6PPD-Quinone Induces Anxiety-like Behavior in Mice: A Potential Mechanism Shared Across PPD-Quinones.
- 1Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, School of Public Health, Southeast University, Nanjing 210009, China.
- 2State Key Lab of Reproductive Medicine and Offspring Health, Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
Abstract
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.
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BibTeX
@article{xu20266ppdquinone,
title = {{6PPD-Quinone Induces Anxiety-like Behavior in Mice: A Potential Mechanism Shared Across PPD-Quinones.}},
author = {Su Xu and Leyan Gao and Yongquan Yu and Ying Kang and Xinting Chen and Shou-Lin Wang and Zengliang Ruan},
journal = {Toxics},
year = {2026},
month = oct,
doi = {10.3390/toxics14100909},
url = {https://europepmc.org/article/MED/42931696},
note = {CC BY},
}
RIS
TY - JOUR
TI - 6PPD-Quinone Induces Anxiety-like Behavior in Mice: A Potential Mechanism Shared Across PPD-Quinones.
AU - Su Xu
AU - Leyan Gao
AU - Yongquan Yu
AU - Ying Kang
AU - Xinting Chen
AU - Shou-Lin Wang
AU - Zengliang Ruan
PY - 2026
DA - 2026/10/14
JO - Toxics
DO - 10.3390/toxics14100909
UR - https://europepmc.org/article/MED/42931696
AB - 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.
SN - 2305-6304
ER -