Subacute Exposure to Macrocyclic Lactone Insecticides Induces Parkinson's Disease-like Motor Deficits and Neuropathology in Mice.
Subacute Exposure to Macrocyclic Lactone Insecticides Induces Parkinson's Disease-like Motor Deficits and Neuropathology in Mice.
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Hefei, CN · Author affiliation
Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, Anhui Province230036, China.Location evidence
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Original abstract
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 Ca2+ 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.