Chronic exposure to the tire-wear contaminant 6-PPDQ induces senescence-associated biomarkers and neurobehavioral deficits: Involvement of ABL1-p53-autophagy signaling.

While 6-PPD quinone (6-PPDQ) is known for its acute lethality to salmonids, its chronic impacts on non-target species remain elusive. Here, we evaluated the chronic toxicity of 6-PPDQ across multiple biological models. Our results demonstrate that 6-PPDQ exposure significantly curtailed the survival and physiological motility of the nematode Caenorhabditis elegans, while inducing cellular senescence-associated biomarkers and a secretory phenotype (SASP) in human MRC-5 cells. In adult zebrafish, chronic exposure over a 28-month follow-up window precipitated cognitive and neurobehavioral deficits, characterized by impaired spatial learning, elevated agonistic reactivity, and glutamatergic excitotoxicity. Through computational screening, molecular docking, and pharmacological rescue, we identified ABL1 as a prioritized candidate target and functional mediator of 6-PPDQ toxicity. Total ABL1 protein abundance was elevated in exposed zebrafish brains alongside p53 accumulation and autophagic substrate (p62 and LC3-II) retention. Importantly, concurrent treatment with the ABL1 kinase inhibitor nilotinib attenuated p53 induction, restored autophagic flux, and rescued locomotor deficits, implicating the ABL1-associated pathway in these phenotypes. Because overt organismal morbidity was manifest predominantly at upper-bound exposure concentrations (10 µg/L), these phenotypes reflect chronic toxic stress rather than an acceleration of natural aging. These findings identify an ABL1-associated mechanism of chronic neurotoxicity and emphasize the need to assess long-term neurological risks associated with tire-wear pollution.