Life-cycle exposure to tris(2-butoxyethyl) phosphate at environmentally relevant concentrations induces progressive Parkinsonian-like neurodegeneration via lysosomal dysfunction in Caenorhabditis elegans

Environmental contaminants are increasingly recognized as key risk factors for chronic diseases, including neurodegenerative disorders. Tris(2-butoxyethyl) phosphate (TBOEP) is a representative organophosphate ester that is widely detected in environmental matrices and human tissues, yet whether chronic exposure to environmentally relevant concentrations of TBOEP drives progressive neurodegenerative pathology remains unclear. Here, using Caenorhabditis elegans as a model organism, we performed a 20-day, time-resolved life-cycle exposure to environmentally relevant concentrations of TBOEP (50-5000 ng/L) to systematically assess chronic neurotoxicity. TBOEP exposure induced progressive, age-dependent neurodegenerative phenotypes. Early effects were characterized by selective impairment of locomotor performance starting at 50 ng/L, followed by broader systemic toxicity, including growth retardation, feeding deficits, and accelerated aging. Consistent with a Parkinson's disease-like trajectory, hallmark pathological features progressively worsened with exposure duration, including dopamine-dependent functional impairment, while α-synuclein aggregation and dopaminergic neuronal impairment were mainly observed at concentrations ≥ 500 ng/L. Mechanistically, time-resolved transcriptomics identified the lysosomal pathway as a central target of TBOEP. Functional assays further confirmed that TBOEP significantly impaired lysosomal acidification. Pharmacological validation with the lysosomal chaperone ambroxol showed that improving lysosomal function mitigated TBOEP-induced neurotoxicity, supporting lysosomal dysfunction as a primary contributor to the observed pathology. Collectively, our findings identify TBOEP as a potential environmental risk factor for neurodegeneration, providing important insights that could inform further studies assessing the environmental health risks of organophosphate esters.