镉对大鼠促肾上腺皮质激素释放因子的影响

目的观察镉对大鼠中枢和外周促肾上腺皮质激素释放因子(CRF)水平的影响.方法CdCl2和CdCl2+α-hCRF(α螺旋CRF)染毒大鼠,中枢下丘脑和外周血浆中的CRF含量.结果CdCl2组动物下丘脑CRF含量均高于对照组(P＜0.05),并伴随着染镉剂量升高(r=0.6803,P＜0.05);外周血浆CRF含量各组间无统计学差异(P＞0.05).CdCl2+α-hCRF组下丘脑CRF含量与CdCl2组间无统计学差异(P＞0.05),但高于对照组(P＜0.05);外周血浆CRF水平有升高趋势.提示α-hCRF能减轻镉对中枢CRF的影响.结论镉可引起下丘脑CRF含量升高,受体拮抗剂α-hCRF能改善镉的中枢毒作用.     

Differential effects of lithium on platelet protein phosphorylation in bipolar patients and healthy subjects

In the present study we have investigated the cAMP-dependent phosphorylation system in platelets of euthymic bipolar patients and healthy volunteers before and after 15 days of lithium treatment. The results showed that 15 days of lithium treatment enhanced the basal and the cAMP-stimulated ³²P incorporation in the 22 and 38 kDa phosphoproteins in bipolar patients, but not in healthy subjects. Moreover, we provided further evidence of increased phosphorylation in the 22 kDa platelet phosphoprotein in untreated euthymic bipolar patients when compared with controls. Overall, these findings suggest an implication of protein phosphorylation in the biochemical action of lithium and in the pathophysiology of bipolar disorder. Received: 9 April 1996/Final version: 1 September 1996     

Effects of tranylcypromine on serotonin content and monoamine oxidase activitity of the human blood platelet

Inhibition (>80 per cent) of platelet monoamine oxidase (MAO-B type) and and an increase of platelet serotonin content were observed after tranylcypromine administration. It is suggested that the increase in platelet serotonin reflects MAO-A inhibition, which may be correlated with antidepressant and hypotensive effects of MAO inhibitors.     

Binding of cadmium on metallothionein in man: an analysis of a fatal poisoning by cadmium iodide

This study presents data on the organ distribution of cadmium, and Cd-protein complexes in the body of a man fatally poisoned with CdJ₂, after an oral dose of about 5 g.The levels of cadmium in different tissues were (in g per g fr. wt.): liver and kidney cortex about 80, kidney medulla, heart and testes 8.9–10.0, bile 1.9, brain 0.5 and blood 1.1.Almost all cadmium detected in the organism was bound to a low molecular weight protein, tentatively identified as metallothionein.Total amount of 18 mg cadmium was excreted in urine within 6 days of hospitalization, most likely due to Ca-EDTA treatment.The data are suggestive that cadmium induced biosynthesis of metallothionein in the subject.This paper was presented at the 2nd Symposium of Toxicology and Seminar of Pharmacology, Dvoák, September 18–19, 1970.     

Effects of long-term low-dose cadmium exposure on genomic DNA methylation in human embryo lung fibroblast cells

Cadmium is a toxic transition metal of continuing occupational and environmental concern. As a well-recognized human carcinogen, its carcinogenic mechanisms are still poorly understood. Cadmium has long been considered a non-genotoxic carcinogen and thought to act through epigenetic mechanisms. In the present study, we tested the effects of long-term low-dose cadmium exposure on DNA methylation in human embryo lung fibroblast (HLF) cells. After 2 months of exposure to 0-1.5 micromol/L cadmium, both the level of genomic DNA methylation and the enzyme activity of DNA methyltransferases (DNMTs) were increased in a concentration-related manner. Moreover, our results showed that cadmium exposure up-regulated the mRNA levels of DNMT1, DNMT3a and DNMT3b at higher concentrations. We further tested the growth dynamics of HLF cells, and observed significantly elevated growth rates, decreased cell population of G0/G1-phase and increased cell population of S-phase at 0.9, 1.2, and 1.5 micromol/L concentrations. Our study indicated that long-term low-dose cadmium exposure could disrupt DNA methylation, which may be one of the possible underlying carcinogenic mechanisms of cadmium.     

Effects of subchronic cadmium poisoning on DNA methylation in hens

Cadmium is a persistent pollutant that poses a threat to most biological organisms including birds. Although toxicity of cadmium is mainly linked to cancer, the mechanism of its carcinogenic activity remains poorly understood. Since DNA methylation is linked to cancer, we have examined the effect of cadmium on DNA methylation and DNMTs mRNA expression in hen liver and kidney. Sixty 50-day-old hyline-white hens were randomly allocated into 3 equal groups; a control group fed a basal diet, a low-dose group fed the basal diet spiked with 140 mg/kg CdCl₂, and a high-dose group fed the basal diet spiked with 210 mg/kg CdCl₂. After 60 days, liver and kidney samples were analysed for cadmium by FAAS, DNA methylation level by HPLC and DNMTs mRNA levels by semi-quantitative RT-PCR. The DNA methylation levels and the expressions of DNMT1 and DNMT3a mRNA in liver and kidney were significantly elevated by the cadmium treatment but there was no change in the expression of DNMT3b mRNA in the two tissues. The fact that cadmium increases DNA methylation and the expressions of DNMT1 and DNMT3a mRNA in liver and kidney suggests DNA methylation may be involved in the carcinogenic action of cadmium.     

硒和镉联合作用对大鼠肝脏TERT mRNA表达的影响

目的研究亚硒酸钠、氯化镉及其联合作用对大鼠肝脏端粒酶逆转录酶(TERT)mRNA表达的影响。方法健康雄性SD大鼠随机分组,每组动物5只。对照组,硒组(2.5、5和10μmol/kg Na2SeO3)、镉组(5、10和20μmol/kgCdCl2)以及硒镉联合作用组。染毒48h后取出肝脏,用RT-PCR方法检测TERT基因的表达。结果与对照组比较,3个剂量硒组的TERT mRNA虽有增高,但P>0.05,而3个剂量的镉组TERT mRNA表达均增多(P<0.01);在硒镉联合作用组中,虽然3个剂量的硒均可分别使3个剂量的镉诱导的大鼠肝脏TERT mRNA表达下降,但仅在2.5μmol/kg Na2SeO3 5μmol/kg CdCl2组、2.5μmol/kg Na2SeO3 10μmol/kg CdCl2组和5μmol/kg Na2SeO3 10μmol/kg CdCl2组,与相应剂量的镉组比较,TERT mRNA水平降低,差异具有显著性。10μmol/kg Na2SeO3 5、10和20μmol/kg CdCl2联合作用组与对照组相比,TERT mRNA水平均升高,与对应镉组相比,差异无显著性。结论镉在5~20μmol/kg的剂量条件下可以诱导大鼠肝脏高表达TERT mRNA,而一定剂量的硒对一定剂量镉引起的TERT mRNA的表达具有一定的拮抗作用。     

Effects of cadmium exposure on thyroid gland and endochondral ossification in Rana zhenhaiensis

Discovery of elevated concentrations of cadmium in the natural environment has increased awareness because of their potential threats. Amphibians are negatively affected due to their moderate sensitivity to cadmium. Here, we conduct acute and subchronic toxicity tests to examine whether, and to what extent, cadmium exposure disturbs metamorphosis, growth, and kinetic ability of Rana zhenhaiensis. We set different concentration treatment groups for the subchronic toxicity test (0, 10, 40, 160 μg Cd L⁻¹). Our findings demonstrate that cadmium exposure reduces growth parameters and the cumulative metamorphosis percent of R. zhenhaiensis. Decreases in follicular size and follicular epithelial cell thickness of thyroid gland are found in the treatment group. Further, subchronic exposure to cadmium decreases ossification ratio of hindlimbs in all treatment. Also, adverse effects of cadmium exposure on aquatic tadpoles can result in the reduced physical parameters and weak jumping ability in adult frogs. In this sense, our study suggests that cadmium adversely influences body condition and metamorphosis of R. zhenhaiensis, damages thyroid gland and impairs endochondral ossification. Meanwhile, we speculated that cadmium-damaged thyroid hormones inhibit skeletal development, resulting in the poor jumping ability, which probably leads to reduced survival of R. zhenhaiensis.     

硫酸锌对镉染毒至脐静脉内皮细胞损伤的影响

目的研究硫酸锌对镉染毒至脐静脉内皮细胞(HUVECS)损伤的保护作用及其机制。方法人脐静脉内皮细胞体外培养,随机分为正常对照组、模型组、硫酸锌组,分别以空白血清、Cdcl2血清、Cdcl2及硫酸锌血清培养48h,收集培养液,硝酸还原酶法测定NO浓度;免疫学酶联免疫吸附法测定细胞间黏附因子(sICAM-1)及细胞色素C(CytC)含量;流式细胞术检测细胞凋亡率。结果镉染毒内皮细胞损伤后NO浓度明显低于正常对照组,sICAM-1和CytC含量明显升高,细胞凋亡率明显增加,且呈剂量依赖性效应;同时补充硫酸锌处理后NO值增加,sICAM-1和CytC含量下降,细胞凋亡率与正常对照组差异无统计学意义(P>0.05)。结论补锌可通过改善内皮细胞功能,抑制内皮细胞凋亡,达到保护内皮细胞的目的。     

Effects of vinblastine on malondialdehyde formation, serotonin release and aggregation in human platelets

Effects of the microtubular agent vinblastine on human platelet malondialdehyde formation, [14C]serotonin release and aggregation were studied in suspensions of [14C]serotonin-labelled platelets. Vinblastine caused dose-dependent inhibition of malondialdehyde formation and aggregation in platelet suspensions stimulated with thrombin, ADP or palmitaldehyde acetal phosphatidic acid (PGAP). Malondialdehyde formation, aggregation and [14C]serotonin release caused by threshold doses of thrombin were reduced but not abolished by 100 muM vinblastine; 30-100 muM vinblastine abolished ADP- and PGAP-induced malondialdehyde formation and [14C]serotonin released and transformed ADP- and PGAP-induced irreversible aggregation to a diminished reversible response. Arachidonate conversion to malondialdehyde catalysed by human platelet microsomes was inhibited by vinblastine and the cyclooxygenase inhibitors indomethacin and aspirin, but not by salicylate. Vinblastine inhibited the microsome-catalysed formation of malondialdehyde from prostaglandin H2. It is concluded that vinblastine inhibits the thromboxane pathway of arachidonate metabolism in stimulated platelets, consequently inhibiting release and aggregation, and that this effect of vinblastine may be, at least in part, independent of its antimicrotubular actions.     

Effect of smoking on cadmium and lead concentrations in human amniotic fluid

The amniotic fluids of 155 pregnant women, non-smokers (n = 128) and smokers (n = 27), were investigated on their cadmium (Cd) and lead (Pb) concentrations. The mean +/- s range of Cd in the amniotic fluid of non-smokers amounted to 2.58 +/- 1.36 ng/l, that of smokers to 7.29 +/- 2.39 micrograms/l. Moreover, there was a correlation between the extent of daily cigarette consumption and Cd levels. With Pb, higher concentrations were found ranging between 23.98 +/- 9.41 ng/l for non-smokers and 21.53 +/- 7.16 micrograms/l for smokers. No correlations were seen between age, week of pregnancy, blood pressure, disorders of pregnancy and the amniotic Cd or Pb concentrations. Thus, the maternal and fetal risks of the higher Cd levels in the amniotic fluid of smoking women remain unanswered.     

Effects of cadmium exposure on zinc and copper distribution in neonatal rats

Tissue zinc and copper concentrations undergo marked changes in the neonatal rat during the first several weeks of life and it was of considerable interest to study the effect of cadmium exposure on these ontogenic changes. Long evans rats received either 2 or 10 mol cadmium chloride per kg SC at 9 days of age and were sacrificed at 20 or 36 days of age. Tissue copper and zinc concentrations in cadmium-treated rats were compared to those of age-matched controls for statistically significant changes. The tissue affected, the element altered and the direction of change in concentration, increased (+) or decreased (-), are summarized for the two dosing groups (age at dosing, age at sacrifice in days): 2 mol/kg (9, 20): kidney Zn (+), blood Zn (-), cerebral Cu (-), cerebellar Cu (+); 2 mol/kg (9, 36): blood Zn (-); 10 mol/kg (9, 20); liver, kidney, cerebral and cerebellar and blood Zn (-), cerebellar Cu (+); 10 mol/kg (9, 36]: liver and heart Zn (+), blood Zn (-); liver and heart Zn (+), blood Zn (-); kidney, cerebral, cerebellar and heart Cu (+). Changes in tissue zinc or copper concentrations produced by cadmium treatment could not be accounted for by the direct replacement of these elements by cadmium and may be due to alterations in transport of these elements. These results indicate that early life exposure to low levels of camium can have large and persistent effects on the distribution of the essential metals, copper and zinc.     

Historical perspectives on cadmium toxicology

The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and gastrointestinal symptoms occurred among persons using Cd-containing polishing agent. The first experimental toxicological studies are from 1919. Bone effects and proteinuria in humans were reported in the 1940's. After World War II, a bone disease with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and toxicodynamics of Cd were described including its binding to the protein metallothionein. International warnings of health risks from Cd-pollution were issued in the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a quantitative assessment of these effects in humans is still subject to considerable uncertainty. The World Health Organization in its International Program on Chemical Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134, IPCS. WHO, Geneva, 1-280.) identified renal dysfunction as the critical effect and a crude quantitative evaluation was presented. In the 1990's and 2000 several epidemiological studies have reported adverse health effects, sometimes at low environmental exposures to Cd, in population groups in Japan, China, Europe and USA (reviewed in other contributions to the present volume). The early identification of an important role of metallothionein in cadmium toxicology formed the basis for recent studies using biomarkers of susceptibility to development of Cd-related renal dysfunction such as gene expression of metallothionein in peripheral lymphocytes and autoantibodies against metallothionein in blood plasma. Findings in these studies indicate that very low exposure levels to cadmium may give rise to renal dysfunction among sensitive subgroups of human populations such as persons with diabetes.     

Effects of cadmium on platelet thromboxane and vascular prostacyclin production

The interaction between cadmium and arachidonic acid metabolism in platelets and vascular tissue was evaluated, in ex vivo experiments, by determining the thromboxane levels in serum and the prostacyclin production by the aortic walls in cadmium-treated rabbits. Cadmium given parenterally for 4 days in doses of 0.25, 0.5, and 1 mg/kg/day produced a dose-dependent increase of serum thromboxane B₂ levels. The effect of cadmium on prostacyclin release was biphasic. The metal, in doses of 0.25 and 0.5 mg/kg/day, inhibited prostacyclin production in an inverse ratio with administered doses. At the higher dose (1 mg/kg/day) cadmium caused an increase in prostacyclin formation. The present results suggest that the vascular action of cadmium is due, in part at least, to the involvement of the vascular-wall and platelet prostaglandin systems.     

Tricyclic antidepressant drug treatment decreases alpha 2-adrenoreceptors on human platelet membranes

The rate of thermal inactivation of [³H]5-HT, [³H]spiroperidol and [³H]LSD binding sites in a membrane preparation from the rat frontal cortex has been studied. The binding sites were inactivated as different rates and the results are interpreted as supporting the claim that [³H]5-HT and [³H]spiroperidol bind to different sites within the frontal cortex of the rat.     

肝脏损害对染镉大鼠镉分布的影响

大鼠腹腔内注射ＣｄＣｌ２０．５ｍｇＣｄ＾２＋／Ｋｇ体重，每周三次，共１０周。注射ＣｄＣｌ２第４周末，其中一组动物灌胃ＣＣｌ４９００ｍｇ／ｋｇ体重。结果表明ＣｄＣｌ２＋ＣＣｌ４组动物肝脏损害后肝镉浓度明显低于单纯ＣｄＣｌ２组，同时伴随血镉，肾镉水平显著升高。肝、肾中金属硫蛋白浓度也与相应组织中隔浓度呈类似的变化形式。ＣｄＣｌ２＋ＣＣｌ４组动物尿镉和尿金属硫蛋白浓度均明显高于ＣｄＣｌ２组。这些实验     

Effects of cadmium exposure during pregnancy on cadmium and zinc concentrations in neonatal liver and consequences for the offspring

The effects of cadmium exposure during pregnancy (by means of daily subcutaneous injections of 4.4 mol/kg to the mother) on the neonates were investigated. No effect was observed on fetal or neonatal body weights, nor on neonatal liver weights. These parameters were examined up to 5 weeks after birth. The weight of neonatal thymuses was decreased 7 and 14 days after birth due to cadmium exposure of the mothers as compared with controls. This may be caused by zinc deficiency, because zinc concentrations in fetal and neonatal livers after cadmium exposure were found to be very low 20 days after conception and 5 h after birth. Cadmium concentration in neonatal liver decreased; however, cadmium in malignant liver increased as age increased. In the mother, cadmium was transferred to the milk, as it was demonstrated in the stomach contents of the pups. Simultaneous administration of zinc in amounts equimolar to cadmium did not have any noticeable effect on the amount of cadmium transferred to the fetus or on cadmium concentrations in any of the organs investigated. It could not prevent zinc deficiency in fetal and neonatal liver. In addition, growth retardation of the thymus from exposed pups could not be prevented by zinc administration.