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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 \u03b1-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\u2013receptor 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.<\/jats:p>","DOI":"10.1021\/acs.est.5c18533","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T19:43:05Z","timestamp":1782762185000},"page":"20182-20196","source":"Crossref","is-referenced-by-count":0,"title":["Subacute Exposure\nto Macrocyclic Lactone Insecticides\nInduces Parkinson\u2019s Disease-like Motor Deficits and Neuropathology\nin Mice"],"prefix":"10.1021","volume":"60","author":[{"given":"Jinjing","family":"Xiao","sequence":"first","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaijie","family":"Dai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuang","family":"Ye","sequence":"additional","affiliation":[{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengxue","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3653-3450","authenticated-orcid":true,"given":"Haiqun","family":"Cao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-9782","authenticated-orcid":true,"given":"Yanhong","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Agri-products Quality and Biosafety (Anhui Agricultural University), Ministry of Education , , ,","place":["Hefei, Anhui Province, China, 230036"]},{"name":"Anhui Agricultural University , , , ,","place":["Hefei, Anhui Province, China, 230036"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2026072809084678800_cit1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1038\/s43017-025-00673-y","article-title":"Transboundary impacts of pesticide use in food production","volume":"6","author":"Tang","year":"2025","journal-title":"Nat. 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