspring brain development across structural, diffusion, resting-state functional, and task-based functional MRI. Methods Following PRISMA guidelines, PubMed, Web of Science, and Embase were searched through September 4, 2026, for MRI studies comparing prenatally exposed offspring with non-exposed controls across any modality. Study quality was assessed using Joanna Briggs Institute tools, and certainty of evidence was evaluated using the GRADE framework. Results Eighteen studies (2004–2026) met inclusion criteria, with participants ranging from the fetal period to young adulthood. Structural MRI showed no consistent global brain-volume reductions, although some studies reported region-specific differences, particularly in frontal regions and intracranial-volume trajectories. Diffusion MRI identified alterations in selected white-matter pathways, including frontolimbic and corticostriatal tracts, but findings were inconsistent and not uniformly replicated. Resting-state functional MRI studies showed heterogeneous connectivity differences across hippocampal, salience, thalamic, and auditory networks, and task-based functional MRI studies reported variable reward- and executive-control activation, including some null findings. Overall certainty of evidence was low to very low because of risk of bias, inconsistency, imprecision, residual confounding, and methodological heterogeneity. Interpretation PCE may be associated with subtle, regionally specific differences in brain structure, microstructure, and function rather than consistent global abnormalities. However, structural MRI showed no consistent global abnormalities, diffusion MRI findings were inconsistent, and resting-state and task-based fMRI findings were heterogeneous. Causal interpretation remains limited by confounding, cohort overlap, exposure assessment, and methodological heterogeneity.
Miroplastic (MP) pollution which affects both humans and animals, has emerged as a global health concern. Evidence from in vivo rodent studies, in vitro human cell models, and multi-omics analyses indicates that ingested and inhaled MPs can accumulate in the gastrointestinal tract, cross epithelial barriers, and alter host–microbe interactions. Nanoplastics (NPs, <1 μm), owing to their small size and high surface-area-to-volume ratio, may exhibit greater cellular uptake, tissue translocation, and neurotoxic potential than larger MPs. These processes contribute to systemic effects, including immune activation, oxidative stress, and metabolic dysregulation. Recent studies suggest that MPs influence gut–brain communication, with changes in microbiota composition, neurotransmitter metabolism, and neuroinflammatory signaling linked to cognitive and behavioral deficits in animal models. Promising interventional strategies—including fecal microbiota transplantation (FMT), probiotic supplementation (e.g., Lactobacillus plantarum), and bile acid therapy—have shown efficacy in mitigating MP/NP-induced neurotoxicity in preclinical models. Particle size, surface chemistry, and eco-corona formation modulate these effects, highlighting the importance of physicochemical heterogeneity. Despite progress, translating findings from animals to humans remains challenging, and standardized exposure models are lacking.
