6PPD-Quinone Induces Anxiety-like Behavior in Mice: A Potential Mechanism Shared Across PPD-Quinones

The increasing occurrence of anxiety disorders caused by emerging environmental toxicants has become a significant global health concern. While recent evidence indicates that 6PPD-Q can induce anxiety-like behavior, the specific mechanisms connecting 6PPD-Q to anxiety-like behavior are still largely unknown. This gap in understanding restricts our knowledge of their neurotoxic potential and complicates the development of targeted treatment strategies. Here, adverse effects, including neuronal degeneration, synaptic dysfunction, and impaired GABAergic signaling in the amygdala, were observed in mice exhibiting anxiety-like behavior following 6PPD-Q exposure. Integrated network toxicology and transcriptomic analysis revealed that inhibition of the cAMP signaling pathway was associated with PPD-Q-related anxiety-like behavior, and adenosine receptors, particularly ADORA2A, as potential targets of 6PPD-Q. Specifically, molecular docking and molecular dynamics simulations suggested that 6PPD-Q may stably interact with the orthosteric ligand-binding pocket of ADORA2A, potentially interfering with receptor activation. Importantly, the predicted interaction with ADORA2A may represent a potentially shared neurotoxicological feature among PPD-Qs, consistent with the computationally predicted interaction profiles across PPD-Qs. Moreover, pharmacological activation of ADORA2A with the selective agonist significantly alleviated the 6PPD-Q-induced neurobehavioral deficits in mice. Collectively, our research provides evidence supporting the involvement of ADORA2A and the cAMP-related signaling pathway in 6PPD-Q-induced anxiety-like behavior, providing a timely foundation for preventing neuropsychiatric disorders associated with PPD-Q exposure.