ABSTRACT
Background: Pruritus has been reported as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been systematically investigated. To investigate the association of arsenic exposure with pruritus, we performed observational, interventional, and Mendelian randomization studies.
Methods: A cross-sectional study was conducted in Shimen, China. A Mendelian randomization study was conducted to confirm the causal relationship between susceptibility to arsenic toxicity, in terms of genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine, and chronic pruritus in the UK Biobank participants. Then, a case-control study in Shimen participants was conducted to determine the biomarker for pruritus, and arsenite-treated mice were used to confirm the biomarker. Last, a randomized, double-blind, placebo-controlled trial was conducted to test the efficacy of naloxone, a μ-opioid receptor antagonist, in arsenic-exposed patients with pruritus in Shimen.
Results: Hair arsenic showed a dose-response relationship with the intensity of itch in 1092 participants. The Mendelian randomization analysis confirmed the causal relationship in the UK Biobank participants, with odds ratios of 1.043 for MMA% and 0.904 for DMA% above versus under median. Serum β-endorphin was identified as a significant biomarker associated with the intensity of itch. Consistently, treatment with arsenite in mice upregulated the level of β-endorphin. The randomized controlled trial showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic-exposed participants.
Conclusion: Arsenic exposure is associated with pruritus, and β-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.
Key words: arsenic exposure; β-endorphin; Mendelian randomization; pruritus; randomized controlled trial.
INTRODUCTION
High arsenic is found in groundwater in parts of the United States, Chile, Mexico, China, Argentina, India, and Bangladesh1, where inorganic arsenic exposure is reported to be associated with cancers, cardiovascular diseases, neurological diseases, and arsenic-related skin lesions (ArSL) including hyperkeratosis, skin cancers, and pigmentary changes2-4. Even in low-exposure populations (water arsenic <1 μg/L) in the US, rice consumption was associated with higher risk of squamous cell carcinoma of skin5. Arsenic-related pruritus was reported in very limited number of literatures, as an adverse drug reaction of arsenic trioxide (As2O3) therapy among patients with acute promyelocytic leukemia6 and patients with multiple myeloma7, as well as a highly frequent symptom among occupational workers with arseniasis8. Among the epidemiologic studies in arsenicosis regions worldwide, however, pruritus, a possible consequence of arsenic exposure, remained nearly unstated.
After decades of economic development in China, concerns about environmental consequences have been raised, and remarkable ecological improvements have been achieved in recent years. Shimen, a county located in central south China, had the largest realgar mineral in Asia. Mines and plants mushroomed in the realgar-rich area near Heshan village from the 1950s until 2011 when they were completely shut down by the government due to the pollution they caused. The local government embarked on a massive environment improvement project since 2012. In 1994, the arsenic concentration in river (the main source of drinking water before 1985) was reported to be 14531±1232 µg/L near Heshan9; while in 2014, the peak arsenic concentration in river was 765 µg/L10. In spite of the successful environmental governance, adverse health outcomes after arsenic exposure continue to occur.
Arsenic-related cutaneous symptoms are underappreciated, and comprehensive identification of exposure and outcomes may improve patient prognosis. During the epidemiologic investigation in Shimen, we noticed that many of the participants claimed unrelieved chronic pruritus during the dermatological examination. Owing to a lack of evidence, we performed a series of studies to confirm the causal relationship between arsenic exposure and chronic pruritus.
METHODS