1,2-Dichloroethane (1,2-DCE) is a pervasive
environmental pollutant, and overexposure to this
hazardous material causes
brain edema and
demyelination in humans. We found that 1,2-DCE inhibits
aquaporin 4 (AQP4) and is a primary pathogenic effector of 1,2-DCE-induced
brain edema in animals. However, AQP4 down-regulation's link with cortex
demyelination after 1,2-DCE exposure remains unclear. Thus, we exposed wild-type (WT) CD-1 mice and AQP4 knockout (AQP4-KO) mice to 0, 100, 350 and 700 mg/m3 1,2-DCE by inhalation for 28 days. We applied label-free proteomics and a cell co-culture system to elucidate the role of AQP4 inhibition in 1,2-DCE-induced
demyelination. The results showed that 1,2-DCE down-regulated AQP4 in the WT mouse cortexes. Both 1,2-DCE exposure and AQP4 deletion induced neurotoxicity in mice, including increased brain water content, abnormal pathological vacuolations, and neurobehavioral damage. Tests for interaction of multiple regression analysis highlighted different effects of 1,2-DCE exposure level depending on the genotype, indicating the core role of AQP4 in regulation on 1,2-DCE-caused neurotoxicity. We used label-free quantitative proteomics to detect differentially expressed
proteins associated with 1,2-DCE exposure and AQP4 inhibition, and identified down-regulation in
myelin basic protein (MBP) and
tyrosine-protein kinase Fyn (FYN) in a dose-dependent manner in WT mice but not in AQP4-KO mice. 1,2-DCE and AQP4 deletion separately resulted in
demyelination, as detected by
Luxol fast blue staining, and manifested as disordered nerve fibers and cavitation in the cortexes. Western blot and immunofluorescence confirmed the decreased AQP4 in the astrocytes and the down-regulated MBP in the oligodendrocytes by 1,2-DCE exposure and AQP4 inhibition, respectively. Finally, the co-culture results of SVG p12 and MO3.13 cells showed that 1,2-DCE-induced AQP4 down-regulation in the astrocytes was responsible for
demyelination, by decreasing MBP in the oligodendrocytes. In conclusion, 1,2-DCE induced cortex
demyelination by depressing MBP via AQP4 inhibition in the mice.