TY - JOUR
T1 - Spatial lipidomics and metabolomics reveal brain region-specific metabolic dysregulation in mice exposed to the emerging persistent organic pollutant methoxychlor
AU - Wang, Fuyue
AU - Chen, Yanyan
AU - Lin, Siyi
AU - Wang, Xiaoxiao
AU - Su, Xiuli
AU - Cao, Guodong
AU - Zhang, Jing
AU - Dai, Qingyuan
AU - Wang, Jianing
AU - Yan, Hong
AU - Cai, Zongwei
N1 - This work was supported by the Collaborative Research Fund (No. C2011–21GF) and Start-up Grant for New Academics of Hong Kong Baptist University (HKBU), 165520. We gratefully thank Ms. Kristle Ho for her help in using the Agilent GC-QQQ instrument. We would also like to express our gratitude to Dr. Yingyan Zhou for her assistance in the data analysis of mass spectrometry imaging.
Publisher Copyright:
© 2025 Published by Elsevier B.V.
PY - 2025/10/5
Y1 - 2025/10/5
N2 - Methoxychlor (MXC), an organochlorine pesticide, is an emerging persistent organic pollutant of significant environmental concern due to its notable persistence and bioaccumulation. While compelling evidence supports its neurotoxic effects, the underlying molecular mechanisms remain unclear and warrant systematic investigation. This study establishes an integrated spatial molecular platform combining matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) with lipidomics and metabolomics to investigate region-specific neurotoxic mechanisms in mouse brain tissues. Following 90-day exposure, quantitative analysis revealed preferential MXC bioaccumulation in the midbrain (0.069 ng/mg tissue), 4-fold higher than in the striatum. MALDI-MSI identified significant dysregulation of sulfatides and glycerophospholipids in midbrain and striatal regions, with lipidomic analysis revealing region-specific regulatory patterns between the two brain areas. Mechanistic investigation demonstrated that MXC exerts neurotoxicity through mitochondrial complex I inhibition, triggering region-specific stress responses. Specifically, the striatum exhibited robust antioxidant defense activation while the midbrain showed inadequate compensation and excessive neuroinflammation. Untargeted metabolomic analysis revealed disrupted energy metabolism, glycerophospholipid metabolism, and aromatic amino acid biosynthesis pathways. Targeted analysis confirmed impaired dopamine synthesis and metabolism in both brain regions, with dopamine levels significantly decreased despite opposing metabolic patterns. These findings provide spatial molecular evidence that MXC induces region-specific neurotoxicity through mitochondrial targeting, revealing differential brain vulnerability patterns. This novel analytical framework offers a valuable platform for environmental neurotoxicant assessment and supports enhanced regulatory strategies for persistent organic pollutants.
AB - Methoxychlor (MXC), an organochlorine pesticide, is an emerging persistent organic pollutant of significant environmental concern due to its notable persistence and bioaccumulation. While compelling evidence supports its neurotoxic effects, the underlying molecular mechanisms remain unclear and warrant systematic investigation. This study establishes an integrated spatial molecular platform combining matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) with lipidomics and metabolomics to investigate region-specific neurotoxic mechanisms in mouse brain tissues. Following 90-day exposure, quantitative analysis revealed preferential MXC bioaccumulation in the midbrain (0.069 ng/mg tissue), 4-fold higher than in the striatum. MALDI-MSI identified significant dysregulation of sulfatides and glycerophospholipids in midbrain and striatal regions, with lipidomic analysis revealing region-specific regulatory patterns between the two brain areas. Mechanistic investigation demonstrated that MXC exerts neurotoxicity through mitochondrial complex I inhibition, triggering region-specific stress responses. Specifically, the striatum exhibited robust antioxidant defense activation while the midbrain showed inadequate compensation and excessive neuroinflammation. Untargeted metabolomic analysis revealed disrupted energy metabolism, glycerophospholipid metabolism, and aromatic amino acid biosynthesis pathways. Targeted analysis confirmed impaired dopamine synthesis and metabolism in both brain regions, with dopamine levels significantly decreased despite opposing metabolic patterns. These findings provide spatial molecular evidence that MXC induces region-specific neurotoxicity through mitochondrial targeting, revealing differential brain vulnerability patterns. This novel analytical framework offers a valuable platform for environmental neurotoxicant assessment and supports enhanced regulatory strategies for persistent organic pollutants.
KW - Lipidomics
KW - Mass spectrometry imaging
KW - Metabolomics
KW - Methoxychlor
KW - Organochlorine pesticide
KW - Persistent organic pollutant
UR - https://www.scopus.com/pages/publications/105014200171
U2 - 10.1016/j.jhazmat.2025.139601
DO - 10.1016/j.jhazmat.2025.139601
M3 - Journal article
AN - SCOPUS:105014200171
SN - 0304-3894
VL - 497
JO - Journal of Hazardous Materials
JF - Journal of Hazardous Materials
M1 - 139601
ER -