Evaluation of neurotoxicity of neonicotinoid insecticides using lipidomics

Neonicotinoid (NN) pesticides are widely used globally, but recent studies suggest that even nontoxic doses can induce anxiety-like behaviors and alter brain monoamine neurotransmitter levels in mice. Current neurotoxicity assays may fail to detect subtle toxic effects, such as higher brain function abnormalities caused by small molecule disruptions. These findings highlight the need for highly sensitive and reproducible neurotoxicity testing methods. The brain, a lipid-rich organ, relies on lipids for various functions, and disturbances in lipid homeostasis are linked to numerous diseases. This study uses lipidomics to analyze the cerebral cortex of mice exposed to the NN acetamiprid (ACE), aiming to identify lipid biomarkers of neurotoxicity. Thirty 12-week-old male C57BL/6J mice were randomly divided into control (0 mg/kg), low dose (65 mg/kg), and high dose (130 mg/kg) groups, with 10 mice in each group. Mice were euthanized, and cerebral cortex samples were collected 30 min after oral ACE administration. Lipids were extracted and analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry. A total of 358 lipids were annotated. Fifteen lipids exhibited a fold-change > 2.0 and significant differences between control and high-dose groups, with an area under the curve ≥ 0.900 in receiver operating characteristic analysis. Increased levels of seven fatty acids (FAs; e.g., palmitic acid) and five fatty acyl esters of hydroxy FAs (e.g., FAHFA 22:6_22:5) were observed, suggesting roles in neurodegenerative diseases and inflammation. These findings identify a promising lipid biomarker linked to NN-induced neurotoxicity and contribute to detecting neurotoxic effects from acute exposure to such substances.