Long-term accumulation of diphenylarsinic acid in the central nervous system of cynomolgus monkeys

Abstract

Diphenylarsinic acid (DPAA) is an organic arsenic compound used for the synthesis of chemical weapons. We previously found that the residents of Kamisu city in Ibaraki Prefecture, Japan, were exposed to DPAA through contaminated well water in 2003. Although mounting evidence strongly suggests that their neurological symptoms were caused by DPAA, the dynamics of DPAA distribution and metabolism after ingestion by humans remain to be elucidated. To accurately predict the distribution of DPAA in the human body, we administrated DPAA (1.0 mg/kg/day) to cynomolgus monkeys (n = 28) for 28 days. The whole tissues from these monkeys were collected at 5, 29, 170, and 339 days after the last administration. The concentration of DPAA in these tissues was measured by liquid chromatography–mass spectrometry. We found that DPAA accumulated in the central nervous system tissues for a longer period than in other tissues. This finding would extend our knowledge on the distribution dynamics and metabolism of DPAA in primates, including humans. Furthermore, it may be useful for developing a treatment strategy for patients who are exposed to DPAA.

Decreased regional cerebral blood flow in patients with diphenylarsinic acid intoxication

“…A study in cynomolgus monkeys demonstrated that DPAA persists in the brain 1 year after exposure . Given that DPAA concentrations were similar across brain regions in the monkeys , the characteristic symptoms of DPAA intoxication may be the result of differences in neuronal vulnerability to DPAA.…”

“…A study in cynomolgus monkeys demonstrated that DPAA persists in the brain 1 year after exposure . Given that DPAA concentrations were similar across brain regions in the monkeys , the characteristic symptoms of DPAA intoxication may be the result of differences in neuronal vulnerability to DPAA. Our findings are consistent with those of studies on methylmercury poisoning, which showed that the occipital lobe is most vulnerable to damage .…”

“…It was recently recognized in cynomolgus monkeys that DPAA accumulates and is sequestered in the central nervous system for at least 1 year after last exposure, suggesting that the effects of DPAA exposure on the brain can persist for several years . With regard to DPAA neurotoxicity, DPAA acts on astrocytes, producing oxidative stress, promoting the production and secretion of vasoactive peptides and activating intracellular protein kinase .…”

Hepatic histopathological changes and dysfunction in primates following exposure to organic arsenic diphenylarsinic acid

“…DPAA(V) was dissolved in distilled water at a concentration of 10 mg/mL, and the pH was adjusted to 7.0 with 1N NaOH. Each monkey in the experimental group (n = 28) was orally administered DPAA(V) via a nasogastric tube at a dose of 1.0 mg/kg/day (Masuda et al, 2017). Instead of DPAA(V), distilled water was administered to the control group (n = 4).…”

“…We previously showed that DPAA(V) accumulates at high concentrations not only in the CNS but also in the liver after its oral administration to monkeys (Masuda et al, 2017). In general, arsenic compounds are known to be toxic to hepatocytes (Rehman and Naranmandura, 2012;Xie et al, 2004).…”