Weiwei Zhang,# 1 , 2 , † Xiaojie Zheng,# 2 , † Xiangdong Chen, 1 Xuezhen Jiang, 2 Hexiang Wang, 2 , * and Guoqing Zhan
Keywords: polysaccharide-peptide, lead clearance, chelation, antidotes, edible fungi
Abstract
Lead is a global pollutant that causes widespread concern. When a lead enters the body, it is distributed throughout the body and accumulates in the brain, bone, and soft tissues such as the kidney, liver, and spleen. Chelators used for lead poisoning therapy all have side effects to some extent and other drawbacks including high cost. Exploration and utilization of natural antidotes become necessary. To date, few substances originating from edible fungi that are capable of adsorbing lead have been reported. In this study, we found that two commonly eaten mushrooms Auricularia auricula and Pleurotus ostreatus exhibited lead adsorption capacity. A. auricula active substance (AAAS) and P. ostreatus active substance (POAS) were purified by hot-water extraction, ethanol precipitation from its fruiting bodies followed by ion exchange chromatography, ultrafiltration, and gel filtration chromatography, respectively. AAAS was 3.6 kDa, while POAS was 4.9 kDa. They were both constituted of polysaccharides and peptides. The peptide sequences obtained by liquid chromatography combined with tandem mass spectrometry (LC-MS/MS) proved that they were rich in amino acids with side chain groups such as hydroxyl, carboxyl, carbonyl, sulfhydryl, and amidogen. Two rat models were established, but only a chronic lead-induced poisoning model was employed to determine the detoxification of AAAS/POAS and their fruiting body powder. For rats receiving continuous lead treatment, either AAAS or POAS could reduce the lead levels in the blood. They also promoted the elimination of the burden of lead in the spleen and kidney. The fruiting bodies were also proved to have lead detoxification effects. This is the first study to identify new functions of A. auricula and P. ostreatus in reducing lead toxicity and to provide dietary strategies for the treatment of lead toxicity.
Introduction
Lead, a well-known toxic heavy metal, is widely distributed in soil, water, and air. Various industrial activities contain lead or lead-based components, such as lead acid battery manufacturing, cable and wire products industries, and solder and foundry work, which become the major source of lead contamination (1). Lead can be easily absorbed by the human body via the respiratory system and gastrointestinal tracts. It also has non-biodegradability and a very long half-lifetime (2). After absorption, lead is distributed in the blood, bone, and soft tissues. Lead interferes with cellular metabolism by interacting with the cellular macromolecules in tissues throughout the body, resulting in multisystem effects including hypertension, renal impairment, immunotoxicity, and toxicity to the reproductive organs (3). According to the World Health Organization (WHO) 2021 update, nearly half of the deaths attributable to chemical exposures in 2019 were due to lead exposure and resulted in cardiovascular diseases. Lead exposure is also estimated to be responsible for 30% of the global burden of idiopathic intellectual disability, 4.6% of the global burden of cardiovascular disease, and 3% of the global burden of chronic kidney diseases (4).
Heavy metal poisoning is usually treated with chelation by creating an insoluble, less toxic metal complex that can be easily excreted. According to the “Guideline for clinical management of exposure to lead” published by the WHO, Dimercaprol (British Anti-Lewisite, BAL), 2,3 -dimercaptosuccinic acid (DMSA), penicillamine, and sodium calcium edetate (CaNa2EDTA) were recommended as chelating agents for lead exposure treatment (5). Among them, the first three are sulfhydryl-containing compounds and the last is a hydroxyl-containing compound. CaNa2EDTA is most commonly used for the treatment of childhood lead poisoning. However, these chelators were reported to have several different safety and efficacy concerns. CaNa2EDTA therapy could cause essential metals such as zinc, iron, and manganese to be excreted and depleted because of its relative lack of specificity (6), some of which would even cause secondary damage to patients (7, 8). DMSA, approved by the US FDA, also has side effects such as gastrointestinal discomfort, skin reaction, mild neutropenia, and elevated liver enzymes (8). Therefore, screening for safe and effective lead removal drugs is a focus of current research. Some antagonistic drugs can also reduce the damage of lead to the body by enhancing the body’s immunity or antioxidant capacity, such as beetroot juice and laver (9, 10). Ions such as calcium, iron, zinc, and magnesium have been also reported to have the ability to reduce the absorption of lead by competing with lead for intestinal absorption (11).
Edible fungi contain many pharmacological active ingredients, which have become a focus of much research as important resources for the development of functional food or drugs. Wild mushrooms have been reported to be highly susceptible to the enrichment of heavy metals in polluted areas (12), which indicates their strong affinity for heavy metals. However, the enrichment process depends on the environment polluted by heavy metals (13). Artificially cultivated mushrooms on non-polluted materials not only contain little heavy metal ions but also have the potential to be applied in lead poisoning therapy due to their metal affinity substances (14). In a previous survey of 35 kinds of commonly eaten edible fungi, A. auricular and P. ostreatus could reduce the lead content both in vitro and in vivo. In this study, we purified the active substance with lead absorption and evaluated its ability to reduce the lead level in rats’ blood and tissues. These two kinds of mushrooms have been emphasized to be used for various biological activities such as antioxidative (15, 16), antimicrobial (17, 18), hepatoprotective (15, 19), and hypolipidemic (15, 20) action. This study suggests that these edible fungi could serve as new resources for developing antidotes for lead intoxication.