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Circulating miRNAs Associated with Cadmium Exposure
ОглавлениеCadmium (Cd) is a naturally occurring toxic metal of environmental and occupational concern. The main source of cadmium contamination is related to its use in industries, for example in the production of nickel–cadmium batteries, pigments, chemical stabilizers, and metal coatings (Genchi et al. 2020). Fossil fuel combustion and the use of phosphate fertilizers also contribute to cadmium accumulation in the environment. Human exposure to cadmium occurs mainly through the ingestion of contaminated food and water and through inhalation; cigarette smoking is the most significant source of human exposure to cadmium (Bernhoft 2013; Friberg 1983). Once absorbed, cadmium is bound by metallothionein (MT) within liver cells and is released into circulation in the form of MT-cadmium complexes. These complexes are filtered through the renal glomeruli and reabsorbed by the proximal tubular cells, processes that make the kidney a primary target organ of toxicity (Yuan et al. 2020). Since cadmium remains tightly bound to MT and is almost completely reabsorbed in the renal tubules, excretion in urine is very low, resulting in a twenty-five–thirty-year half-life for cadmium in the body (Genchi et al. 2020). Additionally, women with lower iron status are at risk for greater absorption of cadmium after oral exposure (Olsson et al. 2002). Cadmium can be measured in blood, urine, feces, hair, nails, saliva, and milk. Cadmium in blood indicates recent exposure and its acceptable level ranges between 0.03 and 0.12 μg/dl in blood (Alli 2015). In smokers, cadmium concentrations are typically above 3 μg/L, whereas in the general population the concentration varies between 0.1 and 1.0 μg/L (Fowler et al. 2015). Acute exposure to high levels of cadmium can result from inhalation or ingestion and initial symptoms of inhaled cadmium exposure (8.63 mg/m3 for five hours) include chills, fever, and myalgias. Later, individuals can develop chest pain, cough, and dyspnea (Newman-Taylor 1998). Gastrointestinal symptoms such as nausea, vomiting, diarrhea, abdominal cramps and pain have also been described after the ingestion of cadmium-contaminated food or drinks (Fowler et al. 2015). Long-term or chronic exposure to low levels of cadmium is also of concern. The most common health effects of low-dose chronic exposure include cancers, cardiovascular disease, diabetes, osteoporosis-related fractures, and kidney dysfunction, the kidney being the critical target for cadmium toxicity (Jarup and Akesson 2009). Recent studies have shown adverse kidney effects even at doses lower than the provisional tolerable weekly intake of 1 μg/kg body weight/day (Kobayashi et al. 2006; Noonan et al. 2002; WHO 1993). Hence it is crucial to identify potential biomarkers for the early detection of cadmium exposure.
Few studies have addressed cadmium-induced alterations in miRNA expression in humans. miR-122-5p and miR-326-3p were found to be upregulated in the serum of a cadmium-exposed population from China (Yuan et al. 2020). The commonly used biomarkers for cadmium exposure, urinary β2-microglobulin and retinol-binding protein, remained in the normal range, which suggests that these two miRNAs exhibited greater sensitivity to cadmium exposure than the urinary markers; and this makes them suitable candidates for the early detection of exposure (Yuan et al. 2020). In another study, levels of miRNAs were measured from the serum and urine of patients in China diagnosed with occupational chronic cadmium poisoning (Chen et al. 2021). In the urine, 16 miRNAs were found to be upregulated and 36 downregulated, while in the serum 46 miRNAs were upregulated and 131 were downregulated. An overlap of 59 abnormally expressed miRNAs was found between serum and urine samples of occupational chronic cadmium poisoning patients; these included miR-122-5p, miR-363-3p, miR-129-5p, miR-204-3p and miR-361-3p (Chen et al. 2021). In individuals exposed to low-levels of cadmium in China, the levels of miR-21 and miR-29b in plasma were upregulated. Serum levels of miR-30 were decreased in Chinese chronic obstructive pulmonary disease (COPD) patients with elevated levels of cadmium in serum by comparison to the levels in healthy control subjects. Additionally, an epithelial-mesenchymal transition was observed in the lung tissue of these patients (Zheng et al. 2021). In another study, individuals in India who were occupationally exposed to cadmium presented elevated levels of serum miR-221 and IL-17, a pro-inflammatory cytokine (Goyal et al. 2021; Zenobia and Hajishengallis 2015). Overall, several studies have identified differentially expressed miRNAs in the urine, serum, and plasma of individuals exposed to cadmium only in the Chinese population.