Human plasma proteomic alterations by diphenylarsinic acid poisoning

Diphenylarsinic acid (DPAA), a degradation product of organoarsenic chemical warfare agents, contaminated well water in Kamisu City, Japan, and caused persistent neurological symptoms in the affected population. To gain insight into the systemic molecular processes underlying DPAA-associated neurotoxicity, we characterised plasma proteomic alterations in 30 DPAA-exposed individuals and 30 matched controls using the Olink Reveal platform (1,034 proteins). We identified 84 differentially expressed proteins (DEPs) in DPAA-exposed individuals, and the top-ranked DEPs discriminated the exposed group from controls with high accuracy. Pathway enrichment and correlation analyses revealed a significant overrepresentation of biological pathways related to neurodegeneration, immune and inflammatory responses, and apoptosis. Notably, 34 upregulated DEPs were positively correlated with the interval between cessation of exposure and plasma sampling, which ranged from 130 to 1,269 days. Enrichment analyses of this subset highlighted the same pathways, indicating that the DPAA-associated molecular alterations had not reversed over this interval. These findings indicate that DPAA exposure is associated with systemic proteomic alterations linked to neurodegeneration, inflammation, and apoptosis that persist after exposure has ceased, underscoring the need for long-term clinical and environmental surveillance of the affected areas.