Molecular mechanism of dopaminergic neuron injury induced by PAHs: Regulation of AhR-RORα/Nrf2 axis and α-syn O-GlcNAc modification.

Parkinson's disease (PD) ranks second among prevalent global neurodegenerative disorders. It is pathologically characterized by gradual degeneration of midbrain substantia nigra compacta dopaminergic neurons and excessive α-synuclein (α-syn) accumulation forming Lewy bodies. Clinically, patients suffer from motor dysfunctions including resting tremor and muscle stiffness, accompanied by cognitive decline and other non-motor complications, which greatly impair daily life, and there is still no definitive cure. Both genetic predisposition and environmental stimuli jointly drive PD onset. Fine particulate matter PM2.5, a major environmental hazard, carries lipophilic quinone substances capable of crossing the blood-brain barrier and inducing central nervous system injuries. Certain polycyclic aromatic hydrocarbon (PAH) congeners in PM2.5 are highly toxic and produce abundant reactive oxygen species (ROS) to disrupt intracellular signal transduction. This review centers on PD pathogenesis induced by well-studied PAHs and experimental PAH mixtures. In vitro cell assays and in vivo animal studies demonstrate that these tested PAHs aggravate neuronal damage via established suppression of the aryl hydrocarbon receptor (AhR)-retinoid-related orphan receptor α (RORα)-nuclear factor erythroid 2-related factor 2 (Nrf2) signaling axis and emerging evidence of reduced α-syn O-linked β-N-acetylglucosaminylation (O-GlcNAc) modification. Two mutually crosstalk pathways (partially speculative regulatory models) further trigger oxidative stress, mitochondrial damage, abnormal protein deposition and cell apoptosis. Notably, PAHs represent a large and structurally diverse family; the summarized mechanisms are validated based on limited PAH species with distinct toxicity, bioavailability and environmental abundance, and cannot be generalized to all PAH congeners. further triggering oxidative stress, mitochondrial damage, abnormal protein deposition and cell apoptosis. The paper also clarifies the crosstalk and positive feedback between the two pathways, summarizes targeted therapeutic strategies and research prospects, aiming to lay theoretical and experimental foundations for exploring environmental pollutant-related PD etiology, prevention and clinical treatment.