2,4-dichlorophenoxyacetic acid (2,4-D) potentiates vanadium-induced Parkinsonian neurodegeneration: Evidence from mitochondrial bioenergetic dysfunction and dopaminergic and GABAergic neurodegeneration.

Vanadium is a critical earth element with broad application in modern technologies, particularly in energy storage systems and in steel production. 2,4-dichlorophenoxyacetic acid (2,4-D) is a synthetic auxin herbicide and one of the most widely applied agrochemicals globally. The extensive industrial and agricultural utilization of these chemicals has increased their environmental co-exposure, given that humans are rarely exposed to single chemical stressors. Parkinson's disease (PD) is a neurodegenerative disorder, pathologically characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. PD is the second most prevalent neurodegenerative disease globally, and understanding its pathogenic environmental contributors and mechanisms is a major priority. We investigated the effects of V and 2,4-D individually, and in combination at relevant environmental doses, on Parkinsonian-related symptoms and mitochondrial endpoints in the Caenorhabditis elegans model. Our data showed that developmental co-exposure of C. elegans to 2,4-D and V for 72 h resulted in sublethal survival but led to more severe dopaminergic and GABAergic neurodegeneration and α-synuclein aggregation than individual exposures. High-resolution respirometry analysis of the mitochondria further revealed that V and 2,4-D mixtures induced mitochondrial dysfunction by jointly impairing complex I and II-linked oxidative phosphorylation (OXPHOS) and electron transport system (ETS) capacities. Collectively, our novel findings demonstrate that 2,4-D potentiates V-induced neurotoxicity via amplifying oxidative stress and mitochondrial respiratory dysfunction, exacerbating Parkinsonian phenotypes in C. elegans.