小鼠孕期染镉对子代免疫功能的影响

小鼠在受孕第９～１５天给予氯化镉灌胃，剂量分别为０，１．０，１０．０ｍｇ／ｋｇ，检测其仔鼠在４和８周龄对各项免疫功能的变化。结果发现，从时间上来看，仔鼠外周血白细胞总数、Ｔ淋巴细胞计数和血清溶血素滴度在８周龄时低剂量组有刺激作用，在４周龄时均无影响，表现出迟发作用；从剂量上看，８周龄时上述指标均为低剂量有刺激作用，高剂量无影响。而血清溶菌酶是在４周龄时高剂量组有抑制趋势。母鼠产后２１天肝肾内有明显的镉蓄积，仔鼠胸腺、脾、肝、肾中却未见明显镉蓄积，说明镉对仔鼠免疫功能的影响不是直接作用所致     

胚胎小鼠肾脏发育中神经型一氧化氮合酶的定量分析

目的:探讨神经型一氧化氮合酶在胚胎小鼠妊娠不同时期肾脏发育中的意义。方法:选用成年健康昆明小白鼠,按雌雄比例3:1同窝饲养,采用检查阴道栓脱落的方法确定雌鼠受孕时间。选取胚龄12天(ED12)、14天(ED14)、16天(ED16)、18天(ED18)的胎鼠及出生时(PD0)仔鼠,分5组,每组各6只母鼠,每只母鼠取2只胎鼠或仔鼠,剖腹取肾脏,用免疫印迹技术(Westernblot)及光密度分析系统分别对各组胎鼠或仔鼠肾脏内nNOS进行定量检测。结果:Western blot及光密度分析显示,ED14组肾脏nNOS含量最少,随后逐渐增多,PD0组肾脏nNOS含量最多。结论:胚胎小鼠肾脏nNOS在胚胎第14天开始呈阳性表达,以后含量逐渐升高,出生时含量最高,表明nNOS在胚胎小鼠肾脏发育的早期阶段起重要作用。     

镉对大鼠胚胎和仔鼠发育及肾功能影响的研究

研究结果表明：2mg/kgCd能引起母鼠出现轻微中毒症状及体重减轻，胚胎死亡率明显增高，8mg/kgCd引起胚胎生长发育迟缓，畸形发生率明显高于对照组，胎盘重量减轻，1及2mg/kgCd引起F1代仔鼠个别行为指标异常，4mg/kgCd引起F1代仔鼠存活力明显降低、体格及行为发育迟缓，4mg/kgCd染毒孕鼠孕晚期尿蛋白明显高于对照组，而生后3周仔鼠的肾功能未见明显改变。     

甲基汞对大鼠的行为致畸效应研究

目的探讨妊娠期甲基汞暴露对Wistar大鼠的母体毒性及仔代的行为致畸效应.方法 Wistar孕鼠80只于妊娠第6～9天采用甲基汞0.00、0.01、0.05和2.00mg·kg-1@d-1连续灌胃染毒.分别进行母体毒性、胚胎毒性、仔鼠早期生理发育和神经行为发育指标、仔鼠迷宫和程序控制行为测试、亲仔两代大鼠脑组织形态学观察和单胺类神经递质(去甲肾上腺素、多巴胺、5-羟色胺)的测定.整个实验采用双盲法.结果未观察到明显的母体毒性;3个剂量组胎仔的体重、尾长均低于对照组(P＜0.01);各剂量组仔鼠的体重增长、早期生理及神经行为发育滞后于对照组(P＜0.05);各剂量组仔鼠迷宫错误次数均比对照组多(P＜0.05),具有剂量-效应关系(rs=0.257,P＜0.05);程序控制行为学习成绩比对照组降低(P＜0.05),有剂量-效应关系(rs=-0.727 3,P＜0.01);各剂量组母鼠和仔鼠脑组织均未见形态学改变,但脑组织单胺类神经递质含量均比对照组明显增高(P＜0.05),有剂量-效应关系(s=0.712 4～0.925 7,P＜0.01).结论甲基汞在不引起可观察到母体毒性剂量下,就可产生胚胎毒性,影响仔鼠神经系统的发育,导致神经行为功能的改变.     

苯系混合物对大鼠胚胎及仔鼠行为发育影响的研究

苯系混合物对大鼠胚胎及仔鼠行为发育影响的研究许清，周树森，赵春燕，路锦绣，王兵苯、甲苯、二甲苯在工业生产中应用广泛，而且在车间空气中往往同时存在。有关苯、甲苯、二甲苯联合吸入后对孕鼠及其仔代影响的研究报道很少。郑青等［１］用小鼠进行研究发现，当孕鼠吸...     

应用全胚胎培养方法评价六种工业化学物的发育毒性

应用大鼠全胚胎培养方法,检测了铅、镉、过 量维生素A、二硫化碳、1,2-二氯乙烷、氯乙烯等六种工业化学物的发育毒性,並对检测工业化学物质时染毒途径进行了探讨。结果表明,铅、镉、过量维生素A对大鼠胚胎有明显致畸作用,而二硫化     

褶合曲线分析法同时测定氯麻滴鼻剂中两组分的含量

盐酸丁螺环酮是一种新抗焦虑药，大鼠致畸胎试验结果表明，给药剂量达到７５ｍｇ／ｋｇ时，产生一定的母体毒性和胚胎毒性。但未同凶致畸胎作用。对仔鼠出生存活率、出生生长发育、学习能力、神经行为发育和生殖能力等无影响，无作用剂量水平为２ｍｇ／ｋｇ。     

孕大鼠在胚泡着床前给醋氨酚对移植仔鼠发育及行为的影响

目的:探讨药源性大鼠着床前胚泡异常对移植胚胎发育及行为的影响.方法:采用胚胎移植生物技术,评价亲代孕d 3给醋氨酚(0.25,0.5,1.0 g·kg-1),对胚泡的细胞毒性和遗传毒性及对移植后仔鼠生理功能和行为发育的影响,探索仔鼠发育与胚泡异常间的相关性.结果:醋氨酚1.0 g·kg-1对胚泡细胞产生细胞毒性及剂量依赖性遗传毒作用.孕大鼠胚泡着床前给予醋氨酚0.5,1.0 g·kg-1可引起仔鼠某些生理功能发育延缓,导致仔鼠行为畸形.结论:醋氨酚对着床前胚泡遗传毒作用与仔鼠某些生理功能发育延缓及行为畸形相关.     

镉镍单独及联合作用对小鼠胚胎肢芽细胞蛋白聚糖合成的影响

为探讨镉和镍的发育毒性机制及二者的联合作用特点，应用小鼠胚胎肢芽细胞微团培养和３５ＳＯ４掺入合成方法观察了氯化镉、氯化镍单独及联合作用对胚胎肢芽细胞蛋白聚糖合成情况的影响。结果表明，低剂量氯化镉（０．２μｇ／ｍｌ）可促进蛋白聚糖的合成，高剂量氯化镉（≥０．４μｇ／ｍｌ）可明显抑制蛋白聚糖的合成；氯化镍（１１．０～３３．０μｇ／ｍｌ）对蛋白聚糖的合成有明显的抑制作用，氯化镉和氯化镍联合染毒对胚胎肢芽细胞蛋白聚糖的合成抑制有加强作用。提示，蛋白聚糖合成紊乱可能是镉和镍引起肢体发育异常的机制之一。     

盐酸苯环壬酯对小鼠的围产期毒性试验研究

盐酸苯环壬酯分成２．５、１２．５和６２．５ｐｐｍ３个浓度组，溶于自一不中，供孕鼠从妊娠ｄ１５开始至断乳时饮用。结果显示，在相当于人临床用量１５－７５倍剂量范围内，该药对小鼠胚胎后期生长发育、母鼠分娩、哺乳及新生小鼠神经行为发育无明显影响。６２．５ｐｐｍ组孕鼠给药期间体重增长抑制，死产仔鼠数增多，雄仔鼠肝脏重量增加，表现出一定的母体毒性和发育毒性。     

Effects of sulfhydryl agents on neuromuscular transmission in the presence or absence of cadmium

Summary To test whether thiol groups are involved in neuromuscular transmission and its blockade by cadmium, the influence of sulfhydryl reagents were investigated on neuromuscular transmission, in the presence or absence of cadmium, using isolated mouse phrenic nerve-diaphragm muscles. Cadmium attenuated twitches evoked by indirect shocks but had almost no effect on twitches by direct shocks in the presence of d-tubocurarine (2.5 M). The inhibitory effect was reversed by cysteine or by an increase in external calcium. The sulfhydryl oxidizing agent DTNB 5,5-dithiobis(2-nitrobenzoic acid) potentiated the inhibitory effect of cadmium. Conversely, the reducing agent dithiothreitol (DTT) inhibited this effect. The potentiation by DTNB could be reversed by subsequent application of DTT. The sulfhydryl reagents had no influence on neuromuscular transmission in the absence of cadmium.Neuromuscular transmission was inhibited by the removal of calcium. This inhibition could be reversed by readmission of calcium. This restoration was neither potentiated nor reduced in the presence of these sulfhydryl reagents: It is suggested that an interaction of cadmium with thiol groups is independent of its calcium antagonistic action on neuromuscular transmission. Thiol groups may protect the transmission from the effect of cadmium.     

Sites of action of cadmium in vitro on hepatic,adrenal, and pulmonary microsomal monooxygenases in guinea pigs

Preincubation of hepatic, adrenal, or pulmonary microsomal preparations with cadmium produced time-dependent decreases in monooxygenase (benzphetamine demethylase, benzo(a)pyrene hydroxylase) activities. Addition of cadmium after the preincubation period had little or no effect on microsomal metabolism. As a result of preincubation with cadmium, hepatic cytochrome P-450 levels declined and the magnitude of the benzphetamine-induced type I spectral change in hepatic microsomes decreased. Cadmium also decreased hepatic NADPH-cytochrome c and NADPH-cytochrome P-450 reductase activities but had no effect on NADH-cytochrome c reductase activity. Cadmium similarly decreased cytochrome P-450 concentrations and NADPH-cytochrome c reductase activity in lung microsomes without affecting NADH-cytochrome c reductase activity. Preincubation of adrenal microsomes with cadmium had no effects on cytochrome P-450 levels, on the benzphetamine-induced type I spectrum, or on NADH-cytochrome c reductase activity. However, decreases in adrenal NADPH-cytochrome c and NADPH-cytochrome P-450 reductase activities resulted which closely paralleled the decline in adrenal monooxygenase activities. EDTA extraction of hepatic, adrenal, or pulmonary microsomes after the preincubation exposure removed about 95% of the cadmium but did not diminish the effects of the metal on microsomal monooxygenases. The results indicate that cadmium has somewhat varying sites of action on hepatic, adrenal, and pulmonary monooxygenases, but in all three tissues electron transfer to cytochrome P-450 is compromised. In addition, the effects of cadmium on microsomal metabolism persist fully even after removal of approximately 95% of the metal.     

Effects of Calcium on Cadmium Uptake and Binding in the Rat Intestine

Effects of Calcium on Cadmium Uptake and Binding in the RatIntestine. HOADLEY, J. E., AND JOHNSON, D. R. (1987). Fundam.Appl. Toxicol. 9, 1–9. Cadmium uptake in vitro was evaluatedin everted duodenal, jejunal, and ileal segments of the ratsmall intestine. Washing the sacs with EDTA subsequent to cadmiumexposure distinguished labile and nonlabile cadmium compartments.These compartments were distinct with respect to regional distribution,kinetics, and effect of calcium. Uptake into the nonlabile cadmiumcompartment but not into the labile cadmium compartment wastime dependent, consistent with transport and adsorption processes,respectively. Initial uptake rates for the nonlabile cadmiumcompartment showed both saturable and first-order kinetics.Calcium inhibited only the saturable mechanism. Cadmium uptakerate and sensitivity to calcium were greatest in the duodenumdue to the predominance of the saturable mechanism in this region.Distal to the duodenum cadmium uptake exhibited primarily first-orderkinetics. The V_max for the saturable process was reduced 90%by calcium. The absence of competitive inhibition indicatesthat calcium and cadmium do not share a common carrier-mediateduptake mechanism. The amount of cadmium bound in the labilecompartment was comparable in all segments and could be describedby a nonlinear function which was the sum of the saturable andsecond-order terms. Addition of calcium had an apparent cooperativeeffect on cadmium binding, increasing the second-order termof binding in the labile compartment. Thus calcium was foundto have a dual effect on cadmium accumulation by intestinaltissue: inhibition of saturable duodenal uptake and stimulationof binding throughout the small intestine.     

Neurotoxic effects of cadmium in young rats

This study examined the effects of cadmium on the brain of male, Sprague-Dawley rats of different ages. Cadmium was more toxic in 4-day-old than in adult rats, thus 2 and 4 mg/kg were given sc to the younger rats and 4 and 6 mg/kg to the older rats. The lower doses resulted in no mortality and the higher dose about 10% mortality in both groups. Four days after a sc injection of cadmium chloride (4 mg Cd/kg) to 4-day-old rats, lesions were evident in the corpus callosum, caudate-putamen, and cerebellum, while 2 mg/kg of cadmium produced only slight cerebellar damage. Nineteen days after injection of 4 mg Cd/kg to 4-day-old rats, a large cystic cavity was evident where the corpus callosum is normally located. In contrast, cadmium did not produce any observable brain damage in adult rats at 4 or 6 mg/kg, either 4 or 19 days after injection. Eighteen days after treatment, hyperactivity was evident in newborn rats exposed to 4 mg/kg of cadmium, but not in newborn rats exposed to 2 mg/kg of cadmium or in adult rats treated with 4 or 6 mg/kg of cadmium. Thus, cadmium at a dose that produces only a few deaths is toxic to the brain of newborn rats, as evident by hyperactivity and lesions.     

The inhibitory effect of cadmium on neuromuscular transmission in the rat.

Cadmium (0.125-1 mM) was found to inhibit the isometric response of the isolated rat hemidiaphragm during indirect stimulation, but not during direct stimulation. This effect of cadmium (1 mM) was completely reversed by ethyleneglycol bis-(aminoethyl)-N,N,N',N'-tetra-acetic acid (2 mM) or by L-cysteine (2 mM) but only partially by increased calcium. Cadmium (10 micronM) significantly reduced the quantal release of transmitter in the isolated phrenic diaphragm and a concentration of 0.1 mM frequently caused a complete failure of the endplate response after 30 min. The effect of cadmium on neuromuscular transmission could not be readily reversed by washing with cadmium-free solution. Miniature endplate potential frequency and amplitude were not significantly affected by cadmium (0.1 or 0.5 mM). The results suggest that the effect of cadmium on the isolated phrenic nerve-diaphragm is due largely to inhibition of calcium function at presynaptic nerve terminals.     

Cadmium modification of nucleolar function and structure in Physarum polycephalum

Exposure of Physarum to CdSO₄, 1.5 × 10^?3m for 2–3 hr in early S phase (the onset of DNA synthesis and nucleolar reconstruction) resulted in the appearance of ring-shaped nucleoli. We have investigated the effects of cadmium on nucleolar (ribosomal) RNA synthesis during this interval with acrylamide-agarose gel electrophoresis. Cadmium significantly depressed [³H]uridine incorporation into rRNA, with the extent of inhibition increasing with time. The effect of cadmium on RNA synthesis was quantitative, not qualitative: Cadmium depressed the amplitude of individual RNA peaks but not their distribution in RNA profiles. Cadmium exposure did not result in the appearance of new (or altered) rRNA peaks, induce detectable degradation/turnover of RNA, or alter rRNA processing. Surprisingly, no significant difference in rRNA content and distribution was observed in cells treated with cadmium which induced rings and shorter exposures which did not, suggesting that the inhibition of rRNA synthesis and the formation of ring-shaped nucleoli are coincident manifestations of cadmium toxicity at the cellular level but are not causally related.     

Comparison of the toxicity and tissue distribution of cadmium in newborn and adult rats after repeated administration

Male rats, 4 days or 7 weeks of age, were given seven sc injections of either saline (2 ml/kg) or 2 or 3 mg Cd/kg once every other day. Twelve to sixteen hours after the last injection, the animals were sacrificed and renal function was determined by measuring the in vitro uptake of p-aminohippurate by renal cortical slices, the plasma levels of creatinine and urea nitrogen, and the urinary excretion of glucose and protein. In addition, the morphology of various tissues was examined by light microscopy. The renal function tests mentioned above did not show any difference between the saline- and cadmium-treated rats at either age. However, histopathologically there was minor renal damage in the young adult rats treated with 3 mg Cd/kg. In the young adult rats treated with 2 mg Cd/kg and in the newborn rats treated with either doses of cadmium, there was no difference in the histopathology of the kidney compared with that in the salinetreated controls at the same ages. Cadmium at both doses caused extensive necrosis in the testes of adult rats, but not in newborn rats. In contrast, cadmium did not produce any observable changes in the morphology of other tissues at either age. The concentration of cadmium in the kidney, liver, adrenal, spleen, and heart of newborns treated with cadmium was lower than that of adults at comparable dosages. There was no difference in the concentration of cadmium in the testes, skeletal muscle and plasma of young adult and newborn rats. The concentration of cadmium in the lung, bone, brain, and blood of newborn rats was higher than that of young adults. There is an age difference in both the toxicity and tissue distribution of cadmium after subchronic administration to rats.     

Cadmium inhibits stimulated amylase secretion from isolated pancreatic lobules of the guinea-pig.

The effect of cadmium chloride on pancreatic exocrine secretion 'in vitro' was examined using guinea-pig isolated lobules. Cadmium (10(-3)M) stimulated amylase release when added alone to the incubation medium and the increase of amylase was unaffected by atropine. Cadmium (10(-4)M) did not significantly modify the basal amylase release. Depolarization of pancreatic nerves with potassium stimulated amylase secretion; the stimulant effect of KCl was completely inhibited by atropine. Cadmium (10(-4)M) inhibited, but did not abolish, the stimulant effect of KCl, indicating a direct effect of the metal on the acinar cell. Cadmium (10(-4)M) also inhibited the amylase release evoked by the secretagogues carbachol and caerulein, which are known to act directly on the acinar cell. Taken together with previous data reporting a large increase of pancreatic cadmium concentration following cadmium ingestion, the strong inhibition of pancreatic secretion observed in our experiments suggests that the exocrine pancreas may be regarded as a possible target organ of cadmium toxicity.     

Differences in the uptake of cadmium and mercury by rat hepatocyte primary cultures. Role of a sulfhydryl carrier

Studies measuring the uptake of cadmium or mercury in isolated hepatocytes demonstrated that hepatocytes accumulated more cadmium than mercury in serum-containing medium, serum-free medium, or balanced salt solution. The preferential hepatocellular accumulation of cadmium, independent of medium composition, suggested that the uptake mechanism for cadmium and mercury might be different in hepatocytes. Pretreatment of hepatocytes with 50 microM N-ethylmaleimide decreased cadmium uptake by 23% while having no effect on the uptake of mercury was inhibited in a concentration-dependent manner. The uptake of cadmium was maximally inhibited (80%) with 75 microM parachloromercuribenzenesulfonate or 20 microM mercury respectively. Cadmium had no effect on mercury. Hepatocytes treated with parachloromercuribenzenesulfonate or mercury accumulated cadmium at a rate closely resembling the rate of mercury uptake in untreated hepatocytes. These results suggested that an SH-containing carrier may be operative in the uptake of cadmium by hepatocytes. Mercury can interact with this carrier to inhibit cadmium uptake; however, this carrier does not appear to facilitate mercury uptake.     

Renal kallikrein excretion as a distal nephrotoxicity marker during cadmium exposure in rats

Cadmium exposure is known to induce hypertension, but development of hypertension is not universal in exposed animals. However, the cellular uptake of cadmium could also exert renal cytotoxic effects which have been, until now, essentially only studied at the proximal tubule level. Kallikrein is an enzyme synthetized in renal cortex and excreted in the urine in the distal tubule. Therefore, to evaluate the distal renal effect of cadmium, we studied the daily urinary kallikrein excretion (UKE) in conscious unrestrained female Brown Norway rats during long-term chronic exposure to 2 dosages of cadmium given subcutaneously 3 times a week, a low dose (LD): 0.25 mg/kg and a high dose (HD): 1 mg/kg. Neither dose of cadmium was able to induce significant hypertension in the treated animals. HD administration for 24 weeks resulted in a decreased UKE associated with an increase in plasma renin activity and sodium and potassium excretions. LD administration had no significant effect on UKE. Twenty weeks after stopping cadmium administration, a persistent reduction in UKE was still observed; furthermore, the group which had been previously administered a LD of cadmium, now also exhibited a reduced UKE. During this re-examination period in both groups, the UKE reductions were associated with normal systolic blood pressure, glycosuria, natriuresis. Our data show that cadmium administration can influence UKE, plasma renin activity, plasma aldosterone concentration and electrolyte excretion without inducing any variation of blood pressure. This may reflect a nephrotoxic, non-hypertensive effect. Since this effect persisted after stopping cadmium administration, it may indicate a prolonged irreversible nephrotoxic effect at the distal nephron level. Thus, UKE may be a useful non-invasive index to evaluate distal nephrotoxicity.