Oral Cd Research Articles

Experimental studies on reproductive and perinatal effects of lead and cadmium

Lead is a known reproductive toxicant in humans and animals. Data on cadmium reproductive effects in humans are inconclusive, and in female animals are lacking. More information on the toxicokinetics and toxicity of Pb and Cd during the reproductive period and in developing young is needed. Experimental studies on rats conducted in laboratories in Croatia and in the USA separately and as collaborative research show that Pb or Cd have effects on reproductive function. Chronic or subchronic oral Pb or Cd exposure of the dams causes decreased pup weight and survival, and depressed serum progesterone concentration in Cd‐exposed dams at the term. No paternally mediated Pb effects were found in offspring. Organ Pb or Cd accumulation was accompanied by changes in essential element concentrations in both dam and foetus. Acute in vivo and in vitro exposure to Cd had specific effects on gonadal steroidogenesis in both males and females. Proposes possible sites of action of Cd in the steroidogenic pathway.

Modulation of tissue trace metal concentrations in weanling rats fed different levels of zinc and exposed to oral lead and cadmium

The effects of varying dietary zinc (Zn) and oral lead (Pb) and cadmium (Cd) exposure on tissue trace metal concentrations were investigated in weanling rats using a 4 X 3 factorial design. Male SD rats (72, 6/group) were fed diets containing either Zn deficient (<1 mg/kg; ZnD), Zn control (12 mg/kg; ZnC), 60 mg/kg high Zn (ZnH) or 12 mg/kg Zn PF (pairfed) and given 10 mg/L Na (control), 20 mg/L Pb or 5 mg/L Cd in drinking water for 4 weeks. Zn deficiency and oral Pb and Cd exposure reduced Zn and Cu concentrations in the kidney by 29% and 36% (P≤0.05), respectively. ZnH diet also decreased liver and plasma Cu and lowered kidney Cu in the Cd exposed group. The accretion of Pb was highest in kidney, while Cd levels were greater in the kidney than the liver (42% of control). The data indicate that low Zn status altered Zn and Cu concentrations in tissues and that there was significant interaction among the essential and toxic metals in the liver and kidney of weanling rats.

Effect of orally administered cadmium on in situ pH, PCO2, and bicarbonate concentration in rat testis and epididymis.

Acute injections of high doses of cadmium (Cd) induce marked testicular necrosis. However, the effects of low-dose oral Cd exposure, on a chronic basis, are not well documented. The present investigation was designed to examine the effects of such exposure on in situ pH, PCO2, and bicarbonate concentration ([HCO3-]) in the rat testis and epididymis, plasma testosterone levels, and testis and epididymis weights. Male Sprague-Dawley rats were exposed to 50 or 100 ppm Cd for 40 d. Oral administration of 50 or 100 ppm Cd was associated with significant alkalinization of luminal fluid in seminiferous tubules (ST) but did not alter in situ pH values in proximal caput (PCP), middle caput (MCP), or proximal cauda epididymidis (PCD). The in situ PCO2 values in ST, PCP, MCP, and PCD of control animals were indistinguishable from each other and from values after Cd exposure, and all values were significantly higher than system arterial blood (SAB) PCO2. Oral Cd exposure at 50 or 100 ppm did not change the values for bicarbonate in SAB, PCP, or MCP but increased markedly the value in ST. Plasma testosterone levels and testis and epididymis weights were not altered after oral cadmium administration. These findings suggest that, at the doses employed in this study, Cd exposure may result in subtle alterations in the blood-testis barrier and subsequent impairment of acid-base pathways. Furthermore, the traditional view of Cd-related testicular insult based on acute injection protocols needs to be reevaluated in terms of environmental relevance.

Effect of cadmium on Fe+3-transferrin formation in the rat intestinal mucosa.

The effect of cadmium (Cd) on iron (Fe) metabolism has been an important subject for Cd toxicity, since anemia is usually observed in Itai-Itai patients who are exposed for long periods to Cd from the surrounding environment. It was previously accepted that Cd-induced anemia was not dependent on the route of administration. Thereafter, however, it was shown that oral Cd administration was essential for the development of anemia. Studies suggest that one of the possible sensitive sites of competition between Cd and Fe is in the gastrointestinal tract. Cd competes with Fe at one or more steps in the transport system and these metals undergo the same step(s) during their absorption. An hypothesis implies that these two metals possess a common carrier. Two Fe-binding proteins, ferritin and transferrin are well documented in the case of Fe deficiency but not in Cd exposed animals. Recently, the authors reported that the status of mucosal Fe-binding proteins in rats fed with Cd was similar to that in the Fe deficient rats. The present work was performed in an attempt to clarify the effect of in vivo and in vitro Cd on mucosal transferrin formation, which is one of two main Fe-binding proteins.

Chronic cadmium exposure during pregnancy in the mouse: influence of exposure levels on fetal and maternal uptake.

The uptake and distribution of orally administered cadmium-109 was studied in pregnant mice. Female outbred QS mice were given cadmium (Cd) supplemented drinking water for 1 mo before pregnancy and for the duration of pregnancy. The water contained either 0.0015 ppm Cd, 0.24 ppm Cd, or 40 ppm Cd. For the duration of pregnancy, 1.48 micrograms Cd/l (0.0015 ppm) in each solution was in the form of 109Cd (1 mCi/l). Control mice were given distilled/deionized water. On the day before term the mice were killed and a variety of adult and fetal tissues were examined in a gamma counter to determine their 109Cd concentrations. For each group the 109Cd concentration was highest in the maternal gastrointestinal tract, liver, and kidneys and lowest in the central nervous system (CNS) and blood. In general, the 109Cd concentrations in each organ were similar for each group of mice and were therefore independent of the overall oral Cd dose. A notable exception was the lower level in the duodenum in the 40 ppm group. In the fetal unit the chorioallantoic placenta contained the highest concentration of 109Cd. Concentrations in the fetuses were very low, comparable to those in the adult CNS. The 109Cd levels in the fetuses from group A were about fivefold greater than those of the fetuses from group C. There was no statistically significant evidence of specific localization in the fetal brain, kidney, or liver.

Binding of cadmium chloride and Cd-metallothionein to mucosal brush border membrane of the rat small intestinal tract.

Even though Cd is categorized as a metal with low absorption from the gastrointestinal tract, its total body burden predominantly results from its gastric absorption. Oral Cd also eventually triggers an endemic disease, Itai-Itai disease, in certain areas of Japan. Cd absorption is influenced by several endogenous or exogenous factors such as aging, sex, and food components. To resolve the mechanism of Cd absorption from the gastrointesinal tract, metallothionein (MT) is one of the most interesting endogenous substances. Although the protein induced by Cd exists mainly in the mucosal cytosol fraction as well as in those of liver or kidneys, compared to the function of renal or hepatic MT, its function seems to be slightly different. So far, it is reasonable to assume that the protein is involved in the prevention of the transfer of Cd from the mucosa to the body. However, the behavior of MT in/on the mucosal brush border membrane (BBM) is unclear. In order to gain a better understanding of this point, the authors estimated the Cd binding of CdCl/sup 2/ and Cd-Mt to BBM isolated from control and Cd-exposed rats.

Dose response of rat liver to low level cadmium.

Acute exposure of mammals to a large cadmium dose is know to result in overt liver injury. This is preceded by the enhanced formation of metallothionein (MT) and possibly by changes in cellular glutathione (GSH). Moreover, disturbances in the metabolism of zinc, copper and calcium have been reported in various organs of mammals following large single or multiple subcutaneous or oral Cd doses. Recently, the liver has been considered also to represent a major target organ in long term Cd toxicity. The previously employed oral low level Cd dosage regimen (25 ug Cd per kg per day) resulted in hepatic Cd levels in rats which approximated those found in environmentally Cd exposed man. The objective of the present study was to investigate additionally the effect of a lower (2.5 ug Cd/kg) and a higher oral Cd dosage (250 ug Cd/kg) on liver thiols, essential metals and urea as a measure of the metabolic integrity of liver cells. Since in vitro and in vivo studies indicate that mitochondria may be affected by Cd these organelles were also investigated.

Role of mucosal metallothionein preinduced by oral Cd or Zn on the intestinal absorption of a subsequent Cd dose.

Intestinal absorption of Cd is one of the main channels of Cd entry into the body leading to systemic toxicity. When Cd is absorbed, it first comes into contact with the gastrointestinal mucosa, particularly the duodenum mucosa. Therefore, the mucosal behavior of Cd is one of the most important factors, not only for determining the absorption rate, but also as concerns the interactions between Cd and other metals.

Metallothionein mRNA induction in mouse small bowel by oral cadmium and zinc.

Induction of metallothionein mRNA was investigated in organs of mice receiving oral zinc and cadmium. The low molecular weight, heat stability, and 30% cysteine content of metallothionein facilitated its detection in cell-free translation products analyzed by Sephadex G-50 chromatography and by gel electrophoresis. Native and heat-denatured [35S]cysteine-labeled polypeptides directed by poly(A)+ mRNA from organs of mice exposed orally to 3 mg CdCl2 or 15 mg ZnCl2 were compared with those of control mice. Although parenteral administration of CdCl2 (30 micrograms) did not elicit a measurable metallothionein mRNA accumulation in gut, oral administration of this metal induced intestinal metallothionein mRNA to high levels; translatable metallothionein mRNA was not detected in control organs. Five hours after oral CD or Zn, metallothionein constituted 12-17% of [35S]cysteine directed into protein by gut mRNA, and metallothionein mRNA was induced to similar levels in liver, kidney, and spleen of the same mice. After oral Zn, metallothionein mRNA levels in proximal jejunum were twice those in other regions of intestine. Metallothionein mRNA accumulates rapidly in small bowel after oral Zn and Cd; simultaneous induction in other mouse organs indicates a systemic response.

Chronic cadmium exposure: relation to male reproductive toxicity and subsequent fetal outcome.

Acute injections of high doses of Cd induce marked testicular necrosis. However, the effects of low-dose, oral Cd exposure on a chronic basis are not well documented. The present investigation was designed to examine the effects of such exposure as reflected in parameters of spermatotoxicity and histology. Moreover, the impact on fetal outcome was measured by evaluating teratological and postnatal neurobehavior endpoints. Male Long-Evans hooded rats (100 d of age) were exposed to 0, 17.2, 34.4, or 68.8 ppm Cd for 70 d. During this period, the animals were maintained on a semipurified diet to control for the contributions of Zn and other trace elements. Near the end of exposure the males were mated to three female rats. One was sacrificed on d 21 of pregnancy for teratological assessment, including fetal weight, and determination of preimplantation and postimplantation loss. The other two dams were allowed to deliver, and their offspring were tested on tasks of exploratory behavior (d 21) and learning (d 90). Subsequently, the male parent was sacrificed and a variety of measures recorded including weights of testes and caudae epididymides, sperm count and sperm morphology, and Cd content of liver and kidney. One of the testes was also evaluated histologically. No significant effects were observed on any of the parameters of reproductive toxicity or fetal outcome. These findings suggest that, at the doses employed in this study, Cd did not have significant deleterious effects on the male reproductive system. Morever, the traditional view of Cd-related testicular insult, based on acute exposure, injection protocols, needs to be reevaluated in terms of environmental relevance.

Effects of dietary and inhalative cadmium on hemoglobin and hematocrit in rats.

Th dfference of the effects of dietary and inhalative cadmium on hemoglobin and hematocrit was investigated using Wistar male rats. For the inhalation studies, rats were exposed to CdCl/sub 2/ aerosols (0.2 mg Cd/m/sup 3/) for 66 days. For the dietary experiments the rats received 25, 50 and 100 ppM cadmium as CdCl/sub 2/ in drinking water. The following parameters were measured: the body weights of the animals, hematocrit and hemoglobin in blood, and the Cd content of liver and kidney. The results showed a retardation of growth in the aerosol-exposed group and the group with 100 ppM oral Cd intake. The relation of the Cd content of kidney to liver averaged 1.7 for the oral-exposed groups and 4.4 for the inhalation-exposed groups. The hematocrit and hemoglobin values for the inhalation-exposed rats showed no significant differences when compared to the controls, but the values for the dietary cadmium group showed a significant reduction.