de_2023_J.Alzheimers.Dis.Rep_7_751

BACKGROUND: Agent Orange, an herbicide used during the Vietnam War, contains 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Agent Orange has teratogenic and carcinogenic effects, and population-based studies suggest Agent Orange exposures lead to higher rates of toxic and degenerative pathologies in the peripheral and central nervous system (CNS). OBJECTIVE: This study examines the potential contribution of Agent Orange exposures to neurodegeneration. METHODS: Human CNS-derived neuroepithelial cells (PNET2) treated with 2,4-D and 2,4,5-T were evaluated for viability, mitochondrial function, and Alzheimer's disease (AD)-related proteins. RESULTS: Treatment with 250microg/ml 2,4-D or 2,4,5-T significantly impaired mitochondrial function, caused degenerative morphological changes, and reduced viability in PNET2 cells. Correspondingly, glyceraldehyde-3-phosphate dehydrogenase expression which is insulin-regulated and marks the integrity of carbohydrate metabolism, was significantly inhibited while 4-hydroxy-2-nonenal, a marker of lipid peroxidation, was increased. Tau neuronal cytoskeletal protein was significantly reduced by 2,4,5-T, and relative tau phosphorylation was progressively elevated by 2,4,5-T followed by 2,4-D treatment relative to control. Amyloid-beta protein precursor (AbetaPP) was increased by 2,4,5-T and 2,4-D, and 2,4,5-T caused a statistical trend (0.05