Effects of low-level cadmium in rats: influence of pretreatment with thiol-modulating agents

The effects of low-level cadmium (Cd) administration to rats on animal health, liver and kidney thiols, metallothionein, and glutathione reductase (GSSG reductase) and their modulation by cysteine (as a possible protector) and diethyl maleate (as a possible potentiator) have been investigated. Male Sprague-Dawley rats were treated with sodium or Cd acetate (25 micrograms Cd/kg) orally five times a week for 6 weeks. A second group of animals received cysteine (500 mg/kg; po) before each gavage while a third group received diethyl maleate (DEM) (0.85 mg/kg; ip) in addition to sodium or Cd acetate. When rats were treated with cadmium alone neither weight gain nor serum parameters indicative of hepato- or nephro-toxicity were affected. However, acid-soluble thiols, primarily glutathione, were decreased by about 25% in liver only. A tendency to a decrease in hepatic protein thiols was also noted. No changes were observed for hepatic or renal metallothionein in response to this low level of cadmium administration alone or in combination with the other treatments. Animals receiving cysteine, either alone or with cadmium, showed decreased body weight gain, but no change in serum parameters. Acid-soluble thiols in liver were lower in cysteine-treated rats (24%) and cysteine + Cd (33%) while kidney thiols were unaffected. Administration of DEM alone or with Cd did not cause any alteration in body weight gain. When given DEM + Cd, however, an increase in serum bilirubin was observed, which suggests interference with hepatobiliary function. Acid-soluble thiols were decreased by DEM alone (45%) and DEM + Cd (51%) in liver while renal thiols showed no change. Our data indicate that low-level Cd gavage decreases hepatic cellular thiols but not those of kidney. Cysteine gavage does not protect from the Cd-related effect. Indeed, cysteine itself was found to reduce acid-soluble thiols under the experimental conditions. This was observed only in liver, as was the decrease in thiols due to DEM treatment. DEM administration together with Cd resulted in signs of liver toxicity. There is no indication that inhibition of GSSG reductase by Cd might be involved in the thiol-decreasing effect of short-term repeated low-level gavage of Cd to rats.     

Fetal effects of cadmium in pregnant rats on normal and zinc deficient diets

Summary This investigation has shown that not only the extent of fetal resorption and malformation but also the types of malformation seen in rats depend upon the strain used and day of gestation. Furthermore, the effects of zinc deficiency and cadmium administration on the fetus can be at least additive, as was seen for malformations. For fetal resorption, zinc deficiency potentiated the action of cadmium.     

Renal function of workers with low-level cadmium exposure

The influence of occupational exposure to cadmium on renal function was examined in 27 male cadmium workers from plants with second-degree usage of cadmium. The levels of cadmium in the blood and urine and various protein concentrations in the urine and serum were determined. The urinary levels of beta 2-microglobulin, retinol-binding protein, and N-acetyl-beta-D-glucosaminidase were statistically significantly increased in workers with urinary cadmium levels above 50 nmol/l. SDS-PAGE electrophoresis with silver staining is probably a sensitive indicator of the early effects of cadmium on protein excretion. The currently recommended biological exposure limits may have to be lowered.     

Neurotoxic effects of low-level chronic acephate exposure in rats

Rats were administered the organophosphorus insecticide acephate at 1.0 or 10.0 mg/kg.day for 15 weeks. Blood and brain samples were collected at the end of the treatment and analyzed for cholinesterase, acetylcholinesterase, and glutamic acid decarboxylase activities and catecholamine and amino acid levels. No significant inhibition in the activity of brain AChE was noted at doses of 1.0 or 10.0 mg/kg.day. Low levels of acephate exposure (1.0 mg/kg.day), which did not alter plasma cholinesterase or RBC acetylcholinesterase activity levels, resulted in a significant elevation of plasma epinephrine and norepinephrine levels. Decreased GABA, dopamine, and tyrosine levels and glutamic acid decarboxylase activity were observed in brains of these rats. Similar changes occurred in rats exposed to 10 mg of acephate/kg.day; however, plasma cholinesterase and RBC acetylcholinesterase activities were inhibited. These observations suggest that chronic exposure to acephate altered the activity of the noncholinergic system without altering the cholinergic activity, and that low-level chronic exposure to organophosphorous compounds cannot be predicted by measuring the ChE or AChE enzyme activities.     

Interaction of zinc with cadmium and copper on ossification of embryonic chick bone in tissue culture

Histological changes are shown of ossification induced by a simultaneous exposure to zinc and cadmium or to zinc and copper using embryonic chick femur in a culture system. Cadmium caused an atrophic change of the osseous tissue in the absence of zinc but caused an osteomalacic change with a partial degenerative change in the presence of zinc after a 6-day culture. Copper caused an atrophic change in the absence or presence of zinc. These observations were partly supported by the fact that the diaphysial calcium content was significantly decreased by zinc alone, and the decrease was unaffected by cadmium or copper. Zinc significantly decreased cadmium accumulation but not copper accumulation in the diaphysis. Thus, in spite of the inhibitory effect on calcification, zinc prevented a decrease in bone matrix formation caused by cadmium but not that by copper. Exposure of chick femur culture to zinc and cadmium induced changes consistent with osteomalacia, i.e., decreased mineralization of bone, with or without suppression of matrix formation. Exposure to zinc and copper, however, induced changes consistent with osteoporosis, i.e., decreased mineralization and matrix formation.     

镉对大鼠锌代谢及其功能的影响

目的探讨镉对大鼠锌代谢及其功能的影响以及补锌后对这些影响的保护作用。方法于大鼠受孕后7、10、13 d分别注射不同剂量的氯化镉,在第21天剖宫取出仔鼠,另将成年大鼠分为正常对照组及不同的补锌和(或)染不同剂量镉组,补锌至第6天再给各组大鼠分别经腹腔注射氯化镉或生理盐水,24 h后处死动物,取肝、脑组织及血清,测定镉、锌含量及其效应标志物。结果染镉组仔鼠脑组织中的总抗氧化能力(total antioxidative capacity,T-AOC)和乙酰胆碱(Ach)的含量降低,肝组织碱性磷酸酶(AKP)的活力降低,镉含量增加,脑组织锌含量有下降趋势,且脑镉与锌呈负相关关系。成年大鼠染镉组肝和血清镉含量均高于正常对照组;肝锌和丙二醛(MDA)含量升高,但超氧化物歧化酶(SOD)活力下降;血清锌含量降低;肝及血清AKP活力低于正常对照组。预先补锌再染镉,与单染镉组相比,肝组织中的锌含量升高,MDA含量降低,SOD活力明显增高,血清镉降低,肝和血清AKP活力有不同程度的恢复。血清锌和AKP活力、肝SOD和AKP活力均与相应组织中的镉含量间呈负相关关系。结论孕期给母鼠染镉,镉可从母体进入仔鼠体内,引起仔鼠与锌有关的AKP酶活力、神经递质和抗氧化能力降低。镉可引起成年大鼠肝脏和血清中SOD、AKP等含锌酶的活力下降及肝脏脂质过氧化损害,这些损害与体内锌分布异常有关,预补锌可对这些损害有保护作用。     

Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke

Cadmium is a cumulative nephrotoxicant that is absorbed into the body from dietary sources and cigarette smoking. The levels of Cd in organs such as liver and kidney cortex increase with age because of the lack of an active biochemical process for its elimination coupled with renal reabsorption. Recent research has provided evidence linking Cd-related kidney dysfunction and decreases in bone mineral density in nonoccupationally exposed populations who showed no signs of nutritional deficiency. This challenges the previous view that the concurrent kidney and bone damage seen in Japanese itai-itai disease patients was the result of Cd toxicity in combination with nutritional deficiencies, notably, of zinc and calcium. Further, such Cd-linked bone and kidney toxicities were observed in people whose dietary Cd intakes were well within the provisional tolerable weekly intake (PTWI) set by the Joint Food and Agriculture Organization/World Health Organization Expert Committee on Food Additives of 1 microg/kg body weight/day or 70 microg/day. This evidence points to the much-needed revision of the current PTWI for Cd. Also, evidence for the carcinogenic risk of chronic Cd exposure is accumulating and Cd effects on reproductive outcomes have begun to emerge.     

The maternal distribution and placental transfer of cadmium in zinc deficient rats

Summary Although a transitory maternal zinc deficiency has been shown to result in an increased cadmium-induced fetotoxicity, the results of the present investigation indicated that a maternal zinc deficiency apparently did not affect the placental transfer of cadmium. However, a zinc deficiency did alter the maternal distribution of cadmium. The increased cadmium fetotoxicity associated with a maternal zinc deficiency may be caused by a maternal alteration rather than a direct effect on the fetus. Further study is necessary prior to any definitive statement concerning the effects of a maternal zinc deficiency on cadmium. fetotoxicity.     

The maternal distribution and placental transfer of cadmium in zinc deficient rats

Although a transitory maternal zinc deficiency has been shown to result in an increased cadmium-induced fetotoxicity, the results of the present investigation indicated that a maternal zinc deficiency apparently did not affect the placental transfer of cadmium. However, a zinc deficiency did alter the maternal distribution of cadmium. The increased cadmium fetotoxicity associated with a maternal zinc deficiency may be caused by a maternal alteration rather than a direct effect on the fetus. Further study is necessary prior to any definitive statement concerning the effects of a maternal zinc deficiency on cadmium fetotoxicity.     

Effect of ethanol on cadmium uptake and metabolism of zinc and copper in rats exposed to cadmium

Effects of chronic administration of cadmium and ethanol, alone as well as in combination, on the uptake of cadmium and its interaction with other essential trace elements in various tissues of adult rats were investigated. Cadmium given in combination with ethanol led to a pronounced increase in cadmium absorption and accumulation in all the tissues studied relative to both non-exposed controls and rats treated with cadmium alone. Both cadmium and ethanol exhibited specific effects on copper and zinc levels of the tissues. These effects often were significantly altered when the animals were co-exposed to cadmium and ethanol. The results suggested that although both cadmium and ethanol individually pose a hazard to essential trace metal homeostasis of various organs, co-exposure can pose a major threat since animals exposed to ethanol absorb much more cadmium than their unexposed counterparts.     

Effect of cadmium on prenatal development and on tissue cadmium, copper, and zinc concentrations in rats

Administration of 60 and 180 ppm Cd in the drinking water of female rats from Day 1 to Day 20 of gestation resulted in a pronounced accumulation of Cd in all organs examined with the highest increase in the intestinal wall. The copper concentration was decreased in the liver and in the intestine of females from both groups in a dose-dependent manner and in the blood of females given Cd (180 ppm). The zinc concentration was decreased only in the kidney and the intestine of females from the higher level group. The serum glucose level, hemoglobin, and hematocrit were not affected in maternal blood, but the hematocrit was reduced in fetal blood in the 60-ppm Cd group. The fetal body weight and length were decreased in both groups though litter size was not affected. The fetal growth retardation was not concomitant with an increase of Cd concentration or with a decrease of copper and zinc concentration in fetal organs. Cd concentration was not changed in the fetal brain, liver, and kidney and increased only in the gastrointestinal tract of fetuses from the 180-ppm Cd group. The zinc concentration was decreased in fetal liver in the 180-ppm group and in brain of fetuses from the 60-ppm Cd group. The copper concentration was decreased in the gastrointestinal tract and increased in kidney of fetuses from the higher level group. The decrease of copper and zinc concentrations in maternal organs is discussed in terms of the transfer of trace metals to the fetus and their reduced absorption in the intestine.     

Effect of diet on urinary and fecal excretion of cadmium,copper, and zinc from rats preaccumulated heavily with cadmium

The effects of diets on urinary and fecal excretion of cadmium (Cd), copper (Cu), and zinc (Zn) were examined after loading Cd to a maximum concentration in the livers of rats. The amount of diet and volume of water taken upad libitum by the rats were also traced throughout. The amount of Cd excreted into urine was dramatically increased immediately after changing to a low protein diet, while that excreted into the feces was slightly decreased (not significant). Zn and Cu excreted into the urine were highly and significantly increased in amount by Cd loading but less affected by diets (not significant). However, Zn and Cu excreted into the feces were lowered by the low protein diet due to the low content of the two metals in this diet. Thus, Cd, selectively released from the liver after changing to a low protein diet, was excreted primarily in the urine.     

镉对去卵巢大鼠肾脏的类雌激素作用

目的观察镉染毒对去卵巢大鼠肾脏中雌激素受体α(ERα)、雌激素受体β(ERβ)表达的影响。方法将24只健康12周龄SPF级SD雌性大鼠随机分为3组,分别为假手术(蒸馏水)组、去卵巢(蒸馏水)组、染镉(200 mg/L)去卵巢组,每组8只。假手术组切除小块卵巢周围的脂肪,去卵巢组和染镉去卵巢组切除双侧卵巢。术后1周,采用自由饮水方式进行染毒,连续染毒12周。采用电感耦合等离子体质谱法测定大鼠血镉、尿镉水平,采用酶联免疫吸附测定血清雌二醇、β2-微球蛋白水平,采用Western blot技术检测肾脏组织中ERα、ERβ蛋白的表达水平。结果与假手术组相比,去卵巢组染镉组12周末体重下降(P0.05)、肾脏系数升高(P0.05),去卵巢组及染镉去卵巢组雌激素水平降低(P0.05);与去卵巢组相比,染镉去卵巢组体重、雌激素水平降低(P0.05),肾脏系数、β2-微球蛋白、尿镉及血镉水平升高(P0.05);染镉去卵巢组血镉与尿镉、β2-微球蛋白、肾脏ERβ的表达水平正相关(P0.05),而与ERα无统计学相关性(P0.05)。结论重金属镉可降低去卵巢大鼠血清雌激素水平及增加雌激素受体β受体表达,这可能是镉的肾毒性作用机制之一。     

锌,硒对镉损伤肾脏的保护作用的探讨

使用考马斯亮蓝法、碱性苦味酸法、黄嘌呤氧化酶法分别测定镉组、镉锌组、镉硒组及对照组大鼠尿蛋白、尿肌酐、肾组织总超氧化物歧化酶（Ｔ－ＳＯＤ）活力。结果表明，染毒３周后，镉组大鼠尿蛋白、尿肌酐显著增高，肾组织Ｔ－ＳＯＤ活力受到抑制，且均与对照组有显著性差异（Ｐ＜０．０５），而镉锌组、镉硒组各指标均与对照组无显著性差异（Ｐ＞０．０５），且镉硒组各指标较镉锌组更接近于对照组。证实了镉的肾毒性作用及锌、硒的拮抗作用，并初步显示锌的作用较硒为弱。     

Metallothionein induced by cadmium or zinc inhibits lipid peroxidation in rats exposed to dimethylnitrosamine

Dimethylnitrosamine (N-nitrosodimethyamine) is a potent inducer of microsomal lipid peroxidation in the liver and kidneys. The results of this study show that prior exposure of adult rats to cadmium or zinc antagonises the effect of dimethylnitrosamine on lipid peroxidation by inducing increased metallothionein synthesis. Increased concentration of reduced glutathione (GSH) in the liver and kidney of rats pre-treated with cadmium or zinc and exposed to dimethylnitrosamine suggests that metallothionein inhibits oxidative stress. The presented results have been corroborated by findings that exposure of adult rats to cadmium or zinc may activate genes for metallothionein and glutathione-S-transferase, the protective proteins against oxidative stress.