ABSTRACT
Mercury has been shown to be a significant health risk factor and is positively associated with cardiovascular diseases. Evidence reveals that men are more likely to develop cardiovascular diseases than women during reproductive age. However, the effects of mercury in females remain poorly investigated, despite the finding that female hormones demonstrate a cardioprotective role. In the present study, we evaluated whether chronic mercury chloride exposure could alter blood pressure and vascular function of the female rat aorta. Ten-week-old female Wistar rats were divided into two groups: control (vehicle) and mercury treated (first dose of 4.6 µg/kg, subsequent daily doses of 0.07 µg/kg), im. Mercury treatment did not modify systolic blood pressure (SBP) but increased vascular reactivity due to the reduction of nitric oxide bioavailability associated with the increase in reactive oxygen species from endothelial nitric oxide synthase (eNOS) uncoupling. Furthermore, increased participation of the cyclooxygenase-2 pathway occurred through an imbalance in thromboxane 2 and prostacyclin 2. However, the oestrogen signalling pathway was not altered in either group. These results demonstrated that chronic exposure to mercury in females induced endothelial dysfunction and, consequently, increased aortic vascular reactivity, causing vascular damage to the female rat aorta and representing a risk of cardiovascular diseases.
Subject(s)
Cyclooxygenase 2/drug effects , Mercuric Chloride/toxicity , Nitric Oxide Synthase Type III/metabolism , Oxidative Stress/drug effects , Animals , Aorta/drug effects , Aorta/metabolism , Blood Pressure/drug effects , Cyclooxygenase 2/metabolism , Female , Mercuric Chloride/administration & dosage , Nitric Oxide/metabolism , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptors, Estrogen/metabolismABSTRACT
Exposure to heavy metals may have toxic effects on several human organs causing morbidity and mortality. Metals may trigger or exacerbate autoimmunity in humans. Inbred mouse strains with certain H-2 haplotypes are susceptible to xenobiotic-induced autoimmunity; and their immune response to metals such as mercury, gold, and silver have been explored. Serum antinuclear antibodies (ANA), polyclonal B-cell activation, hypergammaglobulinemia and tissue immune complex deposition are the main features of metal-induced autoimmunity in inbred mice. However, inbred mouse strains do not represent the genetic heterogeneity in humans. In this study, outbred Swiss Webster (SW) mice exposed to gold or mercury salts showed immune and autoimmune responses. Intramuscular injection of 22.5 mg/kg.bw aurothiomalate (AuTM) induced IgG ANA in SW mice starting after 5 weeks that persisted until week 15 although with a lower intensity. This was accompanied by elevated serum levels of total IgG antibodies against chromatin and total histones. Exposure to gold led to development of serum IgG autoantibodies corresponding to H1 and H2A histones, and dsDNA. Both gold and mercury induced polyclonal B-cell activation. Eight mg/L mercuric chloride (HgCl2) in drinking water, caused IgG antinucleolar antibodies (ANoA) after 5 weeks in SW mice accompanied by immune complex deposition in kidneys and spleen. Serum IgG antibodies corresponding to anti-fibrillarin, and anti-PM/Scl-100 antibodies, were observed in mercury-exposed SW mice. Gold and mercury trigger systemic autoimmune response in genetically heterogeneous outbred SW mice and suggest them as an appropriate model to study xenobiotic-induced autoimmunity.
Subject(s)
Antibodies, Antinuclear/blood , Autoimmunity/drug effects , B-Lymphocytes/drug effects , Gold Sodium Thiomalate/toxicity , Immunoglobulin G/blood , Lymphocyte Activation/drug effects , Mercuric Chloride/toxicity , Administration, Oral , Animals , Antigen-Antibody Complex , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Chromatin/immunology , Chromosomal Proteins, Non-Histone/immunology , Exoribonucleases/immunology , Exosome Multienzyme Ribonuclease Complex/immunology , Female , Gold Sodium Thiomalate/administration & dosage , Histones/immunology , Injections, Intramuscular , Kidney/drug effects , Kidney/immunology , Mercuric Chloride/administration & dosage , Mice , Spleen/drug effects , Spleen/immunologyABSTRACT
Cardiovascular disease (CVD) is the major cause of morbidity, mortality, and health care costs in the United States, and possibly around the world. Among the various risk factors of CVD, environmental and dietary exposures to mercury (Hg), a highly toxic metal traditionally regarded as a neurotoxin, has been recently suggested as a potential contributor towards human atherosclerotic development. In this study, we investigated the toxicity, type of cell death, dose-dependent uptake, and efflux of inorganic HgII (as HgCl2) and methylmercury or MeHg (as CH3HgCl) in EA.hy926 endothelial cells, as these two forms of Hg are often reported to be present in human blood among the general populations (~20-30% as HgII and ~70-80% as MeHg). Our results showed that HgII is more toxic than MeHg to the endothelial cells, owing to the higher uptake into the cytoplasm and perhaps importantly lower efflux of HgII by the cells, thus the "net" accumulation by the endothelial cells is higher for HgII than MeHg when exposed to the same Hg levels in the media. Furthermore, both HgII and MeHg were found to induce apoptotic and necrotic cell death. This study has important implications for the contributions of these two common Hg species to the development of atherosclerosis, an important process leading to CVD.
Subject(s)
Endothelial Cells/drug effects , Mercuric Chloride/toxicity , Methylmercury Compounds/toxicity , Apoptosis/drug effects , Cell Death/drug effects , Cell Line , Dose-Response Relationship, Drug , Endothelial Cells/pathology , Endothelium, Vascular/cytology , Humans , Mercuric Chloride/administration & dosage , Mercuric Chloride/pharmacokinetics , Mercury/pharmacokinetics , Methylmercury Compounds/administration & dosage , Methylmercury Compounds/pharmacokineticsABSTRACT
Mercury (Hg) is a common environmental toxicant to which humans are exposed regularly through occupational and dietary means. Although selenium supplementation has been reported to prevent the toxic effects of Hg in animals, the mechanisms for this prevention are not well understood. The purpose of the current study was to determine the effects of selenium on the disposition and toxicity of Hg. Wistar rats were injected intravenously with a non-nephrotoxic dose (0.5 µmol kg-1) or a nephrotoxic dose (2.5 µmol kg-1) of HgCl2 (containing radioactive Hg) with or without co-administration of sodium selenite (Na2SeO3). Twenty-four hours after exposure, rats were euthanized, and organs were harvested. Co-administration of SeO32- with HgCl2 reduced the renal burden of Hg and the urinary excretion of Hg while increasing the amount of Hg in blood and spleen. We propose that Hg reacts with reduced selenite in the blood to form large Hg-Se complexes that are unable to be filtered at the glomerulus. Consequently, these complexes remain in the blood and are able to accumulate in blood-rich organs. These complexes, which may have fewer toxic effects than other species of Hg, may be eliminated slowly over the course of weeks to months.
Subject(s)
Mercuric Chloride/toxicity , Mercury/metabolism , Sodium Selenite/pharmacology , Animals , Female , Injections, Intravenous , Ions/metabolism , Kidney/drug effects , Kidney/metabolism , Male , Mercuric Chloride/administration & dosage , Mercuric Chloride/blood , Rats , Rats, Wistar , Sodium Selenite/administration & dosage , Sodium Selenite/blood , Spleen/drug effects , Spleen/metabolism , Tissue DistributionABSTRACT
Solid evidence confirms that glutathione peroxidase (GPx) is a kind of vital protease in the first-line antioxidant defense system and participates in regulation of redox homeostasis as well as the pentose phosphate pathway. However, the current methods cannot achieve real-time and in situ visualization studies of GPx. In addition, GPx is highly reactive and susceptible to external interference, and there is rare research for exploring the roles of GPx under environmental factor exposure. Herein, we report a novel two-photon ratiometric fluorescent probe (TP-SS) for GPx detection for the first time. Using TP-SS, we explore the reversible catalytic cycle and the antioxidant mechanisms of GPx/GSH redox pool in aging and mercury exposure models. We detect the concentration fluctuation of GPx in aging and mercury exposure mice models. Also, we perform GPx detection in deep brain tissue and the imaging depth up to 100 µm. We believe that the novel two-photon ratiometric fluorescent probe TP-SS can facilitate the development of GPx-targeting tools and offer great advances in exploring the physiological/pathological functions of GPx.
Subject(s)
Brain/drug effects , Cellular Senescence/drug effects , Disease Models, Animal , Fluorescent Dyes/metabolism , Glutathione Peroxidase/metabolism , Mercuric Chloride/poisoning , Photons , Animals , Apoptosis/drug effects , Brain/metabolism , Brain/pathology , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Glutathione Peroxidase/analysis , Intravitreal Injections , Mercuric Chloride/administration & dosage , Mice , Mice, Inbred BALB C , Molecular Structure , Optical Imaging , Oxidation-Reduction , Oxidative Stress/drug effectsABSTRACT
Mercury (Hg) is among the most deleterious contaminant in the aquatic environment and presents a serious risk to humans and ecosystems. This study evaluated the effects of Hg on oxidative stress biomarkers, DNA integrity and histological structure of the respiratory tree of Holothuria forskali exposed to different concentrations of mercury chloride HgCl2 (0.04, 0.08 and 0.16 mg L-1) for 96 h. Exposure of H. forskali to Hg led to oxidative stress with an increase in Malondialdehyde (MDA), hydrogen peroxide (H2O2), advanced oxidation protein product (AOPP) and protein carbonyls (PCO) levels in the treated groups. Alteration of the antioxidant system was also confirmed by the significant increase in glutathione (GSH), nonprotein thiol (NPSH) and vitamin C contents. Moreover, the enzymatic activity of superoxide dismutase (SOD), Glutathione peroxidase (GPX) and Catalase (CAT) increased significantly. Our research revealed that total Metallothionein (MTs) content enhanced in a dose-dependent manner. Interestingly, the exposure to this metal provoked a decrease in Acetylcholinesterase (AChE) activity. Hg genotoxicity was further evidenced by a random DNA degradation that was observed in the treated groups. The histopathological findings confirmed the biochemical results. Overall, our results indicated that mercury-induced genotoxicity, oxidative damage and histopathological injuries in the respiratory tree of H. forskali.
Subject(s)
Mercuric Chloride/toxicity , Metallothionein/genetics , Mutagens/toxicity , Water Pollutants, Chemical/toxicity , Animals , Antioxidants/metabolism , Biomarkers/metabolism , Dose-Response Relationship, Drug , Holothuria/drug effects , Mercuric Chloride/administration & dosage , Mutagenicity Tests , Mutagens/administration & dosage , Oxidation-Reduction/drug effects , Oxidative Stress/drug effects , Respiratory System/drug effects , Up-Regulation/drug effects , Water Pollutants, Chemical/administration & dosageABSTRACT
Mercury is a metal widely dispersed in nature that when in contact with human organism, it damages the cardiovascular system. Long-term mercury exposure for 30 days induces endothelial dysfunction without blood pressure changes in normotensive adult rats. However, it is not known whether exposure to mercury can exacerbate endothelial dysfunction and hypertension development in predisposed animals. Thus, we aimed to investigate the effects of long-term mercury exposure on the blood pressure (BP) and in the isolated aortas of young normotensive and prehypertensive spontaneously hypertensive rats (SHRs). Four-week-old male Wistar rats and SHRs were treated daily with mercury chloride (HgCl2) (1st dose, 4.6 µg/kg; subsequent dose, 0.07 µg/kg/day, im, 30 days) or vehicle. BP was assessed weekly and the vascular reactivity to phenylephrine was evaluated in isolated aorta from rats exposed or not to mercury. Mercury exposure did not affect BP in young Wistar rats but accelerated the development of hypertension in young SHRs. Vascular reactivity to phenylephrine increased only in the aorta from mercury-exposed SHRs. While HgCl2 exposure in SHRs did not alter nitric oxide production, we observed increased superoxide anion production and decreased superoxide dismutase-1 protein expression, and enhanced cyclooxygenase-2 (COX-2) participation with increased prostaglandin (PGE2) production and decreased prostacyclin. In the Wistar group, mercury exposure did not alter superoxide anion production or the COX-2 pathway. Mercury exposure accelerated the natural course of hypertension in young SHRs and increased oxidative stress associated with reduced participation of antioxidant enzymes, an activated COX-2 pathway, thereby producing endothelial dysfunction, which is a risk factor in prehypertensive individuals.
Subject(s)
Cyclooxygenase 2/metabolism , Endothelium, Vascular/drug effects , Hypertension/chemically induced , Mercuric Chloride/toxicity , Animals , Blood Pressure/drug effects , Endothelium, Vascular/metabolism , Hypertension/metabolism , Male , Mercuric Chloride/administration & dosage , Nitric Oxide/biosynthesis , Oxidative Stress/drug effects , Phenylephrine/metabolism , Rats , Rats, Inbred SHR , Rats, WistarABSTRACT
Exposure to mercury is associated with numerous health problems, affecting different parts of the human body, including the nervous and cardiovascular systems in adults and children; however, the underlying mechanisms are yet to be fully elucidated. We investigated the role of membrane sulfatide on mercuric ion (Hg2+) mediated red blood cell (RBC) adhesion to a sub-endothelial matrix protein, laminin, using a microfluidic system that mimics microphysiological flow conditions. We exposed whole blood to mercury (HgCl2), at a range of concentrations to mimic acute (high dose) and chronic (low dose) exposure, and examined RBC adhesion to immobilized laminin in microchannels at physiological flow conditions. Exposure of RBCs to both acute and chronic levels of Hg2+ resulted in elevated adhesive interactions between RBCs and laminin depending on the concentration of HgCl2 and exposure duration. BCAM-Lu chimer significantly inhibited the adhesion of RBCs that had been treated with 50⯵M of HgCl2 solution for 1â¯h at 37⯰C, while it did not prevent the adhesion of 3â¯h and 24â¯h Hg2+-treated RBCs. Sulfatide significantly inhibited the adhesion of RBC that had been treated with 50⯵M of HgCl2 solution for 1â¯h at 37⯰C and 0.5⯵M of HgCl2 solution for 24â¯h at room temperature (RT). We demonstrated that RBC BCAM-Lu and RBC sulfatides bind to immobilized laminin, following exposure of RBCs to mercuric ions. The results of this study are significant considering the potential associations between sulfatides, red blood cells, mercury exposure, and cardiovascular diseases.
Subject(s)
Cell Adhesion/drug effects , Erythrocytes, Abnormal/metabolism , Mercuric Chloride/toxicity , Dose-Response Relationship, Drug , Erythrocytes, Abnormal/cytology , Humans , Laminin/metabolism , Mercuric Chloride/administration & dosageABSTRACT
Chronic exposure to mercury chloride (HgCl2) has been shown to promote oxidative stress and cell death in the central nervous system of adult rats displaying motor and cognitive impairments. However, there are no investigations about neurochemical function after this type of exposure in rodents that may be associated with those behavioral changes already reported. Thus, the aim of this study was to analyze glutamatergic and GABAergic dysfunctions in the motor cortex and hippocampus of adult rats, in a model of chronic exposure to HgCl2 in. Twenty rats were exposed to a daily dose of 0.375 mg/kg for 45 days. After this period, they were submitted to motor and cognitive functions tests and euthanized to collect the motor cortex and hippocampus for measurement of mercury (Hg) levels in the parenchyma and neurochemical assays for analysis of glutamatergic and GABAergic functions. It was observed that chronic exposure to HgCl2 promoted increase in total Hg levels in these two brain areas, with changes in glutamatergic transport, but without changes in GABAergic transport. Functionally this model of exposure caused the decrease of the spontaneous motor locomotion and in the process of learning and memory. In this way, our results provide evidences that glutamatergic neurochemical dysfunction can be pointed out as a strong causal factor of motor and cognitive deficits observed in rats exposed to this HgCl2.
Subject(s)
Behavior, Animal/drug effects , Hippocampus/drug effects , Mercuric Chloride/toxicity , Motor Cortex/drug effects , Administration, Oral , Animals , Hippocampus/metabolism , Male , Mercuric Chloride/administration & dosage , Motor Cortex/metabolism , Rats , Rats, WistarABSTRACT
Cadmium and mercury are among the most toxic and dangerous environmental pollutants that may cause fatal implications. Vitamin C is an important chain-breaking antioxidant and enzyme co-factor against heavy metals. The objective of the present study was to evaluate the toxicological effects of cadmium chloride, mercuric chloride, and their co-administration on biochemical parameters of blood serum and metal bioaccumulation in kidneys and also to elucidate the protective effect of vitamin C in rabbits against these metals. In the current research, cadmium chloride (1.5 mg/kg), mercuric chloride(1.2 mg/kg), and vitamin C (150 mg/kg of body weight) were orally administered to eight treatment groups of the rabbits (1, control; 2, vitamin; 3, CdCl2; 4, HgCl2; 5, vitamin + CdCl2; 6, vitamin + HgCl2; 7, CdCl2 + HgCl2, and 8, vitamin + CdCl2 + HgCl2). After the biometric measurements of all experimental rabbits, biochemical parameters viz. creatinine, cystatin C, uric acid, and alkaline phosphatase (ALP) and metal bioaccumulation were determined using commercially available kits and atomic absorption spectrophotometer, respectively. The levels of creatinine (28.3 ± 1.1 µmol/l), cystatin C (1932.5 ± 38.5 ηg/ml), uric acid (4.8 ± 0.1 mg/day), and ALP (51.6 ± 1.1 IU/l) were significantly (P < 0.05) increased due to administration of mercuric chloride but in the presence of vitamin C, the effects of mercuric chloride on creatinine (21.9 ± 1.4 µmol/l), cystatin C (1676.2 ± 42.2 ηg/ml), uric acid (3.9 ± 0.1 mg/day), and ALP (43.3 ± 0.8 IU/l) were less as compared to metal-exposed specimens. Similar results were found in rabbits treated with cadmium chloride and vitamin C and also with co-administration of both metals and vitamin C. Because of the bio-accumulative nature of cadmium chloride and mercuric chloride, these metals were accumulated in kidneys of rabbits, which might lead to deleterious effects. The results of the present study provide an insight into the toxicity of the cadmium chloride, mercuric chloride, and/or their combination on biochemical parameters as well as kidneys of the rabbits and the ameliorating potential of vitamin C against these metals is also evaluated.
Subject(s)
Ascorbic Acid/pharmacology , Cadmium Chloride/toxicity , Kidney/drug effects , Mercuric Chloride/toxicity , Administration, Oral , Alkaline Phosphatase/blood , Animals , Antioxidants/pharmacology , Cadmium/pharmacokinetics , Cadmium/toxicity , Cadmium Chloride/administration & dosage , Creatinine/blood , Cystatin C/blood , Environmental Pollutants/pharmacokinetics , Environmental Pollutants/toxicity , Kidney/metabolism , Mercuric Chloride/administration & dosage , Mercury/pharmacokinetics , Mercury/toxicity , Protective Agents/pharmacology , Rabbits , Uric Acid/bloodABSTRACT
Mercury is considered to be "a global pollutant" and raises concern worldwide. Once mercury enters the body, it will be distributed all over the body but will accumulate in the brain, kidney and liver. To date, no substance originating from edible fungi capable of adsorbing mercury has been reported. We found that the mushroom Grifola frondosa exhibited mercury adsorption capacity. A polysaccharide-peptide (GFPP), displaying the unique N-terminal amino acid sequence of APPGMHQKQQ and 7 partial sequences with high reliability obtained by LC-MS/MS, was isolated by hot-water extraction of its fruiting bodies followed by ion exchange chromatography and gel filtration chromatography. Two rat models were employed to determine the dose and the duration of HgCl2 treatment (given by acute administration or continuous treatment) to test if G. frondosa could promote mercury elimination. For rats subjected to acute treatment with HgCl2, both GFPP and G. frondosa fruiting bodies (GFFF) could accelerate the decline of blood mercury level, which fell precipitously by 50% on the second day. GFPP and GFFF also promoted elimination of the burden of mercury in the liver and kidneys. For rats receiving continuous HgCl2 treatment, G. frondosa prevented the progressive increase of blood mercury level, and kept the blood mercury level within a relatively stable range.
Subject(s)
Grifola/chemistry , Mercuric Chloride/metabolism , Proteoglycans/metabolism , Animals , Blood Chemical Analysis , Chromatography, Gel , Chromatography, Liquid , Environmental Pollutants/metabolism , Fruiting Bodies, Fungal/chemistry , Mercuric Chloride/administration & dosage , Mercuric Chloride/blood , Metabolic Clearance Rate , Protein Binding , Proteoglycans/administration & dosage , Proteoglycans/genetics , Proteoglycans/isolation & purification , Rats , Tandem Mass Spectrometry , Treatment OutcomeABSTRACT
This work investigated the preventive effect of diphenyl diselenide [(PhSe)2] against the toxic effects of mercury in silver catfish (Rhamdia quelen). The animals were treated during 30 consecutive days with a (PhSe)2 supplemented feed (3.0 mg kg-1) or commercial feed. During the last 5 days the animals received a daily intraperitoneal dose of HgCl2 (1.7 mg kg-1) or Saline (0.9%). Twenty-four hours after the last HgCl2 injection, the animals were euthanized by spinal cord section to biological material obtainment. Hepatic (AST and ALT) and renal (ammonia and creatinine) toxicity biomarkers, δ-ALA-D activity, TBARS, total and non-protein thiols levels and hepatic, renal and blood mercury (Hg) and zinc (Zn) content were evaluated. Considering renal parameters, HgCl2 exposition increased serum creatinine levels and decreased δ-ALA-D activity, total and non-protein thiols and TBARS levels. HgCl2 exposure also decreased blood δ-ALA-D activity. With exception of blood δ-ALA-D activity and total thiols levels, (PhSe)2 supplementation partially prevented mercury induced alterations. Animals exposed to HgCl2 presented an increase in liver and kidney Hg content and a decrease in liver and blood Zn content. The alteration in blood Zn content was partially prevented with (PhSe)2 supplementation. With the exception of mercury and zinc content, no effects of HgCl2 exposure on hepatic tissue were observed. These results show that (PhSe)2 supplementation can represent a promising alternative to prevent the toxic effects presented by Hg exposure.
Subject(s)
Benzene Derivatives/pharmacology , Mercury Poisoning/drug therapy , Mercury Poisoning/prevention & control , Organoselenium Compounds/pharmacology , Animals , Benzene Derivatives/metabolism , Catfishes/metabolism , Creatinine/blood , Diet , Dietary Supplements , Female , Kidney/drug effects , Liver/drug effects , Male , Mercuric Chloride/administration & dosage , Mercury/blood , Mercury Poisoning/blood , Organoselenium Compounds/metabolism , Sulfhydryl Compounds/blood , Zinc/bloodABSTRACT
The objective of this study was to determine the effects of mercury chloride (HgCl2) on laying performance, egg quality, hepatic and renal histopathology, and serum biochemical profiles in laying hens. A total of 768 Hy-line brown laying hens aged 40 weeks were randomly allocated to four groups (8 pens per group and 24 hens per pen). The concentrations of mercury (Hg) in four groups were 0.280, 3.325, 9.415, and 27.240 mg/kg. Results revealed that dietary Hg could significantly reduce laying performance (P < 0.05) and egg quality (P < 0.05) and was dose-dependently deposited in albumen, yolk, eggshell, and whole egg. Meanwhile, the thicknesses of palisade layer, mammillary layer, and total layer, and the percent of palisade layer were significantly decreased (P < 0.05), while the percent of mammillary layer was sharply increased (P < 0.05) in eggshell. In addition, with increasing dietary dosage of Hg, accumulation of Hg in viscera was significantly increased (P < 0.05), and histopathological damages in liver and kidney were more and more severe. Serum alanine aminotransferase, aspartate aminotransferase, and globulin were significantly increased (P < 0.05), while serum albumin and albumin to globulin ratio were significantly decreased (P < 0.05) in 27.240 mg/kg Hg group. Blood urea nitrogen, uric acid, and creatinine were significantly increased (P < 0.05) in 3.325, 9.415, and 27.240 mg/kg Hg groups. These results suggested that dietary HgCl2 could reduce laying performance and egg quality with hepatic and renal function disorders in laying hens.
Subject(s)
Egg Shell/drug effects , Egg Yolk/drug effects , Eggs/standards , Kidney/drug effects , Liver/drug effects , Mercuric Chloride/toxicity , Oviposition/drug effects , Animals , Chickens , Diet , Kidney/pathology , Liver/pathology , Mercuric Chloride/administration & dosage , Mercuric Chloride/blood , Microscopy, Electron, Scanning , Random AllocationABSTRACT
Mercury sulfides are used in Ayurvedic medicines, Tibetan medicines, and Chinese medicines for thousands of years and are still used today. Cinnabar (α-HgS) and metacinnabar (ß-HgS) are different from mercury chloride (HgCl2) and methylmercury (MeHg) in their disposition and toxicity. Whether such scenario applies to weanling and aged animals is not known. To address this question, weanling (21d) and aged (450d) rats were orally given Zuotai (54% ß-HgS, 30mg/kg), HgS (α-HgS, 30mg/kg), HgCl2 (34.6mg/kg), or MeHg (MeHgCl, 3.2mg/kg) for 7days. Accumulation of Hg in kidney and liver, and the toxicity-sensitive gene expressions were examined. Animal body weight gain was decreased by HgCl2 and to a lesser extent by MeHg, but unaltered after Zuotai and HgS. HgCl2 and MeHg produced dramatic tissue Hg accumulation, increased kidney (kim-1 and Ngal) and liver (Ho-1) injury-sensitive gene expressions, but such changes are absent or mild after Zuotai and HgS. Aged rats were more susceptible than weanling rats to Hg toxicity. To examine roles of transporters in Hg accumulation, transporter gene expressions were examined. The expression of renal uptake transporters Oat1, Oct2, and Oatp4c1 and hepatic Oatp2 was decreased, while the expression of renal efflux transporter Mrp2, Mrp4 and Mdr1b was increased following HgCl2 and MeHg, but unaffected by Zuotai and HgS. Thus, Zuotai and HgS differ from HgCl2 and MeHg in producing tissue Hg accumulation and toxicity, and aged rats are more susceptible than weanling rats. Transporter expression could be adaptive means to reduce tissue Hg burden.
Subject(s)
Aging/drug effects , Drugs, Chinese Herbal/toxicity , Mercuric Chloride/toxicity , Mercury Compounds/toxicity , Methylmercury Compounds/toxicity , Administration, Oral , Aging/metabolism , Animals , Animals, Newborn , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/metabolism , Mercuric Chloride/administration & dosage , Mercuric Chloride/metabolism , Mercury/administration & dosage , Mercury/metabolism , Mercury/toxicity , Mercury Compounds/administration & dosage , Mercury Compounds/metabolism , Methylmercury Compounds/administration & dosage , Methylmercury Compounds/metabolism , Rats , Rats, Sprague-Dawley , WeaningABSTRACT
Identifying novel biomarkers to detect nephrotoxicity is clinically important. Here, we attempted to identify new biomarkers for mercury-induced nephrotoxicity and compared their sensitivity to that of traditional biomarkers in animal models. Comparative proteomics analysis was performed in kidney tissues of Sprague-Dawley rats after oral treatment with HgCl2 (0.1, 1, or 5 mg/kg/day) for 21 days. Kidney cortex tissues were analyzed by two-dimensional gel electrophoresis/matrix-assisted laser desorption/ionization, and differentially expressed proteins were identified. The corresponding spots were quantitated by RT-PCR. Selenium-binding protein 1 (SBP1) was found to be the most markedly upregulated protein in the kidney cortex of rats after HgCl2 administration. However, blood urea nitrogen, serum creatinine, and glucose levels increased significantly only in the 1 or 5 mg/kg HgCl2-treated groups. A number of urinary excretion proteins, including kidney injury molecule-1, clusterin, monocyte chemoattractant protein-1, and ß-microglobulin, increased dose-dependently. Histopathological examination revealed severe proximal tubular damage in high-dose (5 mg/kg) HgCl2-exposed groups. In addition, urinary excretion of SBP1 significantly increased in a dose-dependent manner. To confirm the critical role of SBP1 as a biomarker for nephrotoxicity, normal kidney proximal tubular cells were treated with HgCl2, CdCl2, or cisplatin for 24 h. SBP1 levels significantly increased in conditioned media exposed to nephrotoxicants, but decreased in cell lysates. Our investigations suggest that SBP1 may play a critical role in the pathological processes underlying chemical-induced nephrotoxicity. Thus, urinary excretion of SBP1 might be a sensitive and specific biomarker to detect early stages of kidney injury.
Subject(s)
Cadmium Chloride/toxicity , Kidney Diseases/chemically induced , Mercuric Chloride/toxicity , Selenium-Binding Proteins/metabolism , Animals , Biomarkers/metabolism , Blood Urea Nitrogen , Cadmium Chloride/administration & dosage , Cisplatin/administration & dosage , Cisplatin/toxicity , Creatinine/blood , Dose-Response Relationship, Drug , Electrophoresis, Gel, Two-Dimensional , Kidney Cortex/drug effects , Kidney Cortex/pathology , Kidney Diseases/pathology , Male , Mercuric Chloride/administration & dosage , Metals, Heavy/administration & dosage , Metals, Heavy/toxicity , Proteins/drug effects , Proteins/metabolism , Proteomics/methods , Rats , Rats, Sprague-Dawley , Sensitivity and Specificity , Spectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationABSTRACT
Zuotai (mainly ß-HgS) and Zhusha (also called as cinnabar, mainly α-HgS) are used in traditional medicines in combination with herbs or even drugs in the treatment of various disorders, while mercury chloride (HgCl2) and methylmercury (MeHg) do not have known medical values but are highly toxic. This study aimed to compare the effects of mercury sulfides with HgCl2 and MeHg on hepatic drug processing gene expression. Mice were orally administrated with Zuotai (ß-HgS, 30mg/kg), α-HgS (HgS, 30mg/kg), HgCl2 (33.6mg/kg), or MeHg (3.1mg/kg) for 7days, and the expression of genes related to phase-1 drug metabolism (P450), phase-2 conjugation, and phase-3 (transporters) genes were examined. The mercurials at the dose and duration used in the study did not have significant effects on the expression of cytochrome P450 1-4 family genes and the corresponding nuclear receptors, except for a slight increase in PPARα and Cyp4a10 by HgCl2. The expressions of UDP-glucuronosyltransferase and sulfotransferase were increased by HgCl2 and MeHg, but not by Zuotai and HgS. HgCl2 decreased the expression of organic anion transporter (Oatp1a1), but increased Oatp1a4. Both HgCl2 and MeHg increased the expression of multidrug resistance-associated protein genes (Mrp1, Mrp2, Mrp3, and Mrp4). Zuotai and HgS had little effects on these transporter genes. In conclusion, Zuotai and HgS are different from HgCl2 and MeHg in hepatic drug processing gene expression; suggesting that chemical forms of mercury not only affect their disposition and toxicity, but also affect their effects on the expression of hepatic drug processing genes.
Subject(s)
Cytochrome P-450 Enzyme System/genetics , Gene Expression Regulation/drug effects , Liver/drug effects , Mercuric Chloride/pharmacology , Mercury/pharmacology , Methylmercury Compounds/pharmacology , Organic Anion Transporters/genetics , Sulfides/pharmacology , Animals , Cytochrome P-450 Enzyme System/biosynthesis , Cytochrome P-450 Enzyme System/metabolism , Gene Expression Regulation/genetics , Liver/enzymology , Liver/metabolism , Male , Mercuric Chloride/administration & dosage , Mercury/administration & dosage , Methylmercury Compounds/administration & dosage , Mice , Mice, Inbred Strains , Organic Anion Transporters/biosynthesis , Organic Anion Transporters/metabolism , Sulfides/administration & dosageABSTRACT
Mercury (Hg) is a highly hazardous pollutant widely used in industrial, pharmaceutical and agricultural fields. Mercury is found in the environment in several forms, elemental, inorganic (iHg) and organic, all of which are toxic. Considering that the liver is the organ primarily involved in the regulation of metabolic pathways, homeostasis and detoxification we investigated the morphological and ultrastructural effects in Danio rerio liver after 96 h exposure to two low HgCl2 concentrations (7.7 and 38.5 µg/L). We showed that a short-term exposure to very low concentrations of iHg severely affects liver morphology and ultrastructure. The main effects recorded in this work were: cytoplasm vacuolization, decrease in both lipid droplets and glycogen granules, increase in number of mitochondria, increase of rough endoplasmic reticulum and pyknotic nuclei. Pathological alterations observed were dose dependent. Trough immunohistochemistry, in situ hybridization and real-time PCR analysis, the induction of metallothionein (MT) under stressor conditions was also evaluated. Some of observed alterations could be considered as a general response of tissue to heavy metals, whereas others (such as increased number of mitochondria and increase of RER) may be considered as an adaptive response to mercury.
Subject(s)
Liver/drug effects , Mercuric Chloride/toxicity , Metallothionein/metabolism , Zebrafish/anatomy & histology , Animals , Dose-Response Relationship, Drug , Endoplasmic Reticulum Stress , Glycogen/metabolism , Lipid Droplets/metabolism , Liver/metabolism , Liver/ultrastructure , Mercuric Chloride/administration & dosage , Metallothionein/genetics , Mitochondria/drug effects , Mitochondria/ultrastructure , Zebrafish/metabolism , Zebrafish Proteins/metabolismABSTRACT
Traditional Chinese medicines (TCM) are increasingly being used as alternative medicines in many countries, and this has caused concern because of adverse health effects from toxic metal bioavailability such as mercury (Hg) and arsenic (As). The aim of this study was to investigate the bioavailability of As and Hg from TCM after a single exposure dose using an animal model of female Sprague-Dawley rats. The rats were divided into 6 groups which included four groups treated with sodium arsenite (NaAsO2), arsenic sulfide (As2S3), mercuric chloride (HgCl2), mercuric sulfide (HgS), and two groups treated with TCM containing high Hg or As (Liu Shen Wan: As 7.7-9.1% and Hg 1.4-5.0%; Niuhang Jie du Pian: As 6.2-7.9% and Hg <0.001%). The samples of urine, faeces, kidney and liver were collected for analysis and histological assay. The results indicated that relatively low levels of As and Hg from these TCM were retained in liver and kidney tissues. The levels of As in these tissues after TCM treatment were consistent with the levels from the As sulphide treated group. With the exception of the mercuric chloride treated group, the levels of Hg in urine from other groups were very low, and high levels of As and Hg from TCM were excreted in faeces. The study showed poor bioavailability of As and Hg from TCM as indicated by low relative bioavailability of As (0.60-1.10%) and Hg (<0.001%). Histopathological examination of rat kidney and liver tissues did not show toxic effects from TCM.
Subject(s)
Arsenicals/pharmacokinetics , Arsenites/pharmacokinetics , Drug Contamination , Drugs, Chinese Herbal/pharmacokinetics , Mercuric Chloride/pharmacokinetics , Mercury Compounds/pharmacokinetics , Sodium Compounds/pharmacokinetics , Sulfides/pharmacokinetics , Administration, Oral , Animals , Arsenicals/administration & dosage , Arsenicals/urine , Arsenites/administration & dosage , Arsenites/toxicity , Arsenites/urine , Biological Availability , Drugs, Chinese Herbal/administration & dosage , Drugs, Chinese Herbal/toxicity , Feces/chemistry , Female , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Mercuric Chloride/administration & dosage , Mercuric Chloride/toxicity , Mercuric Chloride/urine , Mercury Compounds/administration & dosage , Mercury Compounds/toxicity , Mercury Compounds/urine , Rats, Sprague-Dawley , Risk Assessment , Sodium Compounds/administration & dosage , Sodium Compounds/toxicity , Sodium Compounds/urine , Sulfides/administration & dosage , Sulfides/toxicity , Sulfides/urine , Tissue DistributionABSTRACT
The aim of the present work was to study the response of a suite of cellular and biochemical markers in the terrestrial snail Cantareus apertus exposed to mercury in view of future use as sensitive tool suitable for mercury polluted soil monitoring and assessment. Besides standardized biomarkers (metallothionein, acetylcholinesterase, and lysosomal membrane stability) novel cellular biomarkers on haemolymph cells were analyzed, including changes in the spread cells/round cells ratio and haemocyte morphometric alterations. The animals were exposed for 14 days to Lactuca sativa soaked for 1h in HgCl2 solutions (0.5 e 1 µM). The temporal dynamics of the responses were assessed by measurements at 3, 7 and 14 days. Following exposure to HgCl2 a significant alteration in the relative frequencies of round cells and spread cells was evident, with a time and dose-dependent increase of the frequencies of round cells with respect to spread cells. These changes were accompanied by cellular morphometric alterations. Concomitantly, a high correspondence between these cellular responses and metallothionein tissutal concentration, lysosomal membrane stability and inhibition of AChE was evident. The study highlights the usefulness of the terrestrial snail C. apertus as bioindicator organism for mercury pollution biomonitoring and, in particular, the use of haemocyte alterations as a suitable biomarker of pollutant effect to be included in a multibiomarker strategy.
Subject(s)
Helix, Snails/drug effects , Hemocytes/drug effects , Mercuric Chloride/toxicity , Mercury Poisoning/veterinary , Soil Pollutants/toxicity , Acetylcholinesterase/chemistry , Acetylcholinesterase/metabolism , Animals , Biomarkers/blood , Cell Shape/drug effects , Cholinesterase Inhibitors/administration & dosage , Cholinesterase Inhibitors/toxicity , Dose-Response Relationship, Drug , Environmental Monitoring/methods , Food Contamination/prevention & control , Helix, Snails/enzymology , Helix, Snails/metabolism , Hemocytes/pathology , Humans , Intracellular Membranes/drug effects , Intracellular Membranes/metabolism , Italy , Lysosomes/drug effects , Lysosomes/metabolism , Mercuric Chloride/administration & dosage , Mercury Poisoning/blood , Mercury Poisoning/metabolism , Mercury Poisoning/pathology , Metallothionein/metabolism , Random Allocation , Shellfish/analysis , Shellfish Poisoning/prevention & control , Soil Pollutants/administration & dosage , Time FactorsABSTRACT
We used Drosophila as an animal model to study the digestive tract in response to the exposure of inorganic mercury (HgCl2). We found that after oral administration, mercury was mainly sequestered within the midgut. This resulted in increased cell death, which in turn stimulated the tissue regeneration program, including accelerated proliferation and differentiation of the intestinal stem cells (ISCs). We further demonstrated that these injuries correlate closely with the excessive production of the reactive oxygen species (ROS), as vitamin E, an antioxidant reagent, efficiently suppressed the HgCl2-induced phenotypes of midgut and improved the viability. We propose that the Drosophila midgut could serve as a suitable model to study the treatment of acute hydrargyrism on the digestive systems.