Qiyang Pan

As an emerging tire wear-derived environmental contaminant, 6PPD-quinone (6PPDQ) has raised significant concerns regarding its neurotoxic potential, particularly for children exposed to recycled tire crumb rubber in playgrounds. However, the molecular mechanisms by which 6PPDQ influences neurological disorders such as epilepsy remain poorly understood. In this study, we employed an integrative framework combining network toxicology, bulk analysis of human epileptic brain tissues, Mendelian randomization, and molecular dynamics simulations to elucidate these mechanisms. Our findings, validated through CETSA-WB and SPR, identify 6PPDQ as a direct ligand that binds to and stabilizes neuronal TP53. Through a synergistic double-hit mechanism, 6PPDQ directly engages the TP53 pathway while simultaneously triggering microglial interleukin-6 secretion. These converging pathways lead to the suppression of the master antioxidant regulator Nrf2, resulting in glutathione depletion, excessive reactive oxygen species accumulation, and exacerbated neuronal damage under excitotoxic stress. Experimental validation using glutamate-induced HT22 cell models and microglia–neuron crosstalk systems confirmed that targeting the TP53/Nrf2 axis or scavenging ROS significantly attenuates 6PPDQ-induced neurotoxicity. Our findings highlight critical risks to pediatric neurological health posed by tire-derived contaminants and identify the TP53/Nrf2 axis as a promising therapeutic target. Furthermore, this work provides a robust scientific basis for refining risk assessment frameworks and developing regulatory strategies to mitigate environmental exposure to 6PPDQ.

Objectives: Sleep disturbance is common in depressed adolescents and may be linked to impaired daytime functioning, particularly among those with non-suicidal self-injury (NSSI). We examined associations between sleep characteristics and moderate/severe daytime functional impairment in depressed adolescent outpatients with NSSI. Methods: In this cross-sectional study, depressed adolescent outpatients with NSSI completed self-report measures of sleep over the past month. Daytime functional impairment was assessed using item 8 of the sleep questionnaire. For group comparisons, impairment was dichotomized as no/mild versus moderate/severe. For multivariable analyses, impairment was modeled as an ordinal outcome (none/mild, moderate, severe) using ordinal logistic regression, adjusting for age, sex, sleep duration, and depressive (BDI) and anxiety (BAI) symptom severity. Results: Among participants with available impairment data ( n = 99), 74.7% reported moderate/severe daytime impairment. The moderate/severe group reported shorter sleep duration and greater insomnia symptom burden than the no/mild impairment group. In multivariable analyses including both insomnia symptom burden and sleep duration, greater insomnia symptom burden was independently associated with higher odds of being in a more severe category of daytime functional impairment (OR = 1.83, 95% CI 1.42–2.36; p <.001), whereas sleep duration was not independently associated. Other sleep metrics were not independently associated after adjustment. Conclusions: Daytime functional impairment is highly prevalent in this high-risk adolescent population. The findings suggest that the subjective burden of insomnia symptoms—rather than sleep quantity alone—may be more strongly associated with functional impairment, independent of depressive and anxiety symptom severity. Targeted screening and intervention for insomnia symptoms may be important for improving daytime functioning and quality of life in adolescents with depression and NSSI. Clinical trial number: Not applicable.

With rapid industrial expansion, air pollution’s adverse neurological effects have gained increasing attention. Children face a greater risk of neurological damage because of their higher breathing rates, developing brains, and limited ability to detoxify harmful substances. Fine particulate matter has been identified as a primary neurotoxic contributor affecting developing brains. Strong evidence connects environmental pollutant exposure to the prevalence of Autism Spectrum Disorder (ASD), a neurodevelopmental condition marked by lasting difficulties with social communication and interaction. This study explores the association between long-term PM_2.5 exposure and ASD symptom exacerbation, investigating underlying mechanisms. We hypothesize that long-term PM_2.5 exposure exacerbates ASD symptoms through neuroinflammatory activation, leading to neuronal damage and impaired synaptic plasticity. Our investigation employs three complementary approaches: First, integrated analysis combining Global Burden of Disease data with Mendelian randomization demonstrates a significant association between PM_2.5 exposure and increased ASD severity risk. Second, utilizing the China High-Resolution Air Pollution Database in conjunction with cohort studies, we provide evidence that ambient air pollution substantially influences autism severity, with PM_2.5 identified as the predominant environmental determinant. Third, through network toxicology, single-cell transcriptomics, and animal experimentation, we demonstrate that chronic PM_2.5 exposure exacerbates valproic acid-induced autism-like behaviors in murine models, identifying CTNNB1, PTEN, CCR2, AKT1, and mTOR as potential core mediating genes. Importantly, these findings represent preliminary results. Several potential confounding factors such as co-exposure to other pollutants and socioeconomic variables have not been fully addressed. While our multi-modal approach provides converging lines of evidence, further validation in larger, more diverse populations with refined control of confounders will be essential to establish causality and elucidate mechanisms. Nonetheless, these early insights advance our understanding of PM_2.5-induced neurotoxicity in the context of ASD and offer timely, albeit preliminary, evidence to inform public health policy.