The role of bile and digestive juices in cadmium effect on the absorption processes in rat small intestine

The effects of bile and digestive juices was studied on the intestinal absorption of water, sodium and glucose in the small intestine of rats after their intoxication with one dose of cadmium 1.33 mg/kg of body weight injected intravenously. The investigations were carried out on 60 rats by the method of intestinal perfusion. The obtained results showed that cadmium inhibited the intestinal absorption of these substances. Bile and digestive juices abolished partially this effect during their physiological secretion. After administration of cholagogues no protective role of bile and digestive juices was observed alleviating the toxic effects of cadmium, and the intestinal absorption was even more reduced.     

Iron regulatory protein 1 is not an early target of cadmium toxicity in mice, but it is sensitive to cadmium stress in a human epithelial cell line

Disruption of iron homeostasis at the levels of intestinal absorption or erythropoiesis contributes to cadmium toxicity. Cellular iron homeostasis in metazoans is maintained by the iron regulatory proteins (IRPs) that regulate the synthesis of proteins involved in the transport, use, and storage of iron. The effect of cadmium intoxication on this regulatory system has been investigated in a cellular model of human epithelium. Cadmium exposure of HeLa cells did not activate the IRPs; rather, the amount of these proteins relative to that of housekeeping proteins decreased. Accordingly, the transferrin receptor mRNA level decreased upon cadmium insult. In a more integrated investigation, separate groups of mice had free access to different doses of cadmium in drinking water for 3 weeks. Cadmium accumulated in all analyzed organs, but its concentration in mouse tissues did not correlate with changes of the activity of the IRPs. The intoxicated mice did not show any sign of anemia, indicating that iron homeostasis was not immediately disrupted after the onset of cadmium accumulation. These data establish that cadmium destabilizes IRPs in mammalian cells, but that iron imbalance is not an early event of cadmium intoxication.     

Dietary cadmium effect on iron metabolism in chickens

A control group of 1-day-old chicks, fed on commercial food, were compared with different experimental lots that had all received a supplement of 100 ppm Cd. The hematocrit, hemoglobin and ceruloplasmin concentrations, and metal contents (Fe, Cu, Zn, Cd) in plasma and in the liver were determined after either 4 or 9 weeks of treatment. The intestinal iron absorption and their ferrokinetics were also studied in 10-week-old Cd-fed chicks. The anemia-producing effect of cadmium was already evident after the second week of treatment. The iron supplement (oral or injected) corrected the anemia, but did not correct the depression of growth effect. Plasma iron was not affected, but the liver stores were reduced by 50%. Neither the plasma copper and ceruloplasmin, nor the copper content in liver, were affected. Zinc in the liver increased significantly (P<0.05). No statistical differences in plasma iron turnover were observed between the control and Cd-fed chicks, but the red blood cell utilization was higher (P<0.01) in Cd-fed groups. The intestinal iron absorption was clearly reduced (P<0.001) where cadmium was presented in the perfusion fluid “in vivo” experiments. This suggested that cadmium reduced the iron liver stores through its effect on intestinal iron absorption. However, it also seems that it did not interfere in iron mobilization, since the plasma iron was unaffected and the Cd-fed chicks presented increased plasma iron after estrogen administration. The indirect effect of cadmium on copper metabolism is uncertain.     

Effects of synthetic glycosides on steroid balance in Macaca fascicularis

The predominantly beta-anomer of diosgenin glucoside (DG) was synthesized and its effects on cholesterol homeostasis were tested in monkeys. Cynomolgus macaques (Macaca fascicularis) were fed, during two 3-week periods, a semipurified diet with 0.1% cholesterol and a similar ration containing 1% DG, respectively. A Chow diet was given for 5 weeks between the experimental periods. Cholesterol and bile acid balance were analyzed during the last week of each semipurified diet. Diosgenin glucoside reduced cholesterolemia from 292 mg/dl to 172 mg/dl, decreased intestinal absorption of exogenous cholesterol from 62.4% to 26.0%, and increased secretion of endogenous cholesterol from -0.8 to 93.5 mg/day. The fecal excretion of neutral steroids rose from 40.7 to 157.3 mg/day; that of bile acids changed, nonsignificantly, from 23.1 to 16.0 mg/day. The cholesterol balance was -44 mg/day in the control period, and 88 mg/day in the DG-fed animals. No toxic signs were observed. Thus, when long-term studies demonstrate that the glucoside is well tolerated, DG and other synthetic glycosides with similar activities may be of use in the management of hypercholesterolemia and atherosclerosis.     

Probiotics as a Complementary Therapy in the Model of Cadmium Chloride Toxicity: Crosstalk of β-Catenin,BDNF, and StAR Signaling Pathways

Cadmium chloride (CdCl₂) is a ubiquitous environmental toxicant that causes a variety of disturbances in biological systems, including brain dysfunction and testicular tissue degeneration. On the other hand, it is supposed that beneficial properties of probiotic bacteria (Lactobacillus and Acidobacillus) are related to their capacity to adhere or bind different targets, thus leading to improved intestinal microbial balance and other benefits to the host. Bearing aforementioned in mind, the present study was undertaken to investigate the protective effect of probiotic supplementation against cadmium chloride-induced brain and testis toxicity in mice model. Animals received Lactobacillus and Acidobacillus either alone or added to folic acid for 1 week before CdCl2 intoxication in a dose of 20 mg/kg BW followed by probiotics (5?×?10⁹⁾ and/or folic acid (12 mg/kg) treatment for 3 weeks. The levels of malondialdehyde (MDA), butyrl choline esterase (BCHE), reduced glutathione (GSH), and total superoxide dismutase (SOD) activities were investigated. Finally, cadmium neurotoxicity was determined by estimating the gene expression of β-catenin and brain-derived neurotrophic factor (BDNF), as well as estimating the alterations in testicular function by determining acid phosphatase level in addition to steroidogenic acute regulatory protein (StAR) and 17-hydroxy steroid dehydrogenase (17-β HSD) gene expression. Based on our results, we can conclude that exposure of mice to cadmium chloride resulted in a significant elevation in MDA, BCHE levels accompanied with a significant reduction in GSH and SOD activities compared to the control value. CdCl₂ also downregulated the gene expression of β-catenin and BDNF, as well as acid phosphatase level, in addition to StAR and 17-β HSD gene expression. These deviated parameters were significantly modulated in the co-treated animals with probiotics compared with the cadmium-treated group. In conclusion, Lactobacillus and folic acid in a mixture with cadmium acted beneficially to an organism, increasing the cadmium excretion in feces, and consequently increasing β-catenin and BDNF in brain tissue and StAR and 17-β HSD in testis and improving their functions. Histoarchitecture analysis confirmed these results.     

Absorption of cadmium after a long-term oral administration of cadmium to dogs

A long-term experiment using beagle dogs to investigate the absorption of cadmium was conducted. The dogs in the experimental groups were given a commercial diet and pelleted food containing 1, 3, 10, 50, and 100 mg of cadmium per day. The cadmium concentration in the blood increased continuously, gradually reaching a steady state following the administration of cadmium. The cadmium excreted daily in urine increased continuously. The cumulative excreted amount of cadmium in urine was calculated by using the trapezoidal rule based on the data of excretion of cadmium in urine. Then the absorbed fraction of administered cadmium was estimated on the basis of the relationship between the cumulative excreted amount of cadmium in urine and the cumulative administered dose of cadmium after the cadmium concentration in blood reached a steady state. The absorbed fraction of cadmium decreased with an increase in the administered dose of cadmium. A dose-dependent increase between the absorbed amount and the administered dose was observed.     

Subchronic and acute preclinic toxicity and some pharmacological effects of the water extract from leaves of Petiveria alliacea (Phytolaccaceae)

We tested the effects of the aqueous extract of Petiveria alliacea leaves on acute and sub-chronic toxicity, hematocrit and blood glucose level and intestinal motility of male albino NGP mice of 20 to 25 g mean weight. Treatments were in all cases doses of 1,000 and 2,000 mg/kg animal weight and a control treatment with 0.5 ml distilled water, using 10 animals per treatment and administered orally every day (5 days per week). Experimental periods were 18 and 70 days for acute and sub chronic toxicity, respectively. No mortality nor any toxicity signs could be observed. A slight but significant increase in the glucose levels during the first three weeks was observed with the 1,000 mg/kg dose but not for the higher 2,000 mg/kg dose. After administering the doses once after a starving period of six hours, no significant differences in intestinal motility could be found.     

Intervention of α-lipoic acid ameliorates methotrexate-induced oxidative stress and genotoxicity: A study in rat intestine

Methotrexate (MTX) is an anti-metabolite, widely used in the cancer chemotherapy and rheumatoid arthritis. However, its long-term clinical use is restricted on account of its severe intestinal toxicity. The present study was aimed to investigate the intestinal toxicity of MTX and the possible protective effect of α-lipoic acid (LA) on Sprague–Dawley rats. MTX-induced intestinal toxicity was evaluated at the dose of 2.5 mg/kg for short-term (5 days treatment) and 1 mg/kg for long-term (5 days in a week for four consecutive weeks treatment) study. The possible protective effect of LA was evaluated in both short- as well as long-term study in a dose-dependent manner. MTX treatment induced diarrhoea and mortality in rats, indicating its severe toxicity in the target organ of investigation, i.e., intestine. Further, the intestinal toxicity of MTX was assessed by evaluating different parameters of oxidative stress, DNA damage, cytotoxicity as well as histological changes. Immunostaining for p53 revealed higher genotoxic assault in the intestinal cells due to MTX treatment. Pretreatment of rats with LA led to significant decrease in the oxidative stress, DNA damage, cellular damage, inflammatory changes and apoptosis as determined by malondialdehyde level, glutathione level, comet assay parameters, histological evaluation, immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In the present investigation, we report that LA pretreatment ameliorates MTX-induced intestinal toxicity in rat as evident from the protection against oxidative stress, decrease in DNA damage and protection of cellular morphology as well as improvement in the stool consistency and animal survival rate.     

Cadmium concentrations in the testes, sperm, and spermatids of mice subjected to long-term cadmium chloride exposure.

BACKGROUND: Exposures to cadmium have been reported to reduce male fertility and there are several hypotheses that suggest how reduced male fertility may result from incorporation of cadmium into sperm chromatin. The purpose of this study was to determine whether mice subjected to long-term intraperitoneal cadmium exposure incorporated cadmium into their sperm chromatin. METHODS: Male mice were exposed to 0.1 mg/kg body weight cadmium in the form of CdCl2 via intraperitoneal injection once per week for 4, 10, 26, and 52 weeks and then sacrificed. The cadmium contents of the liver, testes, pooled sperm, and pooled spermatids from dosed and control animals were determined by atomic absorption spectroscopy. Cadmium and zinc contents in individual sperm and spermatid heads were determined by particle-induced x-ray emission. RESULTS: Atomic absorption spectroscopy revealed that although cadmium accumulated in the liver and testes, cadmium was not detected in pooled sperm or spermatid samples down to minimum detectable limits of 0.02 microg/g dry weight. Particle-induced x-ray emission analyses did not show the presence of cadmium in any sperm or spermatid head down to minimum detectable limits of 15 microg/g dry weight. Particle-induced x-ray emission analyses also demonstrated that phosphorus, sulfur, and zinc concentrations in individual sperm and spermatid heads were not altered by exposure to CdCl2. CONCLUSIONS: Because cadmium was not incorporated into sperm chromatin at levels above 0.02 microg/g dry weight, the data cast doubt on hypotheses that suggest that reduced male fertility may result from incorporation of cadmium into sperm chromatin.     

慢性镉负荷雄性大鼠的睾丸及生殖内分泌功能活动

选择健康SD雄性成年大鼠60只,随机分成对照组（C组）、镉负荷中剂量组（M组）和镉负荷高剂量组（H组）,每天分别饲喂含镉0,5,10mg/kg的大鼠全价饲料,连续6周,研究了镉负荷对大鼠睾丸及生殖内分泌功能活动的影响。结果显示：在整个实验期内,M和H组大鼠睾丸组织中的镉含量极明显上升,锌含量销有下降,与对照组差异不显著;血浆镉、锌含量虽分别表现稍有升高和下降,但与对照组比较无明显差异;H组睾丸精子头计数和每日精子生成量在镉负荷第3周极显著下降,第6周时,M和H组均极明显低于对照组;在整个实验期内,H组大鼠ALP活明显低于C组;LDH－X活性在M和H组大鼠均极明显低于C组;M和H组血浆T水平下降,均低于或显著低于C组;3组间的FSH和LH水平无明显差异。结果提示：慢性镉负荷在睾丸组织中逐步蓄积可引起睾丸一些酶活性改变、精子生成减少及内分泌功能活动低下。     

Protective Effects of Lactobacillus plantarum CCFM8610 against Acute Cadmium Toxicity in Mice

This study evaluated the protective effects of Lactobacillus plantarum CCFM8610, a selected probiotic with good cadmium binding capacity, against acute cadmium toxicity in mice. Ninety mice were divided into prevention and therapy groups. In the prevention groups, CCFM8610 was administered at 10⁹ CFU once daily for 7 days, followed by a single oral dose of cadmium chloride at 1.8 mg cadmium for each mouse. In the therapy groups, the same dose of CCFM8610 was administered for 2 days after an identical single dose of cadmium exposure. Mice that received neither cadmium nor culture or that received cadmium alone served as negative and positive controls, respectively. The effects of both living and dead CCFM8610 on cadmium ion concentrations in feces, liver, and kidney were determined. Moreover, the alterations in reduced glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and histopathology in the liver and kidney were investigated. The results showed that compared to the mice that received cadmium only, CCFM8610 treatment can effectively decrease intestinal cadmium absorption, reduce tissue cadmium accumulation, alleviate renal and hepatic oxidative stress, and ameliorate hepatic histopathological changes. Living CCFM8610 administered after cadmium exposure offered the most significant protection. Our results suggested that CCFM8610 is more effective against acute cadmium toxicity than a simple antioxidant treatment due to its special physiological functions and that it can be considered a new dietary therapeutic strategy against acute cadmium toxicity.     

Sexual specificity of change of pancreatic alpha-amylase activity in rats in cadmium intoxication

It was shown that the activity of alpha-amylase in the pancreas tissue, intestine content and blood, as well as kinetic characteristics in different substratum concentration changed in males and females after unitary oral administration of chloride cadmium in the dose 5 mg/kg. It was revealed that, after a single administration of chloride cadmium, growth of the pancreas weight, contents of protein and activity of alpha-amylase in the pancreatic tissue increased with parallel reduction of activity of enzyme in the small intestine. In acute cadmium intoxication, functional reorganizations in the pancreas are identical to initial stages of carcinogenic shifts. Such shifts are more expressed in females in comparison with males, especially after the cadmium intoxication.     

Relation between lipid peroxidation and iron concentration in mouse liver after acute and subacute cadmium intoxication

In this study the effect of acute and subacute cadmium (Cd) intoxication on iron (Fe) concentration and lipid peroxidation (LPO) was investigated in the livers of Swiss mice. Animals were divided into two groups: the Cd group – mice intoxicated with Cd and controls. In acute time-response studies, Fe and malondialdehyde (MDA) levels were determined at 4, 6, 12, 24 and 48 h after a single oral dose of Cd (20 mg Cd/kg b.w.). In the subacute experiment, mice were given 10 mg Cd/kg b.w. orally every day for 14 days; Fe and MDA contents were determined in liver after 1 and 2 weeks. Acute Cd intoxication induced a significantly increased hepatic Fe content after 4 and 6 h, and a statistically significant increase in MDA 6, 12 and 24 h after Cd administration, although a significantly decreased MDA level was observed after 48 h. The results suggest development of early oxidative stress in livers of mice after acute intoxication with Cd. The decreased MDA observed after 48 h occurred presumably due to the adaptive response of the organism. Subacute Cd intoxication induced a significant decrease of hepatic Fe and MDA levels at both investigated time intervals compared with control. These results indicate a positive correlation between hepatic Fe and MDA content and suggest that prolonged Cd intoxication decreases hepatic LPO indirectly, by reducing the Fe content of mouse liver.     

Glycosaminoglycan metabolic disorders in periosteal and endosteal osteogenic cells in phenol poisoning

The analysis of 35S sulphate incorporation into the growing bone structures in the experiment with 2-3 week guinea pigs subjected to long-term phenol intoxication made it possible to conclude that 35S sulphate assimilation by the osteogenic cells of periost and endost is less intensive in the treated animals, particularly in those receiving a large dose of phenol, (40 mg/kg) than in the control ones. This testifies to the reduction of the biosynthesis rates of sulphated glycosaminoglycans in the bone growth regions.     

Effect of cadmium on enzymatic digestion and sugar transport in the small intestine of rabbit

Cadmium compounds are found widely in our environment: for example, in food, water, soil, and ambient air. The most important exposure route of animals to cadmium in the general environment is via oral exposure. In oral cadmium intoxication, the immediate target organ is the gastrointestinal tract. The aim of the present work was to determine how cadmium acts on the intestinal absorption of sugars and on the sucrase activity through rabbit jejunum, after in vitro administration and/or oral administration of CdCl₂ in drinking water. Results obtained show that cadmium decreasesD-galactose accumulation in the jejunum tissue. This effect seems to be the result of an action mainly located on Na⁺-dependent sugar transport of the mucosal border of the intestinal epithelium, because cadmium seemnnot to modify the sugar diffusion across the intestinal epithelium. Cadmium has also been shown to inhibit the (Na⁺-K⁺)-ATPase activity of the enterocyte, which might explain the inhibition of theD-galactose Na⁺-dependent transport. Nevertheless, a direct action of the cadmium molecule on the Na⁺-dependent carrier cannot be discarded. Cadmium altered the sucrose activity when it was administered in the drinking water for 4 d.     

Effect of supplemental magnesium on the kidney levels of cadmium, zinc, and copper of mice exposed to toxic levels of cadmium

In this report, we present the results of our investigations on the effect of Mg pretreatment on Cd and bioelements (Cu and Zn) contents in kidney of mice exposed to acute and subacute Cd intoxication. Acute intoxication was performed on male Swiss mice given a single oral dose of 20 mg Cd/kg body weight and mice given the same dose of Cd but pretreated with 40 mg Mg/kg body weight. For subacute intoxication one group of mice was given 10 mg Cd/kg body weight every day, for 2 wk, and the other one received the same dose of Cd after oral Mg intake of 20 mg/kg body weight. Cd, Cu, and Zn content was determined in kidney by atomic absorption spectrophotometry. In acute Cd intoxication, Mg pretreatment resulted in significant decrease of Cd in kidney after 4 and 6 h, compared with animals given only Cd. Under the condition of subacute Cd intoxication, Mg supplementation reduced Cd kidney content after 2 wk for about 30%, compared with animals treated with Cd only. The effect of Mg on Cu and Zn kidney content was also beneficial.     

镉在大鼠前列腺组织内的蓄积

为比较重金属镉在去势与非去势雄性大鼠前列腺组织内蓄积量的变化,将60只健康雄性SD大鼠随机分为六组:对照组、去势对照组、低剂量镉组(2.5 mμmol·Kg^-1)、高剂量镉组(20 mμmol·Kg^-1)、去势低剂量镉(2.5 mμmol·Kg^-1)组、去势高剂量镉(20 mμmol·Kg^-1)组,18个月后取材进行实验.利用原子吸收分光光度法检测大鼠前列腺组织中重金属镉含量.与非去势对照组相比,各去势组大鼠前列腺组织内镉含量明显降低;注射镉后,大鼠前列腺组织镉含量明显高于对照组,但高、低剂量组之间无显著差别.实验表明长期镉暴露后,前列腺组织内镉含量明显增加;经去势手术的大鼠,长期镉暴露后前列腺组织内镉含量未升高,但机制并不明确.     

Effect of dietary calcium on cadmium absorption and retention in suckling rats

The effect of calcium supplementation on absorption and retention of cadmium in the suckling period was evaluated in Wistar rat pups of both sexes. Animals were maintained in the litters with the mother rats and supplemented with 1%, 3% or 6% calcium (as CaHPO₄×2H₂O) in cow's milk by artificial feeding from day of birth 6 through 14. All rats were exposed to cadmium (as CdCl₂×H₂O) either orally or parenterally. Oral cadmium dose of 0.5 mg/kg body weight a day was administered through nine-day period of calcium supplementation and parenteral cadmium dose was injected subcutaneously in a single dose of 0.5 mg Cd/kg body weight prior to calcium supplementation. On experimental day 10 (at the age of pups of 15 days) all animals were killed and the liver, kidneys, brain and carcass (body without organs and skin) were removed for element analyses. Cadmium and essential elements calcium, zinc and iron were analysed in the tissues by atomic absorption spectrometry. Results showed that after oral exposure cadmium concentrations in all calcium-supplemented groups were significantly decreased in the organs and carcass and that the effect was dose-related. No such effect of calcium was found after parenteral cadmium exposure. Calcium supplementation per se significantly increased calcium concentration in the carcass and had no effect on iron in organs and zinc in carcass. It was concluded that calcium supplementation during the suckling period could be an efficient way of reducing oral cadmium absorption and retention without affecting tissue essential trace element concentrations.     

A Possible Antineoplastic Potential of Selective,Irreversible Proteasome Inhibitor,Carfilzomib on Chemically Induced Hepatocarcinogenesis in Rats

The antineoplastic effect of carfilzomib (CFZ) against chemically induced hepatocarcinogenesis was studied. A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group. Rats in group 1 (control group) were given dimethylsulphoxide (DMSO) (0.4 mL/kg i.p) twice a week for 3 weeks from week 8 to week 10. Animals in groups 2 and 3 were given CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. Rats in group 4 were given diethylnitrosamine (DENA) at a dose of 0.01% in drinking water for 10 weeks and received a DMSO (0.4 mL/kg i.p) twice a week from week 8 to week 10. Animals in groups 5 and 6 were given DENA at a dose of 0.01% in drinking water for 10 weeks and treated with CFZ (2 and 4 mg/kg i.p) twice a week from week 8 to week 10, respectively. CFZ succeeded in suppressing the elevated serum tumor marker α‐fetoprotein and carcinoembryonic antigen. The antineoplastic effect of CFZ was also accompanied by normalization of elevated hepatic tissue growth factors, matrix metalloproteinase‐2 and tissue inhibitor of metalloproteinase‐1, and augmentation of hepatic endostatin and metallothionein. A histopathological examination of liver samples treated with CFZ after DENA intoxication correlated with the biochemical observation. Treatment with CFZ confers an antineoplastic activity against chemically induced hepatocarcinogenesis. These findings suggest that CFZ plays a pivotal role in the treatment of hepatocarcinogenesis.     

Effect of (-)-para-fluoro-deprenyl on survival and copulation in male rats.

Six-month old male rats were treated with 0.25 mg/kg, s.c., (-)p-fluoro-deprenyl (n = 40) or salt solution (n = 20) three times a week for 25 months. Three of the 20 saline-treated and 15 of the 40 drug-treated males survived (p = 0.05). Sexual activity of the survivors was tested at the end of the experiment. Three of the (-)p-fluoro-deprenyl-treated 31-month-old males proved to be sexually fully active, though, Wistar rats lose their ability to ejaculate by completing their second year of life. Non-copulator, 13 month old male rats were treated instead of the usually used 0.25 mg/kg dose with 0.01 mg/kg, s.c., (-)deprenyl (n = 9), (-)p-fluoro-deprenyl (n = 9) and salt solution (n = 9), three times a week, for 82 weeks and mating activity was tested weekly. The lifespan of the non-copulators was very short: 102 weeks for saline (n = 9), 106 weeks for (-)deprenyl (n = 8) and 104 weeks for (-)p-fluoro-deprenyl (n = 7). Survival was lightly changed by this very small dose treatment, one (-)deprenyl-treated male and two (-)p-fluoro-deprenyl-treated rats remained alive. The copulatory activity, however, was substantially improved.