Microplastics (MPs) and nanoplastics (NPs) are pervasive environmental contaminants increasingly investigated for their potential neurotoxicological relevance. This narrative review critically evaluates experimental and emerging human evidence linking plastic exposure to microbiota–gut–brain communication and brain-related vulnerability. MPs and NPs are considered separately because differences in particle size, surface properties, cellular uptake, barrier interactions, and biodistribution constrain toxicological extrapolation across particle classes. Controlled animal studies provide the strongest mechanistic evidence, reporting microbiota compositional and metabolic perturbations, intestinal barrier alterations, systemic inflammatory signaling, neurovascular effects, and neurobehavioral changes under defined exposure conditions. However, these findings are limited by heterogeneous particle characterization, frequent use of pristine model particles, uncertain dose relevance, variable study quality, and incomplete distinction between intrinsic particle effects and toxicity associated with additives or co-contaminants. Evidence for a sequential microbiota–barrier–lipopolysaccharide–neuroinflammation pathway remains incomplete, and individual components should be interpreted as interacting candidate mechanisms rather than an established causal cascade. Human evidence is substantially weaker and is dominated by biomonitoring, post-mortem detection, and early observational associations that cannot establish parenchymal brain exposure or causality for neuropsychiatric or neurodegenerative disease. Progress will require environmentally representative particle libraries, chronic low-dose and route-specific models, spatial validation of brain entry, harmonized contamination-controlled biomonitoring, longitudinal human cohorts, explicit causal frameworks, and validated multi-omic integration. Current evidence therefore supports MPs and NPs as candidate environmental modifiers of neurobiological vulnerability rather than established human neurotoxicants.
Background Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers. Prenatal OPE exposure has been associated with adverse childhood neurodevelopment, but these outcomes are not often evaluated until well into childhood. We leveraged infants’ innate preference for faces to evaluate gestational OPE exposure in relation to an early measure of cognitive processing. Methods We measured nine mid-pregnancy urinary OPE metabolites in a U.S. UPSIDE pregnancy cohort (n = 166). At age 1 month, infants were presented with a randomized series of three face-like images: standard features, scrambled features, and a featureless face shape. Using latent profile analysis, we identified three looking profiles (short, long, and selective lookers). We evaluated associations with OPE metabolites using multivariable multinomial logistic models. OPEs with > 70% detection were considered continuously; less prevalent OPEs were dichotomized. Results Infants of mothers with detectable bis(2-methylphenyl) phosphate had greater odds of being long vs. short lookers (OR: 2.80, 95% CI: 0.99, 7.96), with stronger associations observed among females. Among boys, higher maternal dibutyl phosphate + di-isobutyl phosphate exposure was associated with 6 times the odds of being a long looker (OR: 6.05, 95%CI: 1.05, 34.92). Among girls, detectable maternal dipropyl phosphate was associated with lower odds of being a long (OR: 0.01, 95% CI: 0.001, 0.75) or a selective looker (OR <0.001, 95% CI: <0.001, 0.05). Conclusion Prenatal OPE exposure may influence early face-processing, potentially in a sex-dependent manner. Follow-up is needed to assess this measure’s ability to predict downstream neurodevelopmental outcomes.
Microplastics (MPs) and nanoplastics (NPs) (MNPs) have been linked to various health risks, but their presence in the human brain and association with Alzheimer’s disease (AD)-related pathological proteins remain poorly understood. In this study, superior temporal gyrus tissues of 16 northeast Chinese postmortem donors were analyzed via pyrolysis-gas chromatography-mass spectrometry (Py-GC/MS) and laser direct infrared spectroscopy (LDIR) to characterize MNPs, while AD-related pathological proteins Aβ and p-tau levels in the hippocampus were detected by immunohistochemical staining and quantified by H-score. Py-GC/MS quantification revealed polymers corresponding to polyethylene (PE), polyvinyl chloride (PVC), polystyrene (PS) and polypropylene (PP) in all samples, with PE as the dominant type (63.3% of total polymers concentrations). The overall mean concentration of these four polymers was 105.70 μg/g ranging from 24.69 μg/g to 184.77 μg/g. LDIR of four selected samples further identified 17 additional types of MPs besides the aforementioned four; additionally, 80.8% of MPs had diameters smaller than 60 μm, and 84.7% were spherical and irregular in shape. Exploratory multiple linear regression suggested positive associations of PE and PS with Aβ levels. This study provided evidence of plastic polymers in fresh human brain tissue and established a preliminary association between polymers burden and AD-related pathological proteins, might provide a valuable basis for future studies investigating the association between MNPs and AD.
The prolonged neuroparalytic effect of botulinum neurotoxin type A (BoNT/A) is largely attributable to the high intracellular stability of its light chain (LC), highlighting the need for strategies to promote LC clearance. Although deubiquitinating enzymes (DUBs) regulate LC turnover through both proteasomal and non-proteasomal pathways, the latter remains poorly understood. Here, we investigated the role of the DUB USP9X in regulating LC stability. Using a stable LC-overexpressing cell model, we found that pharmacological inhibition of USP9X with Degrasyn markedly promoted LC clearance. Transcriptomic analysis following lentivirus-mediated USP9X knockdown revealed enrichment of autophagy-related pathways, accompanied by suppression of PI3K-AKT signaling. Mechanistically, USP9X knockdown did not affect total mTOR protein levels but suppressed AKT-mTOR signaling, as shown by reduced phosphorylation of AKT and mTOR. This was associated with decreased ULK1 phosphorylation at the inhibitory site Ser757, increased phosphorylation at the active site Ser555, elevated p-AMPK levels, increased LC3-II/LC3-I ratio, and reduced p62 levels. All of those pointed to enhanced autophagic activity in response to USP9X inhibition. In BoNT/A-intoxicated rats, chloroquine-mediated autophagy inhibition delayed recovery from paralysis, whereas rapamycin-induced autophagy activation accelerated muscle strength recovery. Consistently, systemic administration of Degrasyn promoted functional recovery. Collectively, these findings indicate that USP9X inhibition promotes intracellular LC clearance, likely through an autophagy-lysosome-dependent mechanism involving suppression of AKT-mTOR signaling and activation of AMPK-ULK1-related pathways. Our study identifies USP9X as a host negative regulator of LC clearance and a potential therapeutic target for accelerating recovery following botulinum toxin intoxication.
