An approach based on a combination of toxicological experiments and in silico predictions to investigate the adverse outcome pathway (AOP) of paraquat neuro-immunotoxicity

• Published in: Journal of hazardous materials 2024-07, Vol.473, p.134607-134607, Article 134607
• Main Authors: Zhang, Chunhui, Shi, Ge, Meng, Qi, Hu, Rong, Li, Yang, Hu, Guiling, Wang, Kaidong, Huang, Min
• Format: Article
• Language: English
• Subjects: Adverse outcome pathway; Adverse Outcome Pathways; Animals; Brain - drug effects; CD11b Antigen - metabolism; Complement C1q - immunology; Complement C1q - metabolism; Complement C3 - metabolism; Computer Simulation; Early damage; Herbicides - toxicity; Male; Mice; Mice, Inbred C57BL; Microglia - drug effects; Molecular Docking Simulation; Molecular simulation docking; Neuro-immunotoxicity; Neurotoxicity Syndromes - etiology; Neurotoxicity Syndromes - immunology; Neurotoxicity Syndromes - pathology; Paraquat; Paraquat - toxicity; Phagocytosis - drug effects; Synapses - drug effects
• ISSN: 0304-3894; 1873-3336
• DOI: 10.1016/j.jhazmat.2024.134607

Paraquat (PQ) exposure is strongly associated with neurotoxicity. However, research on the neurotoxicity mechanisms of PQ varies in terms of endpoints of toxic assessment, resulting in a great challenge to understand the early neurotoxic effects of PQ. In this study, we developed an adverse outcome pathway (AOP) to investigate PQ-induced neuro-immunotoxicity from an immunological perspective, combining of traditional toxicology methods and computer simulations. In vivo, PQ can microstructurally lead to an early synaptic loss in the brain mice, which is a large degree regarded as a main reason for cognitive impairment to mice behavior. Both in vitro and in vivo demonstrated synapse loss is caused by excessive activation of the complement C1q/C3-CD11b pathway, which mediates microglial phagocytosis dysfunction. Additionally, the interaction between PQ and C1q was validated by molecular simulation docking. Our findings extend the AOP framework related to PQ neurotoxicity from a neuro-immunotoxic perspective, highlighting C1q activation as the initiating event for PQ-induced neuro-immunotoxicity. In addition, downstream complement cascades induce abnormal microglial phagocytosis, resulting in reduced synaptic density and subsequent non-motor dysfunction. These findings deepen our understanding of neurotoxicity and provide a theoretical basis for ecological risk assessment of PQ. [Display omitted] •PQ regulates the response of key signaling factors in the complement cascade.•Molecular docking revealed the interaction between PQ and C1q.•C1q is a key target for the prevention and treatment of PQ-induced neuro-immunotoxicity.•The AOP framework for PQ-induced neuro-immunotoxicity is refined.