A comprehensive review of the neurobehavioral and neurotoxic effects of 6PPD-Q in fish, rodents, and humans.

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.