Involvement of testicular DAAM1 expression in zinc protection against cadmium‐induced male rat reproductive toxicity

In order to verify the effects of exposure to Cd and Zn on testicular DAAM1 gene and protein expression and also to ascertain their involvement in the protective role of Zn in prevent the testicular toxicity Cd‐induced in male offspring rats at adult age after gestational and lactational exposure, male offspring rats, from mothers receiving either tap water, Cd, Zn, or Cd + Zn during gestation and lactation periods, were scarified on postnatal days (PND) 70. The reproductive organ (testis, epididymis, and vesicle seminal) were collected, weighed, and analyzed. The results showed that exposure to Cd in utero and through lactation decreased the relative reproductive organ weight, altered the testicular histology at the interstitial and tubular levels, and causing a significant reduction in the daily sperm production (DSP) per testis and per gram of testis, and other then altering the epididymal sperm quality. Furthermore, both mRNA and protein expression of rat testicular DAAM1 were also inhibited in Cd‐treated group. Zn supply has completely corrected the most of these toxic effects. Our results imply that Zn could prevent Cd‐induced testicular toxicity and sperm quality alteration in adult male rat after gestational and lactational exposure, probably via the restoration of the testicular DAAM1 expression inhibited by Cd.     

High Urinary Iodine Concentration Among Breastfed Infants and the Factors Associated with Iodine Content in Breast Milk

Cadmium (Cd) is a highly toxic element, which may cause toxicity to most organs in the body. Zinc (Zn) and magnesium (Mg) are essential minerals with probable benefits on Cd harmful effects. Finding an efficient and non-pathological treatment against Cd toxicity seems promising. Fifty adult rats were divided into ten experimental groups of five rats each. The Cd group was treated with 1 mg Cd/kg and the control group received 0.5 cm³ normal saline. The other eight groups received Zn (0.5 and 1.5 mg/kg) and Mg (0.5 and 1.5 mg/kg) either alone or in combination with 1 mg Cd/kg through IP injection for 3 weeks. Testis malondialdehyde (MDA), sperm parameters, and testis histopathology were investigated. Cd reduced sperm parameters and increased testis MDA. Moreover, Cd exposure caused a significant histological damage in testis of male rats. However, Zn or Mg treatment prevented and reversed Cd toxic alterations in testis. These findings suggest that co-administration of Zn or Mg could improve cadmium testicular toxicity in male Wistar rats.     

Effects of diallyl sulfide and zinc on testicular steroidogenesis in cadmium-treated male rats

Cadmium (Cd) is one of the environmental pollutants that affect various tissues and organs including testis. Harmful effect of cadmium on testis is known to be germ cell degeneration and impairment of testicular steroidogenesis. In the present study, the effect of diallyl sulfide (DAS), a sulfur-containing volatile compound present in garlic, and zinc (Zn) was investigated on cadmium-induced testicular toxicity in rats. Male adult Wistar rats treated with cadmium (2.5 mg/kg body wt, five times a week for 4 weeks) showed decreased body weight, paired testicular weight, relative testicular weight, serum testosterone, luteinizing hormone, follicle-stimulating hormone, and testicular total antioxidant capacity (TAC) and protein levels. Testicular steroidogenic enzymes, such as 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD), and marker enzymes, such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), acid phosphatase (ACP), alkaline phosphatase (ALP), and glucose-6-phosphate dehydrogenase (G6PD), showed a significant decrease in activities whereas that of gamma-glutamyl transferase was significantly increased after cadmium exposure. The results have revealed that concurrent treatment with DAS or zinc restored key steroidogenic enzymes, SDH, LDH, and G6PD and increased testicular weight significantly. DAS restored the TAC level and increased testosterone level and relative testicular weight significantly. Zinc restored testicular protein level and body weight. It can be concluded that cadmium causes testicular toxicity and inhibits androgen production in adult male rats probably by affecting pituitary gonadotrophins and that concurrent administration of DAS or zinc provides protection against cadmium-induced testicular toxicity.     

Morin mitigates cadmium-induced testicular impairment by stimulating testosterone secretion and germ cell proliferation in mice

Cadmium (Cd) is one of the heavy metal pollutants present in the environment due to human intervention. It is well known that Cd causes toxicological effects on various organs, including the testes. Morin hydrate is a plant-derived bioflavonoid with antioxidant, anti-inflammatory, and anti-stress properties. Thus, the question can be raised as to whether Morin has an effect on Cd-intoxication-induced testicular impairment. Therefore, the aim of this study was to investigate the role of Morin on Cd-mediated disruption of testicular activity. Mice were divided into three groups: group 1 served as the control group, group 2 was given Cd (10 mg/kg) orally for 35 days, and group 3 was given Cd and Morin hydrate (100 mg/kg) for 35 days. To validate the in vivo findings, an in vitro study on testicular explants was also performed. The results of the in vivo study showed that Cd-intoxicated mice had testicular disorganization, reduced circulating testosterone levels, decreased sperm density, and elevated oxidative stress and sperm abnormality. The expression of the germ cell proliferation marker, germ cell nuclear acidic protein (GCNA), and adipocytokine visfatin were also downregulated. It was observed that Morin hydrate upregulated testicular visfatin and GCNA expression in Cd-intoxicated mice, along with improvement in circulating testosterone, testicular histology, and sperm parameters. Furthermore, the in vitro study showed that Cd-mediated downregulation of testicular visfatin and GCNA expression, along with the suppressed secretion of testosterone from testicular explants, was normalized by Morin treatment, whereas visfatin expression was not. Overall, these data indicate that environmental cadmium exposure impairs testicular activity through downregulation of visfatin and GCNA expression, and Morin might play a protective role against Cd-induced testicular toxicity.     

Cadmium-induced adaptive resistance and cross-resistance to zinc in Xanthomonas campestris

Cadmium (Cd) and zinc (Zn) are environmental pollutants affecting both soil and water. The toxicity resulting from the exposure of Xanthomonas campestris, a soil bacterium and plant pathogen, to these metals was investigated. Pretreatment of X. campestris with sub-lethal concentrations of Cd induced adaptive protection against subsequent exposure to lethal doses of Cd. Moreover, Cd-induced cells also showed cross-resistance to lethal concentrations of Zn. These induced protections required newly synthesized proteins. Unexpectedly, Zn-induced cells did not exhibit adaptive protection against lethal concentrations of Zn or Cd. These data suggested that the increased resistance to Cd and Zn killing probably involved other protective mechanisms in addition to ion efflux.     

Testicular toxicity induced by dietary cadmium in cocks and ameliorative effect by selenium

Cadmium (Cd) is an ubiquitous environmental pollutant that has been associated with male reproductive toxicity in animal models. However, little is known about the reproductive toxicity of Cd in birds. To investigate the toxicity of Cd on male reproduction in birds and the protective effects of selenium (Se) against subchronic exposure to dietary Cd, 100-day-old cocks received either Se (as 10 mg Na₂SeO₃ per kg of diet), Cd (as 150 mg CdCl₂ per kg of diet) or Cd + Se in their diets for 60 days. Histological and ultrastructural changes in the testis, the concentrations of Cd and Se, amount of lipid peroxidation (LPO), the activities of the antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx), and apoptosis and serum testosterone levels were determined. Exposure to Cd significantly lowered SOD and GPx activity, Se content in the testicular tissue, and serum testosterone levels. It increased the amount of LPO, the numbers of apoptotic cells and Cd concentration and caused obvious histopathological changes in the testes. Concurrent treatment with Se reduced the Cd-induced histopathological changes in the testis, oxidative stress, endocrine disorder and apoptosis, suggesting that the toxic effects of cadmium on the testes is ameliorated by Se. Se supplementation also modified the distribution of Cd in the testis.     

Testicular toxicity induced by dietary cadmium is associated with decreased testicular zinc and increased hepatic and renal metallothionein and zinc in the bank vole <Emphasis Type="Italic">(Clethrionomys glareolus)</Emphasis>

Mechanism of testicular toxicity induced by dietary cadmium (Cd) has been less investigated than that following acute Cd injection. In the present study we characterized testicular injury in a small rodent, the bank vole, exposed subchronically to dietary Cd in a quantity of 0.9 mol/g, and determined the importance of some factors (Cd accumulation, metallothionein (MT), oxidative stress, and zinc (Zn)) in the injury. Dietary Cd induced moderate histopathological changes (hemorrhage in interstitium, necrosis and apoptosis in seminiferous tubule epithelium) in young (1 month old) bank voles fed, for 6 weeks, Fe-adequate (1.1–1.4 mol/g) and Fe-enriched (4.5–4.8 mol/g) diets. In contrast, adult (5 months old) bank voles appeared to be resistant to the toxic effects of dietary Cd, despite the fact that testicular Cd contents were higher and MT levels lower than those in the young animals. The Cd-induced histopathological changes and apoptosis were accompanied by increased testicular lipid peroxidation, decreased testicular Zn concentration and elevated levels of hepatic and renal MT and Zn. Supplemental dietary Zn (1.7–1.8 mol/g) prevented the Cd-induced testicular Zn depletion and injury. The data indicate that dietary Cd produces testicular lesions indirectly, through decreasing testicular Zn, which seems to be due to the sequestration of this element by the Cd-induced hepatic and renal MT.     

Alteration of trace element distribution and testis ACE activity in mice with high peritoneal aluminum

The present investigation was conducted to assess the effects of subacute aluminum (Al) exposure on testicular zinc (Zn), copper (Cu), and iron (Fe) distribution in mice. Animals were intraperitoneally exposed to 0, 13, or 35 mg Al/kg body weight/d for a period of 14 d. Al concentrations in serum and testis in Al-treated animals were significantly higher than those of controls. The serum concentrations of Fe were lower, whereas serum Zn and Cu showed a pattern comparable to that of controls. The accumulation of testicular Fe and Cu remarkably increased in Al-exposed groups, whereas the Zn concentration in testis was significantly reduced only at the highest dose of Al exposure. The values of testicular thiobarbituric acid reactive substances (TBARS) were also increased after Al administration, indicating increased lipid peroxidation and oxidative stress. In addition, when the testicular Al was increased, the testis-specific angiotensin-converting enzyme (testis ACE) was noted. The results of this study indicated that part of the effect of Al intoxication on testis might contribute to abnormal metabolism of other minerals, such as Fe, Zn, and/or Cu. It was also suggested that reduced testis ACE activity presumably plays an important role in oxidative damage of Al-induced testicular toxicity.     

Cadmium-Induced Adaptive Resistance and Cross-Resistance to Zinc in Xanthomonas campestris

Cadmium (Cd) and zinc (Zn) are environmental pollutants affecting both soil and water. The toxicity resulting from the exposure of Xanthomonas campestris, a soil bacterium and plant pathogen, to these metals was investigated. Pretreatment of X. campestris with sub-lethal concentrations of Cd induced adaptive protection against subsequent exposure to lethal doses of Cd. Moreover, Cd-induced cells also showed cross-resistance to lethal concentrations of Zn. These induced protections required newly synthesized proteins. Unexpectedly, Zn-induced cells did not exhibit adaptive protection against lethal concentrations of Zn or Cd. These data suggested that the increased resistance to Cd and Zn killing probably involved other protective mechanisms in addition to ion efflux.Received: 4 December 2002 / Accepted: 24 January 2003     

Unravelling cadmium toxicity and tolerance in plants: Insight into regulatory mechanisms

The occurrence of heavy metals in soils may be beneficial or toxic to the environment. The biota may require some of these elements considered essentials (like Fe, Zn, Cu or Mo) in trace quantities, but at higher concentrations they may be poisonous. Due to the difficulty in controlling environmental metal accumulation, organisms have to cope with exposure to unwanted chemical elements, specially those considered biologically nonessential. Cadmium (Cd) belongs to this latter group. The effect of Cd toxicity on plants has been largely explored regarding inhibition of growth processes and decrease of photosynthetic apparatus activity. This article reviews current knowledge of uptake, transport and accumulation of Cd in plants and gives an overview of Cd-detoxification mechanisms, Cd-induced oxidative damage and antioxidant defenses in plants. It also presents a picture of the role of reactive oxygen and nitrogen species in Cd toxicity; signalling and gene regulation are topics critically discussed. This review aspires to pinpoint new avenues of research that may contribute to a more differentiated view of the complex mechanisms underlying Cd toxicity in target tissues.     

Combined Effect of Dietary Cadmium and Benzo(a)pyrene on Metallothionein Induction and Apoptosis in the Liver and Kidneys of Bank Voles

Bank voles free living in a contaminated environment have been shown to be more sensitive to cadmium (Cd) toxicity than the rodents exposed to Cd under laboratory conditions. The objective of this study was to find out whether benzo(a)pyrene (BaP), a common environmental co-contaminant, increases Cd toxicity through inhibition of metallothionein (MT) synthesis-a low molecular weight protein that is considered to be primary intracellular component of the protective mechanism. For 6 weeks, the female bank voles were provided with diet containing Cd [less than 0.1 μg/g (control) and 60 μg/g dry wt.] and BaP (0, 5, and 10 μg/g dry wt.) alone or in combination. At the end of exposure period, apoptosis and analyses of MT, Cd, and zinc (Zn) in the liver and kidneys were carried out. Dietary BaP 5 μg/g did not affect but BaP 10 μg/g potentiated rather than inhibited induction of hepatic and renal MT by Cd, and diminished Cd-induced apoptosis in both organs. The hepatic and renal Zn followed a pattern similar to that of MT, attaining the highest level in the Cd + BaP 10-μg/g group. These data indicate that dietary BaP attenuates rather than exacerbates Cd toxicity in bank voles, probably by potentiating MT synthesis and increasing Zn concentration in the liver and kidneys.     

Effects of zinc pre-treatment on blood glutathione,serum zinc and kidney histological organisation in male rats exposed to cadmium

The effects of sub-chronic exposure to cadmium (Cd) on the blood glutathione, serum zinc and on the kidney histological organisation in rats as well as the possible protective role of zinc (Zn) are the object of this study. For this purpose, 60 male Wistar rats (8 weeks old) were divided into three groups: the first group was exposed to Cd in the form of CdCl₂, administered in five doses (each of 0.4 mg Cd/kg b.w.) on days 5, 10, 15, 20 and 25, giving a total dose of 2 mg Cd/kg b.w., i.p.; the second group was simultaneously exposed to Zn and Cd with the same timeline and the same doses of Cd as the first group but with, in addition, injections of Zn in the form of ZnCl₂, administered in doses of 0.8 mg Zn/kg b.w., giving a total dose of 4 mg Zn/kg b w, i.p.; a control group received 0.5 mL of physiological saline in an identical manner. Intoxication with Cd was followed by a significant decrease in blood glutathione, increase in oxidized glutathione as well as histological damage in kidneys. Pre-treatment with Zn exhibited a protective role against Cd toxicity with a significant decrease in serum zinc content. This fact may be explained by an excessive use of zinc in metallothionein synthesis as a cadmium detoxification agent.     

Role of beta-carotene in ameliorating the cadmium-induced oxidative stress in rat brain and testis

The role of oxidative stress in chronic cadmium (Cd) toxicity and its prevention by cotreatment with beta-carotene was investigated. Adult male rats were intragastrically administered 2 mg CdCl2/kg body weight three times a week intragastrically for 3 and 6 weeks. Brain and testicular thiobarbituric acid reactive substances (TBARS) was elevated after 3 and 6 weeks of Cd administration, indicating increased lipid peroxidation (LPO) and oxidative stress. Cellular damage was indicated by inhibition of adenosine triphosphatase (ATPase) activity and increased lactate dehydrogenase (LDH) activity in brain and testicular tissues. Chronic Cd administration resulted in a decline in glutathione (GSH) content and a decrease of superoxide dismutase (SOD) and glutathione S-transferase (GST) activity in both organs. Administration of beta-carotene (250 IU/kg i.g.) concurrent with Cd ameliorated Cd-induced LPO. The brain and testicular antioxidants, SOD, GST, and GSH, decreased by Cd alone, were restored by beta-carotene cotreatment. Concurrent treatment with beta-carotene also ameliorated the decrease in ATPase activity and the increase in LDH activity in brain and testis of Cd-treated rats, indicating a prophylactic action of beta-carotene on Cd toxicity. Therefore, the results indicate that the nutritional antioxidant beta-carotene ameliorated oxidative stress and the loss of cellular antioxidants and suggest that beta-carotene may control Cd-induced brain and testicular toxicity.     

Induction of metallothionein in a human trophoblast cell line by cadmium and zinc

The induction of metallothionein (MT) in a cell line derived from a malignant trophoblastic tumor (JAr cells) was demonstrated using the Cd/heme radioassay following exposure to Cd or Zn. Cd at an optimal concentration of 1 microM produced a 30-fold increase in MT following a 24 hr incubation. Induction by Cd was both time and dose dependent, with a significant increase in MT noted as early as 3 hr, with levels continuing to increase up to 24 hr. Zn was also quite effective in inducing MT synthesis in this cell line. Exposure to 80 microM Zn for 24 hr produced a 70-fold increase in MT. Although Cd was a more potent inducer of MT, exposure to Zn resulted in a greater magnitude of induction. The magnitude of MT induction in JAr cells was much greater than that seen in cultured trophoblasts from term chorion laeve. The degree of induction seen in this cell line makes it an interesting model for the study of MT's role in trophoblast function. MT induction in trophoblasts may reflect a protective mechanism against heavy metal toxicity and/or an integral aspect of normal zinc homeostasis.     

Enhanced zinc consumption prevents cadmium-induced alterations in lipid metabolism in male rats

It has been investigated, based on a rat model of human exposure to cadmium (Cd), whether zinc (Zn) supplementation may prevent Cd-induced alterations in lipid metabolism. For this purpose, the concentrations of free fatty acids (FFA), phospholipids (PL), triglycerides (TG), total cholesterol (TCh), and high and low density lipoprotein cholesterol (HDL and LDL, respectively) as well as the concentrations of chosen indices of lipid peroxidation such as lipid peroxides (LPO), F₂-isoprostane (F₂-IsoP) and oxidized LDL (oxLDL) were estimated in the serum of male Wistar rats administered Cd (5 or 50 mg/l) or/and Zn (30 or 60 mg/l) in drinking water for 6 months. The exposure to 5 and 50 mg Cd/l resulted in marked alterations in the lipid status reflected in increased concentrations of FFA, TCh, LDL, LPO, F₂-IsoP and oxLDL, and decreased concentrations of PL and HDL in the serum. The concentrations of LDL, LPO, F₂-IsoP and oxLDL were more markedly enhanced at the higher Cd dosage. The supplementation with Zn during the exposure to 5 and 50 mg Cd/l entirely prevented all the Cd-induced changes in the serum concentrations of the estimated lipid compounds and indices of lipid peroxidation, except for the F₂-IsoP for which Zn provided only partial protection. Based on the results it can be concluded that Zn supplementation during exposure to Cd may have a protective effect on lipid metabolism consisting in its ability to prevent hyperlipidemia, including especially hypercholesterolemia, and to protect from lipid peroxidation. The findings seem to suggest that enhanced dietary Zn intake during Cd exposure, via preventing alterations in the body status of lipids may, at least partly, protect against some effects of Cd toxicity, including oxidative damage to the cellular membranes and atherogenic action. The paper is the first report suggesting protective impact of Zn against proatherogenic Cd action on experimental model of chronic moderate and relatively high human exposure to this toxic metal.     

Cd/Zn exposure interactions on metallothionein response in Eisenia fetida (Annelida, Oligochaeta)

We studied metallothionein (MT) response in the manure worm Eisenia fetida after exposures to cadmium (Cd), zinc (Zn) or cadmium and zinc spiked media. MT was studied both at the protein level by Dot Immunobinding Assay, (DIA) and at the expression level by Northern blotting. Cd was highly accumulated by worms whereas Zn body concentration was regulated. In addition, Zn would limit Cd accumulation in worms exposed to low Cd concentrations (1 and 8 mg Cd kg(-1) of dry soil). Exposure to a mixture of Cd and Zn at high concentrations increased cytosolic MT levels. This increase would allow worms to regulate body Zn concentrations and also to limit Cd toxicity. Cd exposures increased gene expression of Cd-binding MT isoform (MT 2A) whereas Zn did not. However, when both metals were at high concentrations in the exposure medium, this expression was further increased. Several hypotheses are proposed to explain the results and the best approach to estimate metal exposure of this earthworm species is given. Further experiments have now to be performed to evaluate the usefulness of these MT responses for field contaminated soils toxicity assessment using this earthworm species.     

Protective effect of zinc supplementation on blood antioxidant defense system in rats exposed to cadmium

The aim of this study was to assess the effects of subchronic exposure to cadmium (Cd) on the antioxidant defense system of red blood cells (RBCs) and lipid peroxide concentration in the plasma, as well as the possible protective role of zinc (Zn). For this purpose, 60 male Wistar rats (8 weeks old) were divided into three groups: the first group was exposed to Cd in the form of CdCl₂, administered in five doses (each of 0.4 mg Cd/kg BW) on days 5, 10, 15, 20 and 25, giving a total dose of 2 mg Cd/kg BW, i.p.; the second group was simultaneously exposed to Zn and Cd with the same timeline and the same doses of Cd as the first group but with, in addition, injections of Zn in the form of ZnCl₂, administered in doses of 0.8 mg Zn/kg BW, giving a total dose of 4 mg Zn/kg BW, i.p.; a control group received 0.5 mL of physiological saline in an identical manner.

It was shown that exposure to Cd induced a significant decrease (p<0.05) in superoxide dismutase (Zn/Cu SOD) and catalase (CAT) activities in RBCs. Increased lipid peroxide concentration, measured by thiobarbituric acid reactive substances (TBARS), was also observed in the plasma of cadmium-exposed rats. Cd had no effect on glutathione peroxidase (GSH-Px) activity. Zn administration had a beneficial effect on the Cd-induced decrease in Zn/Cu SOD activity (p<0.05) but not on CAT activity. Animals receiving Cd and Zn simultaneously had significantly (p<0.05) lower concentrations of lipid peroxides than rats exposed to Cd alone. Our results indicate that Cd causes oxidative stress and that Zn supply in conditions of exposure to Cd can partially protect against Cd-induced oxidative stress.     

Cadmium-induced ovarian pathophysiology is mediated by change in gene expression pattern of zinc transporters in zebrafish (Danio rerio)

This study explored the potential for expression pattern of genes encoding zinc (Zn) transporters to be involved in the cadmium (Cd)-induced reproductive toxicity in female of zebrafish. For this purpose, oocytes maturity and ovarian histology as well as Cd, Zn and metallothioneins (MTs) accumulation and expression of genes encoding Zrt-,Irt-related protein 10 (ZIP10), Zn transporter 1 (ZnT1) and zebrafish metallothionein (zMT) were examined in ovaries of adult zebrafish exposed to 0.4 mg/L Cd in water and supplemented with Zn (5 mg kg⁻¹) in their diet for 21 days. Cd-exposure decreased the expression of ZnT1 and caused up-regulation of ZIP10 and zMT gene expression. These changes were accompanied by increased Cd and MTs accumulation, decreased Zn contents as well as by histopathological damages in ovarian tissues. The co-exposure of fish to Cd and Zn abolished ZnT1 down-regulation and rendered a persistently increased ZIP10 mRNA level. This treatment also decreased Cd and MTs accumulation, reversed Cd-induced Zn depletion and partially restored Cd-induced histological changes in ovarian tissues. These results imply that the downregulation of ZnT1 as well as the overexpression of ZIP10, in responses to the ovarian Zn depletion induced by Cd, play a major role in Cd accumulation and consequently in its toxicity. The protective effect of dietary Zn supplementation against Cd-induced toxicity is mediated, at least in part, by the increase of Zn availability and subsequently the induction of ZnT1 gene expression.