Subacute Exposure to Macrocyclic Lactone Insecticides Induces Parkinson’s Disease-like Motor Deficits and Neuropathology in Mice

Evidence links multiple environmental contaminants to an increased risk of Parkinson’s disease (PD), yet the identification of PD-relevant pesticides, particularly their combined effects, remains largely unexplored. Herein, we found that subacute exposure to the macrocyclic lactone abamectin or emamectin benzoate via ingestion induced PD-like motor dysfunction and dopaminergic neurodegeneration in mice. These adverse effects were associated with excessive α-synuclein aggregation, dopamine depletion, dopaminergic neuron loss, mitochondrial degeneration, mitochondrial membrane depolarization, and inflammatory responses in the substantia nigra/striatum, and this pathological profile resembled that induced by the known PD toxicant rotenone. We therefore used SH-SY5Y cells to further examine the combined effect of their coexposures and observed potential synergistic/additive effects in vitro . Integrated Biomarker Responses version 2 (IBRv2) analysis identified mitochondrial dysfunction as a key event underlying combined cytotoxicity. Multiomics analyses of differentially abundant metabolites and proteins suggested that the combined cytotoxicity is associated with mitochondrial Ca 2+ overload, extracellular matrix–receptor interactions, ferroptosis, reactive oxygen species accumulation, and mitogen-activated protein kinase (MAPK) signaling, which may collectively contribute to oxidative stress and mitochondrial metabolic dysfunction. These findings offer updated insights into pesticide risks and guidance for pesticide reasonable application.