Early-Life Rotenone Exposure Enhances Nigrostriatal Vulnerability and Parkinsonian Neurodegeneration in Aging Rats

Environmental exposure to neurotoxicants during critical developmental windows may program long-term susceptibility to neurodegenerative diseases such as Parkinson’s disease. Here, we investigated whether rotenone exposure during neurodevelopment induces a more severe Parkinsonian phenotype during aging than adult-onset exposure. Wistar rats were exposed to rotenone (1 mg/kg/day) either during gestation and lactation or from postnatal day 60 to 102. Motor performance was assessed longitudinally, and neurobiological analyses were conducted at 12 months of age. Developmental rotenone exposure induced persistent and severe motor deficits from early adulthood, whereas adult exposure resulted in a progressive phenotype. These alterations were accompanied by greater loss of tyrosine hydroxylase-positive dopaminergic neurons and a marked reduction in Nurr1 expression in the substantia nigra. Developmental exposure also increased cellular senescence, dendritic atrophy and spine loss in striatal medium spiny neurons, insoluble α-synuclein accumulation, and global DNA hypomethylation. Despite low residual serum rotenone levels, neurodegenerative alterations persisted, supporting a hit-and-run mechanism. These findings suggest that early-life rotenone exposure induces long-lasting epigenetic and cellular reprogramming that enhances nigrostriatal vulnerability and accelerates Parkinsonian neurodegeneration during aging.