Research paperCombined toxicity of ethanol and methylmercury in rat
Abstract
The hepatotoxic and nephrotoxic effects of methylmercury (CH3Hg) and ethanol (EtOH) are well known; however, their interaction in vivo is not clearly understood. In order to investigate the combined effects of these 2 substances, 4 groups of male Wistar rats with an initial weight of approximately 190 g were treated for 7 weeks. Each group consisting of 8 rats was gavaged as follows: Group 1 with 5.0 ml/kg body weight of double distilled water, Group 2 with 5.0 ml/kg body weight of 25% EtOH, Group 3 with 2.5 mg/kg of CH3Hg in water, and Group 4 with 2.5 mg/kg of CH3Hg in 25% EtOH.
At the termination of the experiment the mean body weights of the rats in Group 3 (372.5 ± 10.8 S.E.) and Group 4 (383.4 ± 13.4) were significantly lower than that of Group 1 (433.0 ± 7.8). Linear regression showed a positive feed conversion efficiency for Groups 1 and 2 (1.07 and 0.83, respectively), and a negative score for this parameter for Groups 3 and 4 (−1.43, −1.53).
At necropsy, rat livers from Group 3 exhibited random multifocal tan spots. The relative liver weights were similar to those of controls. Semithin sections of liver revealed an increase in lipid droplets in Groups 2 and 3 compared to those in the other 2 groups while vacuolization was more striking in CH3Hg treated rats (Groups 3 and 4). Severe hepatolysis and portal canal edema were noted in the groups of rats exposed to either EtOH alone or in combination with mercury.
The relative weight of left kidney in Group 3 (0.70 ± 0.03) and Group 4 (0.51 ± 0.04) rats was significantly greater than of the control (0.39 ± 0.03). In gross appearance the kidney was pale and the urine production was significantly higher (P<0.05) in Group 3 compared to that of Group 1. Group 4 rats had significantly more (P <0.50) Hg in the kidney than Group 3; however, the inorganic percentages in both groups were similar. Morphological examination of the kidney proximal tubules from CH3Hg treated rats (Groups 3 and 4) revealed an increase in lipid droplets, vacuoles, cell sloughing and tubular degeneration compared to Groups 1 and 2. These histological changes in the proximal tubules of Groups 4 rats indicate an additive effect of EtOH on the kidney pathology caused by CH3Hg. This present study seems to suggest that ethanol in combination with mercury enhances the retention of mercury in the kidney and increases the nephrotoxicity while it has no effect on the neurotoxicity of mercury. EtOH and CH3Hg combination (Group 4) showed increased fibroblast infiltration and fibrosis in the kidney cortex, and larger and more numerous dense bodies and swollen mitochondria in the tubular cells. However, these alterations of nephrotoxicity by EtOH require further study.
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Cited by (26)
Mercury
2021, Handbook on the Toxicology of Metals: Fifth EditionMercury occurs as elemental mercury and as inorganic and organic compounds (mercury vapor, mercury liquid, mercury salts, short-chain alkylmercury compounds, alkoxyalkylmercury compounds, and phenylmercury compounds), all with different toxicological properties. Total mercury can be analyzed in water, air, and biological material by cold vapor atomic absorption methods and by neutron activation analysis and can be detected down to concentrations of a 10th of a nanogram per gram in biological material. Methylmercury (MeHg) can be detected in biological material at levels of a few nanograms by extraction with benzene after strong acidification with hydrochloric acid, followed by gas chromatographic analysis of MeHg chloride. Other analytical methods for speciating inorganic mercury and several of the organomercurial forms have also been published. These methods include isotope dilution mass spectrometry, time-of-flight mass spectrometry, high-performance liquid chromatography inductively coupled plasma (ICP) mass spectrometry, capillary electrophoresis-ICP, gas chromatography-ICP, and X-ray absorption fine structure spectroscopy.
Mercury is circulated naturally in the biosphere, with 5500 metric tons (t) being released into the atmosphere by degassing from the Earth's crust and the oceans. In addition, 2500 t of mercury are released into the environment each year through human activities such as the combustion of fossil fuels and other industrial releases. Approximately 2000 tons of mercury per year is produced for industrial use, a small part of which is used for synthesizing organic mercury compounds. The world production of mercury for commercial uses has been slowly declining over the past 20 years. There is now a ban on the export of mercury from the European Union and the United States.
In nature, MeHg is produced from inorganic mercury as a consequence of microbial activity. In mammals, oxidative demethylation occurs in vivo to produce inorganic mercury. In fish, most mercury is present as MeHg. Factors determining the MeHg concentration in fish are the mercury content in water and bottom sediments, the pH and redox potential of water, and the species, age, and size of the fish.
The toxic properties of mercury vapor are a consequence of mercury accumulation in the brain causing neurological signs involving an unspecific psychasthenic and vegetative syndrome (micromercurialism). At high exposure levels, mercurial tremor is seen, accompanied by severe behavioral and personality changes, increased excitability, loss of memory, and insomnia. Mercurials may also affect other organ systems, such as the kidney. On a group basis, exposure levels are likely to be reflected by mercury concentrations in the blood and urine. Occupational exposure to mercury concentrations in air of >0.1 mg/m3 may produce mercurialism. Micromercurialism has not been reported at concentrations <0.01 mg/m3. Exposure to mercury vapor inhibits brain development in primates and in humans with certain genotypes. The exact dose–response relationship in humans is not known. Inorganic mercury, but not MeHg, has been found to induce and bind to the low molecular weight metal-binding protein, metallothionein.
The acute and long-term actions of mercuric salts, phenylmercury compounds, and alkoxyalkylmercury compounds are likely to be gastrointestinal disturbance and renal damage appearing as tubular dysfunction, with tubular necrosis in severe cases. The lethal dose in humans is approximately 1 g mercuric salt. The mercury load on the kidney is best determined by analysis of renal biopsy. Mercury concentrations in the kidney of between 10 and 70 mg/kg have been reported in poison cases with renal injury. Levels <3 mg/kg may be found in normal cases. Occasionally, mercuric compounds may cause idiosyncratic skin symptoms, which may develop into severe exfoliative dermatitis or cause glomerular nephritis. Animal and clinical observations have shown that mercuric mercury stimulates and MeHg inhibits the immune system. A specific form of idiosyncrasy, called acrodynia or pink disease, is seen in children. Most cases are associated with mercury exposure in which increased levels of mercury in urine are detected.
Hazards involved in the long-term intake of food containing MeHg or ethylmercury (EthylHg) and in occupational exposure to MeHg are a result of the efficient absorption (90%) of alkylmercury in humans and the long retention time (half-life of 70 days for MeHg and shorter for EthylHg) leading to accumulation of alkylmercury in the brain. Chronic poisoning results in degeneration and atrophy of the sensory cerebral cortex, paresthesia, ataxia, hearing, and visual impairment, and an increased risk for cardiovascular diseases such as myocardial infarction and stroke. The latter effects are attenuated by the intake of polyunsaturated fatty acids (PUFAs) through fish consumption. Prenatal exposure causes cerebral palsy and, in less severe cases, psychomotor retardation. MeHg concentration in the blood and hair reflects the body burden and the brain concentration of MeHg. Intake resulting in body burdens of <0.5 mg/kg body weight is not likely to give rise to detectable neurological signs in adults. This intake corresponds to blood values of <200 μg/L and mercury levels in the hair of <50 mg/kg. However, this level of MeHg exposure in pregnant women may result in inhibited brain development of the fetus, with psychomotor retardation of the child. This effect also appears to be reduced by the intake of PUFAs through fish consumption. The highest level of MeHg load in pregnant women that is not associated with inhibition of fetal brain development is not known. Recent epidemiological studies have revealed that genetic polymorphisms can modify mercury metabolism and susceptibility to mercury exposure. Specific genotypes have been associated with increased susceptibility to mercury exposure in humans.
Mechanisms Involved in the Renal Handling and Toxicity of Mercury
2018, Comprehensive Toxicology: Third EditionOne of the most important factors that determines the dispositional and toxicological fate of environmentally relevant forms of mercury in the body is the strong bonding affinity that exists between mercuric ions and reduced sulfur atoms of certain biomolecules. The formation of unique chemical species by the bonding of inorganic and organic mercuric ions in both extracellular and intracellular compartments of the body turns out to be a crucial part of the mechanisms involved in the handling and toxicity of inorganic and organic mercury in specific target tissues and organs, especially in the liver and kidneys. For example, certain membrane transporters present in renal proximal tubular epithelial cells have been shown to import certain species of mercury formed in extracellularly, while other transporters have been shown to export mercuric species formed in intracellular compartments of these target cells. Interestingly, the specific thiol S-conjugates that gain entry into the intracellular milieu of a target (renal) epithelial cell may not be the same type of thiol S-conjugate that is exported out of the cell. Over the last couple of decades, significant progress has been made in identifying membrane transporters in renal proximal tubular cells that take up and export certain thiol S-conjugates mercury. This chapter not only reviews the advances in understanding the roles of the transporters taking up and exporting endogenously formed species of mercury by renal tubular epithelial cells, but it also reviews some of the more relevant findings pertaining to key intracellular biochemical effects of mercuric ions that likely play a role in intoxicating proximal tubular cells. Moreover, discussion of factors that modify the proximal tubular uptake and subsequent toxicity of mercuric species has also been included.
Mercury
2015, Handbook on the Toxicology of Metals: Fourth EditionMercury occurs as elemental mercury and as inorganic and organic compounds (mercury vapor, mercury liquid, mercury salts, short-chain alkylmercury compounds, alkoxyalkylmercury compounds, and phenylmercury compounds), all with different toxicological properties. Total mercury can be analyzed in water, air, and biological material by cold vapor atomic absorption methods and by neutron activation analysis, and can be detected down to concentrations of a tenth of a nanogram per gram in biological material. Methylmercury (MeHg) can be detected in biological material at levels of a few nanograms by extraction with benzene after strong acidification with hydrochloric acid, followed by gas chromatographic analysis of MeHg chloride. Other analytical methods for speciating inorganic mercury and several of the organomercurial forms have also been published. These methods include isotope dilution mass spectrometry, time-of-flight mass spectrometry, high performance liquid chromatography inductively coupled (ICP) plasma mass spectrometry, capillary electrophoresis-ICP, gas chromatography-ICP, and X-ray absorption fine structure spectroscopy.
Mercury is circulated naturally in the biosphere, with 30,000-50,000 tons being released into the atmosphere by degassing from the Earth’s crust and the oceans. In addition, 20,000 tons of mercury is released into the environment each year through human activities such as combustion of fossil fuels and other industrial releases. Approximately 2000 tons of mercury per year is produced for industrial use, a small part of which is used for synthesizing organic mercury compounds. The world production of mercury for commercial uses has been slowly declining over the past 20 years. There is now a ban on the export of mercury from the European Union.
In nature, MeHg is produced from inorganic mercury as a consequence of microbial activity. In mammals, oxidative demethylation occurs in vivo to produce inorganic mercury. In fish, most mercury is present as MeHg. Factors determining the MeHg concentration in fish are the mercury content in water and bottom sediments, the pH and redox potential of water, and the species, age, and size of the fish.
The toxic properties of mercury vapor are a consequence of mercury accumulation in the brain causing neurological signs involving an unspecific psychoasthenic and vegetative syndrome (micromercurialism). At high exposure levels, mercurial tremor is seen, accompanied by severe behavioral and personality changes, increased excitability, loss of memory, and insomnia. Mercurials may also affect other organ systems, such as the kidney. On a group basis, exposure levels are likely to be reflected in mercury concentrations in the blood and urine. Occupational exposure to mercury concentrations in air of > 0.1 mg/m3 may produce mercurialism. Micromercurialism has not been reported at concentrations < 0.01 mg/m3. Exposure to mercury vapor inhibits brain development in primates and in humans with certain genotypes. The exact dose-response relationship in humans is not known. Inorganic mercury but not MeHg has been found to induce and bind to the low molecular weight metal-binding protein, metallothionein.
The acute and long-term actions of mercuric salts, phenylmercury compounds, and alkoxyalkylmercury compounds are likely to be gastrointestinal disturbance and renal damage appearing as tubular dysfunction, with tubular necrosis in severe cases. The lethal dose in humans is approximately 1 g mercuric salt. The mercury load on the kidney is best determined by analysis of renal biopsy. Mercury concentrations in the kidney of between 10 and 70 mg/kg have been reported in poison cases with renal injury. Levels < 3 mg/kg may be found in normal cases. Occasionally, mercuric compounds may cause idiosyncratic skin symptoms, which may develop into severe exfoliative dermatitis or cause glomerular nephritis. Animal and clinical observations have shown that mercuric mercury stimulates and MeHg inhibits the immune system. A specific form of idiosyncrasy, called acrodynia or pink disease, is seen in children. Most cases are associated with mercury exposure in which increased levels of mercury in urine are observed.
Hazards involved in the long-term intake of food containing MeHg or ethylmercury (EthylHg) and in occupational exposure to MeHg are a result of the efficient absorption (90%) of alkylmercury in humans and the long retention time (half-life of 70 days for MeHg and shorter for EthylHg) leading to accumulation of alkylmercury in the brain. Chronic poisoning results in degeneration and atrophy of the sensory cerebral cortex, paresthesia, ataxia, hearing, and visual impairment, and implies an increased risk for cardiovascular disease such as cardiac infarction and stroke. The latter effects are attenuated by the intake of polyunsaturated fatty acids (PUFAs) through fish consumption. Prenatal exposure causes cerebral palsy and, in less severe cases, psychomotor retardation. MeHg concentration in the blood and hair reflects the body burden and the brain concentration of MeHg. Intake resulting in body burdens of < 0.5 mg/kg body weight is not likely to give rise to detectable neurological signs in adults. This intake corresponds to blood values of < 200 μg/L and mercury levels in the hair of < 50 mg/kg. However, this level of MeHg exposure in pregnant women may result in inhibited brain development of the fetus, with psychomotor retardation of the child. This effect also appears to be reduced by intake of PUFAs through fish consumption. The highest level of MeHg load in pregnant women that is not associated with inhibition of fetal brain development is not known. Recent epidemiological studies have revealed that genetic polymorphisms can modify mercury metabolism and susceptibility to mercury exposure. Specific genotypes have been associated with increased susceptibility to mercury exposure in humans.
A general overview of mercury from a historical perspective has been reviewed by Goldwater (1972). The pharmacology and toxicology of mercury was previously reviewed by Clarkson et al. (1972), the chemistry of mercury in biological systems by Carty and Malone (1979), the toxicology of MeHg by a Swedish Expert Group (1971), and the toxicology and epidemiology of mercury by Friberg and Vostal (1972), the Task Group on Metal Accumulation (1973), the Task Group on Metal Toxicity (1976), and the World Health Organization (WHO (World Health Organization), 1976, WHO, 1980, WHO., 1990, WHO., 1991). The toxicology of mercury has been reviewed in the U.S. Environmental Protection Agency Report to Congress (EPA, 1997), the Agency for Toxic Substances and Disease Registry (ATSDR, 1999), National Academy of Sciences National Research Council (NAS/NRC, 2000), and Institute of Medicine Report on Mercury in Vaccines (IOM, 2004).
Mercury
2014, Handbook on the Toxicology of MetalsMercury occurs as elemental mercury and as inorganic and organic compounds (mercury vapor, mercury liquid, mercury salts, short-chain alkylmercury compounds, alkoxyalkylmercury compounds, and phenylmercury compounds), all with different toxicological properties. Total mercury can be analyzed in water, air, and biological material by cold vapor atomic absorption methods and by neutron activation analysis, and can be detected down to concentrations of a tenth of a nanogram per gram in biological material. Methylmercury (MeHg) can be detected in biological material at levels of a few nanograms by extraction with benzene after strong acidification with hydrochloric acid, followed by gas chromatographic analysis of MeHg chloride. Other analytical methods for speciating inorganic mercury and several of the organomercurial forms have also been published. These methods include isotope dilution mass spectrometry, time-of-flight mass spectrometry, high performance liquid chromatography inductively coupled (ICP) plasma mass spectrometry, capillary electrophoresis-ICP, gas chromatography-ICP, and X-ray absorption fine structure spectroscopy.
Mercury is circulated naturally in the biosphere, with 30,000-50,000 tons being released into the atmosphere by degassing from the Earth’s crust and the oceans. In addition, 20,000 tons of mercury is released into the environment each year through human activities such as combustion of fossil fuels and other industrial releases. Approximately 2000 tons of mercury per year is produced for industrial use, a small part of which is used for synthesizing organic mercury compounds. The world production of mercury for commercial uses has been slowly declining over the past 20 years. There is now a ban on the export of mercury from the European Union.
In nature, MeHg is produced from inorganic mercury as a consequence of microbial activity. In mammals, oxidative demethylation occurs in vivo to produce inorganic mercury. In fish, most mercury is present as MeHg. Factors determining the MeHg concentration in fish are the mercury content in water and bottom sediments, the pH and redox potential of water, and the species, age, and size of the fish.
The toxic properties of mercury vapor are a consequence of mercury accumulation in the brain causing neurological signs involving an unspecific psychoasthenic and vegetative syndrome (micromercurialism). At high exposure levels, mercurial tremor is seen, accompanied by severe behavioral and personality changes, increased excitability, loss of memory, and insomnia. Mercurials may also affect other organ systems, such as the kidney. On a group basis, exposure levels are likely to be reflected in mercury concentrations in the blood and urine. Occupational exposure to mercury concentrations in air of > 0.1 mg/m3 may produce mercurialism. Micromercurialism has not been reported at concentrations < 0.01 mg/m3. Exposure to mercury vapor inhibits brain development in primates and in humans with certain genotypes. The exact dose-response relationship in humans is not known. Inorganic mercury but not MeHg has been found to induce and bind to the low molecular weight metal-binding protein, metallothionein.
The acute and long-term actions of mercuric salts, phenylmercury compounds, and alkoxyalkylmercury compounds are likely to be gastrointestinal disturbance and renal damage appearing as tubular dysfunction, with tubular necrosis in severe cases. The lethal dose in humans is approximately 1 g mercuric salt. The mercury load on the kidney is best determined by analysis of renal biopsy. Mercury concentrations in the kidney of between 10 and 70 mg/kg have been reported in poison cases with renal injury. Levels < 3 mg/kg may be found in normal cases. Occasionally, mercuric compounds may cause idiosyncratic skin symptoms, which may develop into severe exfoliative dermatitis or cause glomerular nephritis. Animal and clinical observations have shown that mercuric mercury stimulates and MeHg inhibits the immune system. A specific form of idiosyncrasy, called acrodynia or pink disease, is seen in children. Most cases are associated with mercury exposure in which increased levels of mercury in urine are observed.
Hazards involved in the long-term intake of food containing MeHg or ethylmercury (EthylHg) and in occupational exposure to MeHg are a result of the efficient absorption (90%) of alkylmercury in humans and the long retention time (half-life of 70 days for MeHg and shorter for EthylHg) leading to accumulation of alkylmercury in the brain. Chronic poisoning results in degeneration and atrophy of the sensory cerebral cortex, paresthesia, ataxia, hearing, and visual impairment, and implies an increased risk for cardiovascular disease such as cardiac infarction and stroke. The latter effects are attenuated by the intake of polyunsaturated fatty acids (PUFAs) through fish consumption. Prenatal exposure causes cerebral palsy and, in less severe cases, psychomotor retardation. MeHg concentration in the blood and hair reflects the body burden and the brain concentration of MeHg. Intake resulting in body burdens of < 0.5 mg/kg body weight is not likely to give rise to detectable neurological signs in adults. This intake corresponds to blood values of < 200 μg/L and mercury levels in the hair of < 50 mg/kg. However, this level of MeHg exposure in pregnant women may result in inhibited brain development of the fetus, with psychomotor retardation of the child. This effect also appears to be reduced by intake of PUFAs through fish consumption. The highest level of MeHg load in pregnant women that is not associated with inhibition of fetal brain development is not known. Recent epidemiological studies have revealed that genetic polymorphisms can modify mercury metabolism and susceptibility to mercury exposure. Specific genotypes have been associated with increased susceptibility to mercury exposure in humans.
A general overview of mercury from a historical perspective has been reviewed by Goldwater (1972). The pharmacology and toxicology of mercury was previously reviewed by Clarkson et al. (1972), the chemistry of mercury in biological systems by Carty and Malone (1979), the toxicology of MeHg by a Swedish Expert Group (1971), and the toxicology and epidemiology of mercury by Friberg and Vostal (1972), the Task Group on Metal Accumulation (1973), the Task Group on Metal Toxicity (1976), and the World Health Organization (WHO (World Health Organization), 1976, WHO, 1980, WHO., 1990, WHO., 1991). The toxicology of mercury has been reviewed in the U.S. Environmental Protection Agency Report to Congress (EPA, 1997), the Agency for Toxic Substances and Disease Registry (ATSDR, 1999), National Academy of Sciences National Research Council (NAS/NRC, 2000), and Institute of Medicine Report on Mercury in Vaccines (IOM, 2004).
Renal Handling and Toxicity of Mercury
2010, Comprehensive Toxicology, Second EditionMercury is a unique heavy metal that can exist in the environment in several physical and chemical forms, including elemental mercury, which is a liquid at room temperature. All forms of mercury express some form of toxic effects in target organs, especially in the kidneys. Interestingly, the epithelial cells lining the straight portions of renal proximal tubules are among the most vulnerable to the toxic effects of mercury. The biological and toxicological activity of mercurous and mercuric ions can be defined largely by chemical bonding with critical nucleophilic sites in and around target cells. Due to the high bonding affinity between mercuric ions and sulfur-reduced atoms, particular interest is paid to the interactions that occur between mercuric ions and thiol group(s) of proteins, peptides, and amino acids. Chemical interactions between mercuric ions and sulfhydryl groups in molecules of albumin, metallothionein, glutathione, and cysteine have been implicated in the mechanisms participating in the uptake, accumulation, transport, and toxicity of mercuric ions in the renal proximal tubule. Numerous factors, both within and outside the intracellular compartment of proximal tubular epithelial cells, influence greatly the susceptibility of these target cells to the injurious effects of mercury. These very factors serve as the theoretical basis for most of the currently employed therapeutic strategies used for mercury poisoning in humans. This chapter provides a brief update on the current body of knowledge regarding the mechanisms involved in the renal cellular uptake, accumulation, elimination, and toxicity of mercury.
Mercury Exposure and Public Health
2007, Pediatric Clinics of North AmericaCitation Excerpt :CH3Hg+ is known to cross the placental barrier and concentrate in both the placenta and the developing fetus, resulting in deleterious neurotoxicological outcomes [16,53,56,101–106,W89–W91,W101–W109]. The kidney may also be damaged by CH3Hg+ [99,107–110,W110–W113]. The renal proximal tubular cells may take up the MeHg in a way similar to the renal handling of Hg++ involving GSH [77,111–113,W114–W124].
Mercury is a metal that is a liquid at room temperature. Mercury has a long and interesting history deriving from its use in medicine and industry, with the resultant toxicity produced. In high enough doses, all forms of mercury can produce toxicity. The most devastating tragedies related to mercury toxicity in recent history include Minamata Bay and Niagata, Japan in the 1950s, and Iraq in the 1970s. More recent mercury toxicity issues include the extreme toxicity of the dimethylmercury compound noted in 1998, the possible toxicity related to dental amalgams, and the disproved relationship between vaccines and autism related to the presence of the mercury-containing preservative, thimerosal.