Agent Orange Herbicidal Toxin-Initiation of Alzheimer-Type Neurodegeneration

Article type: Research Article

Authors: de la Monte, Suzanne M.^{a; b; *} | Tong, Ming^b

Affiliations: [a] Departments of Pathology and Laboratory Medicine, Neurology, and Neurosurgery, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA | [b] Department of Medicine, Rhode Island Hospital, Lifespan Academic Institutions, and the Warren Alpert Medical School of Brown University, Providence, RI, USA

Correspondence: [*] Correspondence to: Dr. Suzanne M. de la Monte, MD, MPH, Department of Medicine, Rhode Island Hospital, Providence, RI, 02908, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].

Abstract: Background:Agent Orange (AO) is a Vietnam War-era herbicide that contains a 1 : 1 ratio of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Emerging evidence suggests that AO exposures cause toxic and degenerative pathologies that may increase the risk for Alzheimer’s disease (AD). Objective:This study investigates the effects of the two main AO constituents on key molecular and biochemical indices of AD-type neurodegeneration. Methods:Long Evans rat frontal lobe slice cultures treated with 250μg/ml of 2,4-D, 2,4,5-T, or both (D + T) were evaluated for cytotoxicity, oxidative injury, mitochondrial function, and AD biomarker expression. Results:Treatment with the AO constituents caused histopathological changes corresponding to neuronal, white matter, and endothelial cell degeneration, and molecular/biochemical abnormalities indicative of cytotoxic injury, lipid peroxidation, DNA damage, and increased immunoreactivity to activated Caspase 3, glial fibrillary acidic protein, ubiquitin, tau, paired-helical filament phosphorylated tau, AβPP, Aβ, and choline acetyltransferase. Nearly all indices of cellular injury and degeneration were more pronounced in the D + T compared with 2,4-D or 2,4,5-T treated cultures. Conclusions:Exposures to AO herbicidal chemicals damage frontal lobe brain tissue with molecular and biochemical abnormalities that mimic pathologies associated with early-stage AD-type neurodegeneration. Additional research is needed to evaluate the long-term effects of AO exposures in relation to aging and progressive neurodegeneration in Vietnam War Veterans.

Keywords: Agent Orange, Alzheimer’s disease, brain, herbicide, neurodegeneration, neurons, pesticide, Vietnam Veterans, white matter, 2, 4-D, 2, 4, 5-T

DOI: 10.3233/JAD-230881

Journal: Journal of Alzheimer's Disease, vol. 97, no. 4, pp. 1703-1726, 2024