Tris (1,3-dichloro-2-propyl) phosphate (TDCPP) aggravates Parkinson's disease neurotoxicity through...

Organophosphorus flame retardant TDCPP, a substitute for brominated flame retardants, is widely used in consumer products but readily leaches into the environment, posing human exposure risks. This study investigated the neurotoxic mechanisms of TDCPP in Parkinson's disease (PD). Using an MPTP-induced PD mouse model, TDCPP exposure exacerbated behavioral deficits, reduced tyrosine hydroxylase (TH)-positive neurons in the substantia nigra, and amplified neuroinflammation characterized by enhanced microglial reactivity, elevated pro-inflammatory IFN-γ, and diminished anti-inflammatory IL-4 and regulatory T cells (Tregs). Concurrently, TDCPP lowered glutathione (GSH) levels and altered ferroptosis-related protein expression, indicating oxidative stress involvement. In SH-SY5Y cells, co-treatment with TDCPP and MPTP caused mitochondrial membrane depolarization, increased reactive oxygen species (ROS), and shifted microglia into a pro-inflammatory state-evidenced by increased CD86 expression-and impaired their phagocytic clearance of α-synuclein. These findings demonstrate that TDCPP aggravates PD neurodegeneration through dual mechanisms: ferroptosis-linked oxidative stress and neuroinflammation. This study provides the first evidence linking TDCPP exposure to ferroptosis-mediated neurotoxicity in PD models, bridging environmental toxicology and neurodegenerative research. The results underscore the role of environmental pollutants in PD progression and offer critical insights for refining safety regulations to mitigate human health risks.