Strain difference of cadmium-induced testicular toxicity in inbred Wistar–Imamichi and Fischer 344 rats

Previously, we reported that Wistar–Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl₂, sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.     

Strain differences of cadmium-induced hepatotoxicity in Wistar-Imamichi and Fischer 344 rats: involvement of cadmium accumulation

We previously reported that Wistar-Imamichi (WI) rats have a strong resistance to cadmium (Cd)-induced lethality compared to other strains such as Fischer 344 (Fischer) rats. The present study was designed to establish biochemical and histological differences in Cd toxicity in WI and Fischer rats, and to clarify the mechanistic basis of these strain differences. A single Cd (4.5 mg/kg, s.c.) treatment caused a significant increase in serum alanine aminotransferase activity, indicative of hepatotoxicity, in Fischer rats, but did not in WI rats. This difference in hepatotoxic response to Cd was supported by pathological analysis. After treatment with Cd at doses of 3.0, 3.5 and 4.5 mg/kg, the hepatic and renal accumulation of Cd was significantly lower in the WI rats than in the Fischer rats, indicating a kinetic mechanism for the observed strain differences in Cd toxicity. Thus, the remarkable resistance to Cd-induced hepatotoxicity in WI rats is associated, at least in part, with a lower tissue accumulation of the metal. Hepatic and renal zinc (Zn) contents after administration were similarly lower in WI than in Fischer rats. When Zn was administered in combination with Cd to Fischer rats, it decreased Cd contents in the liver and kidney, and exhibited a significant protective effect against the toxicity of Cd. We propose the possibility that Zn transporter plays an important role in the strain difference of Cd toxicity in WI and Fischer rats.     

Discovery of ZIP transporters that participate in cadmium damage to testis and kidney

It has been known for decades that cadmium (Cd) must enter the cell to cause damage, but there was no mechanism to explain genetic differences in response to Cd toxicity until 2005. Starting with the mouse Cdm locus associated with differences in Cd-induced testicular necrosis between inbred strains, a 24.6-centiMorgan region on chromosome 3 was reduced ultimately to 880 kb; in this segment is the Slc39a8 gene encoding the ZIP8 Zn²⁺/HCO₃⁻ symporter. In endothelial cells of the testis vasculature, Cd-sensitive mice exhibit high ZIP8 expression, Cd-resistant mice exhibit very low expression. A 168.7-kb bacterial artificial chromosome (BAC) from a 129S6 (Cd-sensitive) BAC library containing the Slc39a8 gene was inserted into the Cd-resistant C57BL/6J genome: Cd treatment produced testicular necrosis in BAC-transgenic BTZIP8-3 mice but not in non-transgenic littermates, thereby proving that the Slc39a8 gene is indeed the Cdm locus. Cd-induced renal failure also occurred in these BTZIP8-3 mice. Immunohistochemistry showed highly expressed ZIP8 protein in the renal proximal tubular epithelial apical surface, suggesting that ZIP8 participates in Cd-induced renal failure. Slc39a14, most closely evolutionarily related to Slc39a8, encodes differentially-spliced products ZIP14A and ZIP14B that display properties similar to ZIP8. ZIP8 in alveolar cells brings environmental Cd into the organism and ZIP14 in intestinal enterocytes carries Cd into the organism and into the hepatocyte. We believe these two transporters function endogenously as Zn²⁺/HCO₃⁻ symporters important in combating inflammation and carrying out other physiological functions; Cd is able to displace the endogenous cation, enter the cell, and produce tissue damage and disease.     

Spontaneous and apomorphine-induced locomotor changes parallel dopamine receptor differences in two rat strains

Two inbred strains of rats (F344 and Buffalo) were tested for differences in spontaneous and apomorphine-induced inhibition of locomotor activity. F344 rats showed greater percentage decreases in locomotion after apomorphine (0.25, 1.0 and 2.5 mg/kg) compared to the Buffalo strain. F344 rats also showed higher levels and slower habituation of spontaneous locomotor activity. F344 rats had previously been shown to have significantly higher densities of D₂-dopamine receptors in the striatum and olfactory tubercle and also more apomorphine-induced stereotypy when compared to Buffalo rats. These results confirm and extend previous studies suggesting that genetic differences in brain D₂-dopamine receptors can predict behavioral differences in locomotor activity.     

Age difference in the susceptibility to cadmium-induced testicular damage in rats

Since the concentration of cadmium in the testes after cadmium administration to 4-day-old rats is five times that of adults, the objective of this study was to determine if there is an age difference in the susceptibility of Cd-induced testicular damage. Adult rats treated with Cd (1 mg Cd/kg, iv) at 10 weeks of age developed testicular damage and atrophy which persisted for at least 12 weeks. These rats were found to be sterile at the seventh week after injection. For rats treated at 4 days of age, there was no difference in testicular weight, morphology, and fertility between the saline- and Cd-treated groups during 12 weeks after injection. When rats of various ages were examined, it was found that Cd produced no detectable changes in the testes of rats that are 2 weeks of age and younger but slight degenerative changes were observed in rats 3 to 5 weeks of age. However, in rats 6 weeks of age and older, cadmium produced necrosis and atrophy of the testes. Testicular metallothioneins have been proposed to be involved in the protection against Cd-induced testicular damage after cadmium pretreatment in the adult. However, the testicular concentration of metallothioneins in 4-day-old rats was not higher than that of 10-week-old rats, indicating that the age difference in susceptibility to Cd-induced testicular damage is not due to age differences in testicular metallothionein levels. In conclusion, immature rats are resistant to testicular injury produced by Cd and it appears that testicular levels of metallothionein or cadmium do not play an important role in the difference in sensitivity of various aged rats to Cd.     

Protective effect of theaflavins on cadmium-induced testicular toxicity in male rats

Male Sprague–Dawley rats were treated with cadmium (Cd) (0.4 mg/kg body weight, s.c., once a day) and three concentrations of theaflavins (50, 100 or 200 mg/kg body weight, orally, once a day) for five weeks to evaluate the protective role of theaflavins on Cd-induced testicular toxicity. After five weeks, serum sex hormone levels, sperm characteristics, DNA damage, oxidant-antioxidant status, Cd content in several organs were measured. The results showed that a low dose of Cd caused testicular toxicity, which was represented by decreased serum testosterone levels, induction of DNA damage, increased malondialdehyde (MDA) content, Cd accumulation in several organs. Administration of theaflavins led to a dose-dependent alleviation Cd-induced damage in testis, including enhanced serum testosterone levels, improved sperm characteristics and abrogation of DNA damage. Theaflavins may also reduce the production of Cd-induced MDA content, decrease Cd concentration in liver, testis and blood, increase Cd content in urine and feces. These findings suggest the use of theaflavins as a potential therapeutic agent for Cd-induced testicular toxicity.     

A possible mechanism of resistance to cadmium toxicity in male Long-Evans rats

The susceptibility to cadmium (Cd)-induced toxicity in male Long–Evans (LE) rats was compared with that in male Fischer 344 (Fischer) and Wistar–Imamichi (WI) rats, which are sensitive and resistant, respectively, to Cd toxicity. All rats of the LE and WI strains survived for 7 days after the treatment with a toxic dose of Cd (6.5 mg/kg b.w.). However, all rats of the Fischer strain died by the following day. The strong resistance to Cd toxicity in the LE strain was confirmed to be independent of metallothionein synthesis induced by Cd. The hepatic and renal Cd contents after its administration were significantly lower in the LE strain than in the Fischer strain. Furthermore, the hepatic and renal zinc (Zn) contents after its administration were significantly lower in the LE strain than in the Fischer strain. These limited data suggest that the strong resistance to Cd toxicity in male LE rats results from, at least in part, the lower accumulation of the metal in the liver and kidney, in a similar mechanism as the lower Zn accumulation.     

Differences in morphine reinforcement property in two inbred rat strains: associations with cortical receptors,behavioral activity,analgesia and the cataleptic effects of morphine

The purpose of the current study was to investigate genetic differences between two inbred strains of rats, Fisher-344 (F344/N) and Wistar Albino Glaxo (WAG/GSto), in a number of drug-naive and drug-related behaviors, including oral and intravenous morphine self-administration. F344/N and WAG/GSto rats differed in drug-naive behaviors such as nociception, rearing and sensitivity to lick suppression tests but did not differ in locomotor activity, ambulation or grooming behavior. F344/N rats were less sensitive to thermal stimuli as measured via tail-flick response, and more sensitive to the suppressive effects of intermittent shock in a lick suppression test. The F344/N rats demonstrated a significantly greater amount of rearing in open field tests but did not differ from WAG/GSto rats in locomotor activity, ambulation or grooming behavior. In addition to the behavioral results, naive F344/N and WAG/GSto rats were found to differ in and ₂ receptor concentrations (F344/N>WAG/GSto) and in 5HT₂ and D₂ affinity constants (WAG/GSto>F344/N). These two inbred rat strains also differed in drug-related behaviors. F344/N rats showed significantly greater depression of locomotor activity at morphine 3 mg/kg than WAG/GSto rats. In addition, F344/N rats consumed significantly greater amounts of morphine in a two-bottle choice procedure and morphine maintained significantly greater amounts of behavior during intravenous self-administration sessions. Importantly, drug maintained behavior was significantly greater than with vehicle only in the F344/N rats during operant self-administration sessions.     

Evaluation of involvement of testicular metallothionein gene expression in the protective effect of zinc against cadmium-induced testicular pathophysiology in rat

To investigate the effects of exposure to Cd and Zn on testicular MT-1 and MT-2 gene expression and evaluate their involvement in Zn protection against Cd-induced testicular pathophysiology, male rats received either tap water, Cd or Cd + Zn in their drinking water for 35 days. Cd induced histopathological changes in testicular tissues were accompanied by decreased plasma testosterone level, plasma and testicular Zn concentrations, oxidative stress, and by increased MT-1 and MT-2 gene expression. Co-treatment with Cd and Zn reversed the Cd-induced decrease testosterone level and SOD activity, decreased testicular Cd accumulation and partially restored Cd-induced histological changes, lipid peroxidation, and Zn depletion. The increase of testicular MT-1 and MT-2 gene expression under Cd influence was significantly reduced in Cd + Zn group. These data suggest that Zn enhances the protection against Cd-induced testicular pathophysiology through non-MT gene expression mechanisms but essentially by preventing Cd accumulation, Zn deprivation and by ameliorating the testicular antioxidant status.     

Carcinogenicity of acrylamide in B6C3F1 mice and F344/N rats from a 2-year drinking water exposure

Acrylamide is a component of roasted coffee and certain baked and fried carbohydrate-rich foods prepared at high temperatures. We have assessed the carcinogenicity of acrylamide in male and female B6C3F₁ mice and F344/N rats administered 0, 0.0875, 0.175, 0.35, or 0.70 mM acrylamide in the drinking water ad libitum for 2 years. Acrylamide caused significant dose-related decreasing trends in the body weights of F344/N rats. Acrylamide administration resulted in significant dose-related decreasing trends in survival in both sexes of B6C3F₁ mice and in female F344/N rats. Histopathological analyses indicated significant dose-related increases in Harderian gland and lung tumors in male and female B6C3F₁ mice. Male B6C3F₁ mice also had a significantly increased incidence of forestomach tumors, while female B6C3F₁ mice had significant dose-related increases in mammary gland, ovary, and skin tumors. In male and female F344/N rats, there were significant increases in thyroid tumors. Male F344/N rats also had significant dose-related increases in testes, heart, and pancreas tumors, while female F344 rats demonstrated significant increases in clitoral gland, mammary gland, oral cavity, and skin tumors. These results, combined with previous mechanistic studies, provide strong support for the concept that acrylamide is activated to a carcinogen through metabolism to glycidamide.     

Analysis of strain difference in sensitivity to cadmium-induced hepatotoxicity in Fischer 344 and Sprague-Dawley rats.

Acute administration of cadmium (Cd) in rats results in hepatotoxicity that appears to involve the activation of Kupffer cells and the subsequent production of proinflammatory chemokines and cytokines. However, the importance of these endogenous mediators in Cd-induced hepatotoxicity is unknown. Therefore, this study was conducted to define and utilize a rat strain difference in sensitivity to Cd-induced hepatotoxicity to elucidate the role of cytokines and chemokines in Cd-induced hepatotoxicity. Doses were selected from a dose-response study of the effect of Cd on serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities. Hepatotoxic doses of 2.0 mg Cd/kg in Fischer 344 (F344) rats and 3.0 mg Cd/kg in Sprague-Dawley (SD) rats, as well as a relatively nontoxic dose of 2.0 mg Cd/kg in SD rats, were chosen for the time-course experiment. Blood and liver from F344 (saline or 2.0 mg Cd/kg iv) and SD rats (saline or 2.0 or 3.0 mg Cd/kg iv) were collected at 0, 1, 3, 6, 10, 18, 24, and 48 h after Cd administration. Cadmium treatment caused an increase in serum ALT and SDH by 3 h and peaked between 18 and 24 h in both strains. Hepatic Cd content, metallothionein (MT) induction, and nonprotein sulfhydryl (NPSH) content were quantified and determined to be consistent with dosing rather than strain differences. Total RNA samples isolated from liver samples were analyzed for chemokine (CINC-1 and MCP-1) and cytokine (TNF-alpha, IL-1beta, IL-6, and IL-10) mRNA levels by the Quantigene branched DNA signal amplification assay. Lipopolysaccharide treatment served as a positive control for chemokine and cytokine induction. After Cd administration, F344 rat livers did not contain higher levels or earlier induction of chemokine and cytokine mRNAs than SD rats. Therefore, this study demonstrates a strain difference in sensitivity to Cd-induced hepatotoxicity that appears to be unrelated to Cd, MT, NPSH, or cytokine expression.     

Cadmium-induced hepatic endothelial cell injury in inbred strains of mice.

Susceptibility to cadmium (Cd) hepatotoxicity differs among inbred strains of mice. For example, C3H/HeJ mice are sensitive to Cd-induced hepatotoxicity, whereas DBA/2J mice are resistant. The mechanism of genetic predisposition to Cd hepatotoxicity is unknown. A contemporary theory for acute target organ intoxication maintains that Cd initially damages vascular endothelium and parenchymal cell injury is a secondary event that results from localized ischemia. In the present study, the hypothesis that hepatic endothelial cells (EC) of C3H mice are more susceptible to Cd toxicity than those of DBA mice was tested. Hepatic parenchymal and endothelial cells were grown separately on monolayer cultures for 22 h and subsequently treated with various concentrations of Cd. Hepatocellular toxicity was assessed by lactate dehydrogenase leakage and intracellular K+ loss, whereas endothelial cell injury was assessed by trypan blue exclusion and the inhibition of protein synthesis. The susceptibility of hepatocytes to the cytotoxic effects of Cd was identical between strains. In contrast, the vulnerability of EC to Cd intoxication was strain-dependent. When exposed to 2.5-10.0 microM Cd, EC of Cd-sensitive mice were more susceptible to the cytotoxic effects of Cd than those of Cd-resistant mice. Basal metallothionein (MT) levels as well as Cd uptake into EC were similar in the two strains. Following Cd exposure, EC of Cd-sensitive mice accumulated similar amounts of MT as EC of Cd-resistant mice. These observations suggest that the microvasculature in livers of inbred mice is the target tissue responsible for strain-dependent susceptibility to Cd-induced liver injury. The mechanisms that account for this genetic variation in endothelial cell response to Cd are unknown, but do not appear to be related to the cellular disposition of Cd nor to a defect in the metabolism of MT.     

Decreased uptake and altered subcellular disposition of testicular cadmium as possible mechanisms of resistance to cadmium-induced testicular necrosis in inbred mice

Mechanisms responsible for resistance to Cd-induced testicular necrosis in inbred mice were investigated using strains resistant (A/J) or susceptible (129/J) to Cd-induced testicular damage. Cadmium accumulation was measured in testes of both strains 15 min, 30 min, 1 h, 2 h, 6 h, 12 h and 24 h after intravenous injection of 1 mumol 109CdCl2/kg. The subcellular disposition of Cd was determined at 15 min, 6 h and 24 h by fractionation of testicular cytosol on Sephadex G-75 Superfine. Testicular accumulation of Cd was 5-6 times less in A/J mice than in 129/J mice at all time points examined. Gel filtration revealed 4 Cd-binding peaks; in both strains testicular Cd was bound to a protein with a relative molecular mass (Mr) of 30 000 and to metallothionein (MT). The fraction of the total testicular Cd bound to the 30 000 Mr protein was similar in both strains after 15 min (13-18%) and declined rapidly to 5-7% by 6 h. A/J testes had a significantly greater fraction of the total Cd bound to MT both 15 min; 38% vs. 24% at 6 h). By 24 h both strains had approximately 43% of the total testicular Cd bound to MT. The results indicate 2 possible mechanisms of resistance to Cd-induced testicular necrosis in inbred mice: decreased testicular Cd uptake and sequestration of a greater fraction of the tissue Cd by MT.     

Monogenic inheritance of catechol-O-methyltransferase activity in the rat -- biochemical and genetic studies.

Catechol-O-methyltransferase (COMT) activities in the livers and kidneys of Fischer-344 (F-344) inbred rats were only 58 and 59 per cent, respectively, of those in the same organs of inbred Wistar-Furth (W-F) rats. Breeding experiments were performed to study possible mechanisms of inheritance of COMT activity in these animals. COMT activities in livers and kidneys of F1 (hybrid) animals (N = 36) were intermediate between those of the parental strains, but were closer to W-F (N = 22) than to F-344 (N = 22) values. The results of studies of F2 generation (N = 147) and backcross (N = 171) animals were compatible with the autosomal recessive inheritance of low COMT activity. 25.8 per cent of the F2 animals fell into a “low” COMT group when enzyme activities in both liver and kidney were used for phenotypic classification. This result is compatible with autosomal recessive inheritance of the trait “low” COMT. Statistical estimates of the number of genes involved in the control of COMT activity in these rats were also compatible with monogenic inheritance. Because of the possibility that there might be genetically determined differences in the biochemical properties of COMT in F-344 and W-F rats, COMT activities in tissue homogenates of liver from the two strains were compared with regard to thermal stability, electrophoretic behaviour, apparent Michaelis-Menton (K_m) constant for substrates, and responses to three COMT inhibitors (tropolone, S-adenosyl-l-homocysteine, and calcium). No differences in thermal stability, R_f values after electrophoresis, apparent K_m values for substrates or 50 per cent inhibitory concentrations of the enzyme inhibitors for hepatic COMT were detected between the two strains of rats.     

Protective effect of an aphrodisiac herb Tribulus terrestris Linn on cadmium-induced testicular damage

Aim:

The aim of the present study was to investigate whether Tribulus terrestris Linn (TT) could protect the cadmium (Cd)-induced testicular tissue peroxidation in rats and to explore the underlying mechanism of the same.

Materials and Methods:

In vitro and in vivo studies were conducted to know the protective effect of ethanolic extract of TT (eTT) in Cd toxicity. In in vitro studies, total antioxidant and ferrous metal ion chelating activity of TT was studied. In vivo studies were conducted in rats. A total of 40 Wistar strain adult male rats were divided into four groups. Group 1 served as control, while group 2 to 4 received CdCl₂ (3 mg/kg b. wt. s/c once a week). In addition to Cd, group 3 and 4 rats also received eTT (5 mg/kg b.wt. daily as oral gavage) and α-tocopherol (75 mg/kg daily by oral gavage), respectively. At the end of 6^th week, all the rats were sacrificed and the separated testes were weighted and processed for estimation of tissue peroxidation markers, antioxidant markers, functional markers, and Cd concentration. The testes were also subjected to histopathological screening.

Results:

In in vitro studies, the percentage of metal ion chelating activity of 50 μg/ml of eTT and α-tocopherol were 2.76 and 9.39, respectively, and the antioxidant capacity of eTT was equivalent to 0.063 μg of α-tocopherol/μg of eTT. In in vivo studies, administration of Cd significantly reduced the absolute and relative testicular weight, antioxidant markers such as superoxide dismutase and glutathione, and functional markers such as LDH and ALP, along with significant increase in peroxidation markers such as malondialdehyde and protein carbonyls in testicular tissue. Testes of Cd only-treated group showed histological insults like necrotic changes in seminiferous tubules and interstitium, shrunken tubules with desquamated basal lamina, vacuolization and destruction of sertoli cells, and degenerating Leydig cells. This group also had higher Cd levels in testicular tissue. Co-treatment with eTT and α-tocopherol significantly reduced the Cd burden in the testes along with reversal of the Cd-induced changes.

Conclusions:

eTT exhibited protective effect against Cd-induced testicular damage. The protective effect appears to be mediated through inhibition of testicular tissue peroxidation by antioxidant and metal chelator activity and also, may be indirectly by stimulating the testosterone production from Leydig cells.     

Sulforaphane mitigates cadmium-induced toxicity pattern in human peripheral blood lymphocytes and monocytes

Cadmium (Cd) is a highly toxic and widely distributed heavy metal that induces various diseases in humans through environmental exposure. Therefore, alleviation of Cd-induced toxicity in living organisms is necessary. In this study, we investigated the protective role of sulforaphane on Cd-induced toxicity in human peripheral blood lymphocytes and monocytes. Sulforaphane did not show any major reduction in the viability of lymphocytes and monocytes. However, Cd treatment at a concentration of 50 μM induced around 69% cell death. Treatment of IC₁₀-Cd and 100 μM sulforaphane combination for 24 and 48 h increased viability by 2 and 9% in cells subjected to Cd toxicity, respectively. In addition, IC₂₅ of Cd and 100 μM sulforaphane combination recovered 17–20% of cell viability. Cd induced apoptotic and necrotic cell death. Sulforaphane treatment reduced Cd-induced cell death in lymphocytes and monocytes. Our results clearly indicate that when the cells were treated with Cd + sulforaphane combination, sulforaphane decreased the Cd-induced cytotoxic effect in lymphocytes and monocytes. In addition, sulforaphane concentration plays a major role in the alleviation of Cd-induced toxicity.     

Pubertal cadmium exposure impairs testicular development and spermatogenesis via disrupting testicular testosterone synthesis in adult mice

Cadmium (Cd) is a well-known testicular toxicant. However, the effects of pubertal Cd exposure on testicular development and spermatogenesis remained to be elucidated. The present study investigated the effects of pubertal Cd exposure on testicular development and spermatogenesis. Male CD-1 mice were intraperitoneally injected with CdCl₂ (1 mg/kg) daily from postnatal day 35 (PND35) to PND70. As expected, pubertal Cd exposure significantly decreased the number of spermatozoa in epididymides. In addition, pubertal Cd exposure markedly reduced the weights of testes, epididymides and prostate and seminal vesicle in adult mice. A significant decrease in serum and testicular testosterone (T) was observed in mice exposed to Cd during puberty. Moreover, pubertal Cd exposure markedly reduced mRNA and protein levels of testicular StAR, P450scc, P450_17α and 17β-HSD. Taken together, these results suggest that the decreased testicular T synthesis might partially contribute to pubertal Cd-induced impairment on testicular development and spermatogenesis in mice.     

Cadmium-induced testicular injury

Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based compounds (e.g., bisphenols) may account for the recent declining fertility in men among developed countries by reducing sperm count and testis function. In this review, we critically discuss recent data in the field that have demonstrated the Cd-induced toxicity to the testis is probably the result of interactions of a complex network of causes. This is likely to involve the disruption of the blood-testis barrier (BTB) via specific signal transduction pathways and signaling molecules, such as p38 mitogen-activated protein kinase (MAPK). We also summarize current studies on factors that confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative stress inducer, and how it may disrupt the Zn²⁺ and/or Ca²⁺ mediated cellular events. While much work is needed before a unified mechanistic pathway of Cd-induced testicular toxicity emerges, recent studies have helped to identify some of the likely mechanisms and/or events that take place during Cd-induced testis injury. Furthermore, some of the recent studies have shed lights on potential therapeutic or preventive approaches that can be developed in future studies by blocking or minimizing the destructive effects of Cd to testicular function in men.     

Metallothionein Induction and Pulmonary Responses to Inhaled Cadmium Chloride in Rats and Mice

Inhaled CdCl₂ is a pulmonary carcinogen in rats but not in mice.We hypothesized that pulmonary metallothionein (MT) inductionmay be different in both species and thereby may lead to differentlevels of protection from Cd-induced lung injury. Fisher-344rats and B6C3F₁ mice were exposed for 4 weeks to CdCl₂ aerosolsof 0, 30, 50, and 150 µg/m³ air or 0, 10, 30, and 100µg/m³ air, respectively. Animals from each exposure groupwere terminated at 1, 30, and 133 days after the end of exposure.The lungs were lavaged for cell and biochemical analyses. Cadmiumand MT in lavagate and lung tissue were measured. The retentionhall-time of pulmonary Cd was greater in mice (290 vs 90 days,p<0.05). Cd exposure provoked an inflammatory response whichwas dose-dependent in both species, and while it was only short-livedin rats, it persisted throughout the observation period in miceat the high exposure concentrations. Mice were found to havea greater baseline level of MT (18.046.96 vs 11.71.98 µgMT/g control lung, p<0.05). Mice showed greater inducibilityof MT for a given CdCl₂ exposure concentration; however, bothspecies had a similar relationship between retained pulmonaryCd and MT induction though mice maintained increased MT levelsfor a longer period of time. The greater pulmonary baselineMT together with the longer presence of Cd-induced pulmonaryMT may result in greater protection from Cd carcinogenicityin spite of the greater pulmonary Cd-induced inflammation inmice.