The involvement of the Wnt/β-catenin signaling cascade in tris(1,3-dichloro-2-propyl) phosphate induces nigrostriatal system degeneration.

Tris (1,3-dichloro-2-propyl) phosphate (TDCIPP), a widely used organophosphorus flame retardant (OPFR), is frequently detected in human brain tissue. The nigrostriatal dopaminergic system serves as a critical and vulnerable target for neurotoxic pollutants, raising concerns about its potential toxicity. However, the impact of TDCIPP on this system and its underlying mechanisms remain unknown. Herein, we investigated the neurotoxic effects of TDCIPP exposure on the nigrostriatal system in C57BL/6 mice, focusing on neuronal apoptosis. This study demonstrates that TDCIPP exposure induces movement disorder and anxiety-like behavior. These effects are associated with the loss of dopaminergic neurons, characterized by the reduction of tyrosine hydroxylase expression in the substantia nigra pars compacta, and a decreased in dopamine. Mechanistically, TDCIPP triggers dopaminergic neuronal apoptosis, evidenced by mitochondrial cristae disruption, chromatin condensation, and an elevated Bax/Bcl-2 ratio. Transcriptomic profiling identified the Wnt/β-catenin pathway as among the candidate pathways potentially involved in the regulation of TDCIPP-induced neuronal apoptosis, with molecular docking further suggesting a potential interaction with Wnt1. Notably, activation of this pathway by the agonist alsterpaullone partially mitigated TDCIPP-induced neurotoxicity in vitro, suggesting that targeted activation of this pathway may confer neuroprotection. Collectively, these findings establish a novel mechanistic link whereby TDCIPP impairs Wnt/β-catenin signaling via direct interaction with Wnt1, thereby inducing apoptotic loss of dopaminergic neurons and subsequent movement disorder, thus providing a potential intervention target for OPFR-induced neurotoxicity.