Arsenic exposure and pruritus: Evidence from observational, interventional, and mendelian randomization studies.

Abstract

Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. A cross-sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case-control study was then conducted to determine the biomarker for pruritus. Arsenite-treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double-blind, placebo-controlled trial was conducted to test the efficacy of naloxone in arsenic-exposed patients with pruritus in Shimen. Hair arsenic (μg/g) showed a dose-response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate-to-severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum β-endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of β-endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic-exposed participants in 2 weeks (β = -0.98, p = 0.04). Arsenic exposure is associated with pruritus, and β-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.