硒对氯化汞免疫毒性的影响及其机理

采用免疫毒理学和生化毒理学方法，研究了亚硒酸钠对氯化汞免疫毒性的影响及作用机理。结果表明：氯化汞染毒的ＩＣＲ小鼠血中碳廓清率、ＳＲＢＣ致敏小鼠的ＤＴＨ反应、ＤＮＣＢ所致的ＤＣＨ反应、血清溶血素形成和免疫器官脏体比均明显低于对照组，预先投以亚硒酸钠后，再给同剂量的氯化汞的小鼠上述各指标都有不同程度提高。免疫器官脂质过氧化作用，汞组与对照组比较：脂质过氧化物含量明显升高，而谷胱甘肽过氧化物酶活性明显降低；硒汞组与汞组比较：脂质过氧化物含量明显降低，而谷胱甘肽过氧化物酶活性明显升高。上述结果提示：亚硒酸钠对氯化汞所致的免疫毒性和免疫器官的脂质过氧化损伤具有保护作用     

Mutagenicity study on mice given mercuric chloride

The mutagenic activity of different concentrations of mercuric chloride (0, 2, 4 and 6 mg HgCl2 per kg body wt) has been analysed in Swiss Albino mice at several periods (12, 24, 36 and 48 h) after intraperitoneal injection. No increased frequency of chromosomal aberrations was observed in bone marrow cells or in spermatogonia.     

Inhibition of the enzymes of glutathione metabolism by mercuric chloride in the rat kidney: reversal by selenium

The treatment of rats with 10 mumoles/kg (s.c.) of mercuric chloride (Hg2+) caused time-dependent decreases in the activities of the enzymes of the glutathione (GSH) metabolism pathway in the kidney. Twenty-four hours after administration of Hg2+, the activities of gamma-glutamylcysteine synthetase and glutathione disulfide (GSSG)-reductase in the kidney were decreased by 50-60%, and the activities of the GSH catabolic enzymes, gamma-glutamyl transpeptidase and GSH-peroxidase, were decreased by 25-35%. In the liver, only the activity of GSSG-reductase was decreased at this time. The observed decreases in the enzyme activities were not accompanied by a depression in the cellular protein concentration. The same pattern of enzyme response was noted when rats were given 30 mumoles/kg Hg2+; however, the decreases in the specific activity of the enzymes were accompanied by great losses in the cellular protein concentrations in both the liver and the kidney (35-40%). This dose of Hg2+ also caused significant decreases in the concentration of GSH in both organs. In vitro, Hg2+ only inhibited the activity of GSSG-reductase. When rats were given sodium selenite (Na2SeO3; 5, 10 or 20 mumoles/kg, s.c.) 30 min after Hg2+ treatment (10 mumoles/kg), the Hg2+-related depressions in the activities of the enzymes of GSH metabolism in the liver and the kidney were blocked. Also, in rats treated with 30 mumoles/kg Hg2+, the administration of 10 mumoles/kg selenium significantly decreased the magnitude of depression in the concentration of GSH in the kidney.     

Toxicokinetics of mercuric chloride and methylmercuric chloride in mice.

Future human exposure to inorganic mercury will probably lead to a few individuals occupationally exposed to high levels and much larger populations exposed to low or very low levels from dental fillings or from food items containing inorganic mercury; human exposure to methylmercury will be relatively low and depending on intake of marine food. Ideally, risk assessment is based on detailed knowledge of relations between external and internal dose, organ levels, and their relation to toxic symptoms. However, human data on these toxicokinetic parameters originate mainly from individuals or smaller populations accidentally exposed for shorter periods to relatively high mercury levels, but with unknown total body burden. Thus, assessment of risk associated with exposure to low levels of mercury will largely depend on data from animal experiments. Previous investigations of the toxicokinetics of mercuric compounds almost exclusively employed parenteral administration of relatively high doses of soluble mercuric salts. However, human exposure is primarily pulmonary or oral and at low doses. The present study validates an experimental model for investigating the toxicokinetics of orally administered mercuric chloride and methylmercuric chloride in mice. Major findings using this model are discussed in relation to previous knowledge. The toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex, whereas the mouse strain used is less important. The "true absorption" of a single oral dose of HgCl2 was calculated to be about 20% at two different dose levels. Earlier studies that did not take into account the possible excretion of absorbed mercury and intestinal reabsorption during the experimental period report 7-10% intestinal uptake. The higher excretion rates observed after oral than after intraperitoneal administration of HgCl2 are most likely due to differences in disposition of systemically delivered and retained mercury. After methylmercury administration, mercury excretion followed first-order kinetics for 2 wk, independently of administration route, strain, or sex. However, during longer experimental periods, the increasing relative carcass retention (slower rate of excretion) caused the elimination to deviate from first-order kinetics. Extensive differences in the toxicokinetics of methylmercury with respect to excretion rates, organ deposition, and blood levels were observed between males and females.(ABSTRACT TRUNCATED AT 400 WORDS)     

Diphenyl diselenide potentiates nephrotoxicity induced by mercuric chloride in mice

Following our long‐standing interest in the mechanisms involved in selenium toxicity, the aim of this work was to extend our previous studies to gain a better understanding of mercuric chloride (HgCl₂) + diphenyl diselenide (PhSe)₂ toxicity. Mice received one daily dose of HgCl₂ (4.6 mg kg^?1, subcutaneously) for three consecutive days. Thirty minutes after the last injection of HgCl₂, mice received a single dose of (PhSe)₂ (31.2 mg kg^?1, subcutaneously). Five hours after (PhSe)₂ administration, mice were euthanized and δ‐aminolevulinate dehydratase, catalase (CAT), glutathione S‐transferase (GST) and Na⁺, K⁺‐ATPase activities as well as thiobarbituric acid‐reactive substances (TBARS), ascorbic acid and mercury levels were determined in kidney and liver. Parameters in plasma (urea, creatinine, protein and erythropoietin), whole blood (hematocrit and hemoglobin) and urine (protein) were also investigated. HgCl₂ + (PhSe)₂ exposure caused a decrease in renal GST and Na⁺, K⁺‐ATPase activities and an increase in renal ascorbic acid and TBARS concentrations when compared with the HgCl₂ group. (PhSe)₂ potentiated the increase in plasma urea caused by HgCl₂. HgCl₂ + (PhSe)₂ exposure caused a reduction in plasma protein levels and an increase in hemoglobin and hematocrit contents when compared with the HgCl₂ group. There was a significant reduction in hepatic CAT activity and an increase in TBARS levels in mice exposed to HgCl₂ + (PhSe)₂ when compared with the HgCl₂ group. The results demonstrated that (PhSe)₂ did not modify mercury levels in mice. In conclusion, (PhSe)₂ potentiated damage caused by HgCl₂ affecting mainly the renal tissue. Copyright © 2011 John Wiley & Sons, Ltd.     

Immunological and biochemical responses in mice treated with mercuric chloride

Adult B6C3F1 male mice were given water containing 3, 15, and 75 ppm mercury (as mercuric chloride) for 7 weeks. There were dose-related increases in blood and kidney mercury levels but only the former showed a time-dependent change. Mercury was not detected in any of the lymphoid organs except for the spleen. There was no mortality and only minimal histological changes occurred in kidneys of dosed mice. Nonspecific toxicity occurred at the 75 ppm dose level, consisting of small differences in body and organ weights, hematological changes, and general enzyme inhibition in the bone marrow and spleen. However, there were specific immunotoxic and biochemical alterations in lymphoid organs of mice treated at the lower doses of mercury. The immunological defects were consistent with altered T-cell function as evidenced by decreases in both T-cell mitogen and mixed leukocyte responses. There was a particular association between the T-cell defects and inhibition of thymic pyruvate kinase, the rate-limiting enzyme for glycolysis. The differences in the pattern of enzyme responses among lymphoid organs implied that two mechanisms of mercury toxicity were operative--one at high concentrations that caused physicochemical enzyme inhibition and another at low concentrations that caused indirect enzyme inhibition.     

甲基肼及氯化汞对大鼠的急性肾损伤

大鼠ip甲基肼(MMH)25mg/kg及60mg/kg;sc HgCl_2 0.5 mg/kg及5mg/kg后不同时间测定尿中酶活性及蛋白质含量和组分的变化。结果表明MMH两种剂量对尿中NAG、LDH及ALP均无明显影响,但尿蛋白排泄明显增加及SDS-PAGE图谱明显改变。血液学检查表明血管内无溶血。HgCl_2 0.5mg/kg对尿中NAG,LDH及ALP无明显影响,5mg/kg时尿中这三种酶活性均明显升高。两种剂量均引起尿蛋白排泄增加,SDS-PAGE图谱明显改变。     

Effect of lycopene on nephrotoxicity induced by mercuric chloride in rats

Oxidative stress is an important molecular mechanism for kidney injury in mercury poisoning. We studied lycopene, a potent carotenoid found in tomatoes due to its large antioxidant properties, and also evaluated the ability of lycopene to prevent HgCl(2) nephrotoxicity. Rats were injected with HgCl(2) (0 or 5 mg/kg body weight, subcutaneously) 6 hr after lycopene administration (0, 10, 25 or 50 mg/kg by gavage) and were killed 12 hr after HgCl(2) exposure. HgCl(2)-induced inhibition of delta-aminolevulinate dehydratase activity (approximately 35%) and increase of lipid peroxidation in kidney (approximately 37%) were prevented by lycopene. However, lycopene did not prevent the increase of plasma creatinine levels (approximately 123%) and renal tubular necrosis induced by HgCl(2). Glutathione peroxidase and catalase activities were enhanced (approximately 71% and approximately 41%), while superoxide dismutase activity was depressed (approximately 44%) in HgCl(2)-treated rats when compared to control and these effects were prevented by lycopene. Our results indicate that although lycopene did not prevent HgCl(2)-induced renal failure, it could play a beneficial role against HgCl(2) toxicity by preventing lipid peroxidation and changes in the activity of delta-aminolevulinate dehydratase and antioxidant enzymes.     

硒对糖尿病小鼠血糖及糖代谢的影响

目的　研究硒对糖尿病小鼠血糖及糖代谢的影响 ,探讨硒降血糖的可能机制 ,为临床应用提供实验依据。方法　健康雄性昆明种小鼠 60只 ,随机分成 3组 ;正常对照组 (NC组 )、糖尿病组 (DM )组和糖尿病补硒组 (DM Se组 )。DM Se组每天给补硒液 3 0 0 μg kg ,持续 8周进行相关指标的生化检测。结果　实验结束时DM Se组小鼠血糖 ( 2 0 .4± 6.3 )mmol L较DM组 ( 4 5 .2± 3 .2 )mmol L明显降低( P <0 .0 5 )。DM Se组的全血谷胱甘肽过氧化物酶 (GSH Px)活性、肝硒含量和肝葡萄糖激酶 (GK)活性较DM组明显升高 (P <0 .0 5 ) ,而血浆丙二醛 (MDA)明显下降 (P <0 .0 5 )。结论　硒降血糖的可能机制是硒增加机体的抗氧化能力和硒的胰岛素样作用     

Effect of chlorophyllin on mercuric chloride-induced clastogenicity in mice.

The effect of chlorophyllin (1.5 mg/kg body weight) on the clastogenicity of mercuric chloride (HgCl2) was studied in vivo in mouse bone marrow cells. HgCl2 (3.0, 6.0 and 12.0 mg/kg body weight) administered by gavage induced chromosomal aberrations at frequencies directly proportional to the dose. Chlorophyllin was not clastogenic, and significantly reduced the mitotic index when given alone. Chlorophyllin administered simultaneously with HgCl2 significantly reduced the frequencies of chromosomal aberrations in a dose-dependent manner. When given simultaneously with the lowest HgCl2 concentration tested (3.0 mg/kg body weight), chlorophyllin provided total protection. A lower degree of protection was given by chlorophyllin administered 2 hr before HgCl2. The data demonstrate the potential of green plant components to modify the genotoxic activity of HgCl2 when administered orally.     

Neurotoxicological effects of low-dose methylmercury and mercuric chloride in developing offspring mice

Mercury is a well-known toxic metal and potently induces severe neurotoxicological effects, especially in infants and children. The purpose of this study was to explore the underlying mechanisms of neurotoxic effects of mercurial compounds on the different stages of developing mice. Low-doses (the probability of human exposure in mercury-contaminated areas) of methylmercury (MeHg) (M, 0.02 mg/kg/day) and mercury chloride (HgCl₂) (H, 0.5 mg/kg/day) were administered to mice of the following groups: (1) treatment with distilled water for 7 consecutive weeks after weaning (control-vehicle (CV)); exposure to mercurial compounds at different stages; (2) for 7 consecutive weeks after weaning (control-MeHg (CM) and control-HgCl₂ (CH)); (3) only during perinatal and weaning stages (MeHg-vehicle (MV) and HgCl-vehicle (HV)); and (4) in all experimental stages (MeHg-MeHg (MM) and HgCl₂-HgCl₂ (HH)). Results revealed the neurobehavioral defects (increased locomotor activities, motor equilibrium impairment, and auditory dysfunction) that correlated with increasing Hg accumulation in CM and CH groups. However, it revealed a decrease and an increase in locomotor activities in MV and HV groups, respectively; these became more severe in MM and HH groups than in MV and HV groups. Motor equilibrium performance in MV and HV groups remained normal, while that in MM and HH groups was decreased. The most severe auditory defects (altered auditory brainstem response, ABR test) found in MM and HH groups than those in the respective CM and CH, MV and HV, including absolute wave III delays and interwave I-III latencies, which suggested that the irreversible auditory dysfunction caused by mercurial compounds. Furthermore, the alteration of lipid peroxidation (LPO), Na⁺/K⁺-ATPase activities, and nitric oxide (NO_x) in the brain tissues contributed to the observed neurobehavioral dysfunction and hearing impairment. These findings provide evidence that fetuses were much more susceptible to the effects of mercurial compounds with regard to inducing severely neurotoxicological injuries as that found in human beings. The signaling of ROS/Na⁺-K⁺-ATPase/NO_x plays a crucial role in the underlying mechanism for mercurial compound-induced toxic effects in offspring.     

Effect of mercuric chloride on microbicidal activities of human polymorphonuclear leukocytes

We investigated the effects of mercuric chloride on phagocytic capacity, formation of toxic oxygen species and release of lysosomal enzymes of human polymorphonuclear leukocytes (PMNL). Our results show that HgCl₂ may alter these microbicidal functions of human PMNL without remarkable damage of cell viability. The phagocytic capacity was markedly depressed in a concentration-dependent manner. The formation of toxic oxygen species was also diminished by mercuric chloride when induced by phagocytosis. It was furthermore reduced when the PMNL were activated without phagocytosis by binding of IgG to Fc-receptors or by binding of phorbol myristate acetate to the membrane. In contrast, the release of the lysosomal enzyme lysozyme was enhanced in the presence of mercuric chloride, but not the release of β-glucuronidase. These effects may lead to impaired defense against infections and possibly to inflammatory reactions in adjacent tissues induced by released lysosomal enzymes.     

Disposition and retention of mercuric chloride in mice after oral and parenteral administration

The present study compares effects of dose size on whole-body retention and relative organ distribution of 203HgCl2, after oral and intraperitoneal administration to female mice of two strains (inbred CBA/Bom and outbred Bom:NMRI). Using whole-body retention data of oral and intraperitoneal administration, an estimated "true absorption" of a single oral dose of inorganic mercury was calculated to be about 20% at two different dose levels. At the highest oral dose, a delay in fecal elimination of nonabsorbed mercury was observed, indicating a decreased peristaltic rate. The relative hepatic deposition was larger after oral than after intraperitoneal administration, presumably due to a first-pass effect, and a correspondingly lower relative renal deposition was seen. Increasing doses at both exposure routes resulted in increasing relative deposition in liver, stomach, intestines, and spleen but decreasing relative deposition in lungs and kidneys. Bom:NMRI mice deposited a larger fraction of the whole-body burden in the kidneys and a smaller fraction in the livers than did CBA/Bom mice. Comparison to a previous study with male mice (Nielsen and Andersen, 1989) demonstrates that male and female mice deposit similar fractions of their body burden in the liver, while male mice deposit significantly larger amounts of mercury in the kidneys and smaller amounts in the carcass than do female mice. Thus, the toxicokinetics of inorganic mercury in mice depend on dose size, administration route, and sex; the mouse strain is of less importance than the other factors investigated. The absorption of inorganic mercury was estimated to be about 20%, that is, twice as high as earlier estimates.     

Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice

Mercury intoxication has been associated with male reproductive toxicity in experimental animals and mercury may have the potential to produce adverse effects on fertility in men. Vitamin E may protect against toxic effects of mercury in the liver and other tissues. To investigate the protective role of vitamin E against mercuric chloride toxicity for the testis, epididymis, and vas deferens of adult male mice, animals were treated with either mercuric chloride 1.25 mg/kg/day, vitamin E 2 mg/kg/kg, or a combination of the two treatments. Control animals were treated with water. Treatments were administered by daily gavage for 45 days. An additional group of animals treated with mercuric chloride were permitted to recover for 45 days after mercuric chloride treatments. Parameters studied included serum testosterone, epididymal sperm count, motility, and morphology, epididymal and vas deferens adenosine triphosphatase (ATPase), phosphorylase, sialic acid, glycogen and protein, testicular succinate dehydrogenase (SDH), phosphatases, cholesterol, ascorbic acid, and glutathione. Fertility was evaluated by sperm positive vaginal smears after overnight cohabitation with a female. Mercuric chloride produced a reduction in epididymal sperm count, sperm motility, and sperm viability, and there were no sperm-positive smears in this group. Biochemical tests from the male reproductive organs were also altered by mercuric chloride treatment. Coadministration of vitamin E with mercuric chloride prevented the changes in sperm and biochemical parameters and was associated with control rates of sperm positive smears after cohabitation. Animals given vitamin E with mercuric chloride also had lower concentrations of mercury in the testis, epididimyis, and vas deferens. Permitting animals to recover for 45 days after mercuric chloride treatment resulted in partial recovery of sperm and biochemical parameters. Vitamin E cotreatment has a protective role against mercury-induced male reproductive toxicity.     

Effect of mercuric chloride on contractility and transmen brane potential of the guinea-pig myocardium

1. The effect of HgCl2 in concentrations from 1 times 10(-4) to 4 times 10(-3) M on the force of contraction of the guinea-pig papillary muscles was investigated. A rapidly developing negative inotropic effect was found to be interrupted by a transient increase in contractile force. 2. In papillary muscles from reserpine-pretreated animals only the decrease of force of contraction was observed. Thus the positive inotropic effect is due to an indirect sympathomimetic action of HgCl2. 3. Mercuric chloride in concentrations above 1 times 10(-3) M raised the threshold of stimulation in more than half the muscles. 4. HgCl2 shortened the time to peak force (t1) and the relaxation time (t2); in muscles of animals pretreated with reserpine, however, t2 increased above the control value. 5. When exposed to HgCl2 all muscles developed a contracture beginning during the 5th min. 6. The time course of membrane resting potential, overshoot, and duration of action potential gradually decreased under the influence of mercuric chloride. The direct negative inotropic effect had a slightly faster onset than had the changes of the electrical parameters.     

Effect of four thiol-containing chelators on disposition of orally administered mercuric chloride.

Acute toxicity and the disposition of inorganic mercury depends on the route of exposure. Most previous studies on effect of chelators on inorganic mercury toxicity and toxicokinetics employed parenteral administration of both metal and chelator. However, the most prominent routes for human inorganic mercury exposure are the oral or pulmonary. BAL was previously considered the drug of choice in human intoxications with most heavy metals. This recommendation has been questioned during recent years due to the advent of the less toxic hydrophilic BAL analogues DMSA and DMPS. The present study, using oral administration of HgCl2 labelled with 203Hg, demonstrates that DMPS is superior to the other chelators in preventing mortality. Moreover, both DMSA and DMPS are superior to BAL and NAPA in alleviating acute toxicity and in preventing the undesirable distribution of orally administered mercury, especially to the brain. Further, oral administration of these chelators were more efficient than parenteral administration in reducing whole-body retention and organ deposition of orally administered mercuric chloride, most likely due to the prevention of intestinal uptake of mercury.     

The effect of selenium on the biliary excretion and organ distribution of mercury in the rat after exposure to methyl mercuric chloride.

The influence of selenium compounds on the biliary excretion and the organ distribution of mercury after injection of methyl mercuric chloride (4 mumol/kg) have been tested. Selenite, seleno-di-N-acetylglycine and seleno-methionine strongly inhibited the biliary excretion of mercury. Selenite even in a molar dose of 1/40 of the methyl mercury dose inhibited the biliary excretion of mercury. The less toxic seleno-di-N-acetylglycine was needed in larger molar doses and did not act as rapidly as selenite. Biliary excreted methyl mercury is known to be partly reabsorbed in the gut. Subsequently a part of it is deposited in the kidneys since drainage of the bile lowered the kidney content of mercury. Rats given selenium compounds in combination with bile drainage showed further reduction of the kidney mercury content than bile duct drainage alone. Thus the demonstrated lowering effect of selenium compounds on the kidney mercury content cannot be completely explained by an inhibition of biliary excretion of mercury. The mercury concentration in the brain was increased by the selenium compounds; the effect being dependent of the selenium dose reaching a maximum at an equimolar selenite--to methyl mercury dose ratio. The mechanisms by which selenium influences the methyl mercury kinetics are discussed.     

Effect of dietary antioxidant on mercuric chloride induced lung toxicity and oxidative stress

This study was conducted to evaluate the effect of environmental contaminant mercuric chloride on levels of trace elements and oxidative parameters in rat lungs and to investigate the efficacy of possible protection by natural antioxidant diallylsulphide (DAS) against lung injury. Twenty-four healthy male rats were randomly divided into four groups: I – control, II – DAS (200?mg/kg), III – HgCl₂ (50?mg/kg), and IV – DAS (200?mg/kg) + HgCl₂ (50?mg/kg). Mercuric chloride induced oxidative stress was indicated by a significant decrease in levels of superoxide dismutase, catalase, and glutathione peroxidase as compared to the control group (p–<0.05). Also, hydroxyproline (HYP) content in lung tissues of mercuric chloride-treated group was significantly increased (p?<?0.05). DAS markedly attenuated mercuric-induced biochemical alterations in lungs by upregulating the activities of antioxidant enzymes. These findings indicated that within the doses selected, DAS can provide significant protection against HgCl₂-induced toxicity.