Chronic Methyl tert-butyl ether exposure disrupts neurodevelopment and selectively impairs dopaminergic neurons

Methyl tert-butyl ether (MTBE) is a widely detected environmental contaminant, especially in the water; however, its impact on brain development remains poorly defined. Here, we show that chronic exposure to MTBE (15mg/mL in drinking water) beginning during embryonic development (E9.5) and continuing post-weaning for 18 weeks disrupts neuronal homeostasis and induces long-lasting alterations in dopaminergic neurons and behavior in C57BL/6J mice. In primary neuronal cultures, MTBE suppresses neuronal proliferation, increases apoptotic cell death, and impairs neurite outgrowth, indicating direct neurodevelopmental toxicity. In vivo, MTBE exposure resulted in a reduction of tyrosine hydroxylase-positive dopaminergic neurons, with preferential vulnerability in the ventral tegmental area. Notably, MTBE exposure was associated with increased amyloid precursor protein/β-amyloid-related pathology, suggesting involvement of molecular pathways linked to neurodegeneration. MTBE-exposed mice exhibited consistent motor impairments across multiple behavioral paradigms. Taken together, the results in this study identify MTBE as a developmental neurotoxicant that selectively compromises dopaminergic systems and establishes long-term neurological vulnerability. Therefore, it provides a potential link between environmental exposure and neurodegeneration-related processes.