Carcinogenicity of Oral Cadmium in the Male Wistar (WF/NCr) Rat: Effect of Chronic Dietary Zinc Deficiency

The effect of chronic dietary zinc deficiency on the carcinogenicpotential of dietary cadmium was assessed in male Wistar (WF/NCr)rats. Groups (n=28) of rats were fed diets adequate (60 ppm)or marginally deficient (7 ppm) in zinc and containing cadmiumat various levels (0, 25, 50, 100, or 200 ppm). Lesions wereassessed over the following 77 weeks. Zinc deficiency alonehad no effect on survival, growth, or food consumption. Cadmiumtreatment did not reduce survival or food consumption and onlyat the highest doses of cadmium (100 and 200 ppm) was body weightreduced (maximum 17%). The incidence of prostatic proliferativelesions, both hyperplasias and adenomas, was increased overthat seen in controls (1.8%) in both zinc-adequate (20%) andzinc-deficient rats (14%) fed 50 ppm cadmium. The overall incidencefor prostatic lesions for all cadmium treatment groups was,however, much lower in zinc-deficient rats, possibly becauseof a marked increase in prostatic atrophy that was associatedwith reduced zinc intake. Cadmium treatment resulted in an elevatedleukemia incidence (maximum 4.8-fold over control) in both zinc-adequateand zinc-deficient groups, although zinc deficiency reducedthe potency of cadmium in this respect. Testicular tumors weresignificantly elevated only in rats receiving 200 ppm cadmiumand diets adequate in zinc. Both zinc-deficient and zinc-adequategroups showed significant positive trends for development oftesticular neoplasia with increasing cadmium dosage. Thus, oralcadmium exposure is clearly associated with tumors of the prostate,testes, and he matopoietic system in rats, while dietary zincdeficiency has complex, apparently inhibitory, effects on cadmiumcarcinogenesis by this route.     

Concentration of Metallothionein in Major Organs of Rats after Administration of Various Metals

Concentration of Metallothionein in Major Organs of Rats afterAdministration of Various Metals. WAALKES, M. P., AND KLAASSEN,C. D. (1985) Fundam. Appl. Toxicol. 5, 473–477. The effectof various metals (Cd, Cr, Fe, Pb, Mn, Hg, Ni, Zn) at maximumtolerated doses on metallothionein (MT) concentrations in majororgans (brain, heart, intestine, kidney, liver, lung, pancreas,spleen, stomach, and testes) of rats was measured by the Cd-radioassaytechnique. Zn produced the most dramatic changes in MT, increasingconcentrations 260-, 86-, 44-, and 14-fold over control forpancreas, intestine, liver, and kidney, respectively. Zn increasedMT in every organ examined except brain. Cd was also effectivein increasing MT levels, elevating concentrations in all organsexcept brain and testes. Testes was the only organ in whicha metal decreased MT levels, where Cd produced a 90% decrease.Cr, Fe, Pb, and Mn increased MT concentrations only in hepatictissue, while Hg and Ni increased MT in liver, kidney, and pancreas.Results indicate that Zn is the most effective inducer of MTsynthesis in several tissues and that liver appears to be themost responsive organ to increased MT synthesis following exposureto a number of metals     

Cadmium-Induced Ovarian Toxicity in Hamsters, Mice, and Rats

Cadmium-Induced Ovarian Toxicity in Hamsters, Mice, and Rats.REHM, S., AND WAALKES, M.P. (1988). Fundam Appl. Toxicol. 10,635–647. The effects of cadmium on the female genitaltract of Syrian hamsters (CnRGH), of four mouse strains (BALB/cAnNCr,DBA/2NCr, C57BL/ 6NCr, NFS/NCr), and two rat strains (F344/NCrand WF/NCr) were studied by light microscopy after a singlesc injection of cadmium chloride (CdCl₂). Experiments involvedanimals prior to and after sexual maturity, and employed CdCl₂doses ranging from 20 to 47.5 µmol/kg. Animals were examinedat intervals from 24 hr to 8 weeks following treatment. Syrianhamsters were most susceptible to CdCl₂-induced ovarian hemorrhagicnecrosis at all ages tested. Most severe ovarian lesions occurredin immature hamsters, in mature hamsters at high doses, andshortly before ovulation at all doses. The small arteries ofthe developing follicles and interstitial stroma seemed selectivelysusceptible to CdCl₂ toxicity while the corpora lutea, mesothelium,primordial oocytes, and the rete ovarii appeared resistant.Pretreatment with zinc acetate markedly reduced the extent ofovarian lesions in hamsters. Although reduced in weight by 45%,the hamster ovaries recovered morphologically within 2 monthsafter severe acute hemorrhagic necrosis. Uterine and cervicalstromal hemorrhages were seen only in immature hamsters at dosesof 30 µmol CdCl₂/kg. Of the mice, only the DBA/2NCr strainshowed significant CdCl₂-induced ovarian hemorrhages, and thesehemorrhages occurred at doses also producing lethal liver toxicity.Lesions of the uterus were rare. Rats showed dose- and age-dependenttoxicity in the ovaries, uterus, cervix, and liver. CdCl2 exposurein mature rats induced uterine lesions only in F344 rats, whileacute ovarian and hepatic toxicity was less severe in matureanimals of both strains. No lesions were noted after 7 daysin mature WF rats. In both rats and mice, no cycle dependencyof the ovarian lesions was evident.     

Chronic Toxic and Carcinogenic Effects of Cadmium Chloride in Male DBA/2NCr and NFS/NCr Mice: Strain-Dependent Association with Tumors of the Hematopoietic System, Injection Site, Liver, and Lung

Although the acute toxic effects of cadmium in mice vary greatlywith strain, relatively little is known about strain differences in cadmium carcinogenesis. Therefore, this work was performed to assess the chronic toxic and carcinogenic effectsof cadmium in two strains of mice generally thought to be susceptibleto the acute effects of cadmium. Male DBA/2NCr (DBA) and NFS/NCr(NFS) mice were given CdCl₂ (40 µmol/kg, Sc) either asa single dose (1 x 40) or as weekly doses for 16 weeks (16 x40) starting at 8 weeks of age. Controls received saline. Theanimals were observed for the next 104 weeks and mice at riskwere defined as those surviving to the time of appearance ofa particular tumor. Cadmium-induced dose-related increases inlymphoma (primarily follicular center cell) incidence (1 x 40,11 cases/23 mice at risk; 16 x 40, 16/28) over control (7/27)in DBA mice but not in NFS mice. Only NFS mice receiving repeated cadmium injections (16 x 40) showed sarcoma develop mentat the injection site (9/35), as no sarcomas occurred in controlNFS mice or any group of DBA mice. On the other hand, cadmium-treated(16 x 40) NFS mice, but not DBA mice, had more hepatocellularadenomas and carcinomas (9/27) than control (1/15) but onlyat the high dose (16 x 40). More cadmium-treated NFS mice hadpulmonary tumors than controls, but only at the lower dose (1x 40). Although testicular tumors were rare, nonneoplastic lesions(fibrosis and mineralization) were induced by cadmium to a similarextent in both strains. Clearly cadmium carcinogenicity varieswidely with strain, indi cating a genetic basis to susceptibility.The basis of these strain differences deserves further study.     

Effect of in Vivo Low-Dose Cadmium Pretreatment on the in Vitro Interactions of Cadmium with Isolated Interstitial Cells of the Rat Testes

Effect of in Vivo Low-Dose Cadmium Pretreatment on the in VitroInteractions of Cadmium with Isolated Interstitial Cells ofthe Rat Testes. WAHBA, Z. Z., AND WAALKES, M. P. (1990). Fundam.Appl. Toxicol 15, 641–650. Recent studies have shown thatCd-induced testicular interstitial cell (TIC) tumors can beprevented by low-dose Cd pretreatment. However, the mechanismby which low-dose Cd induces such tolerance is unclear. Thus,in this study we assessed the effects of in vivo Cd pretreatment(3 µmol/kg) on Cd uptake, cytotoxicity, metal content(Zn, K, and Ca), and low molecular weight testicular Cd-bindingproteins (low M_r TC-BPs) of isolated TICs exposed to Cd in vitro.TICs were isolated by collagenase dispersion of Wistar (WF/NCr)rat testes and incubated with Cd (1.0 mM) for 15 to 60 min.In vivo Cd pretreatment decreased in vitro Cd uptake by 24%after 1 hr of incubation with Cd. In vivo Cd pretreatment alsoresulted in a marked reduction of in vitro Cd-induced cytotoxicity,as reflected by reduced loss of cellular K, glutamic-oxaloacetictransaminase, as well as reduced lipid peroxidation and decreasedCd-induced Ca influx into TICs in vitro. These cytotoxic effectswere not attributed solely to cell death as TIC viability remainedhigh even after 1 hr of in vitro Cd exposure. Cd-induced inhibitionof intercellular enzymes, as assessed by cellular lactate dehydrogenaseactivity, was also reduced by low-dose Cd pretreatment. Cd pretreatmentdid not alter basal levels of Zn, Ca, or K. Neither low-dosein vivo Cd pretreatment nor in vitro Cd exposure appeared togreatly alter levels of the low M_r TCBPs as assessed by electrophoresis.In vivo Zn pretreatment, which also effectively inhibits Cd-inducedtesticular tumors, results in a similar reduction in Cd-inducedcytotoxicity in TICs. This indicates that treatments which resultin reduced Cd-induced TIC tumors are consistently capable ofreducing Cd-induced cytotoxicity in isolated TICs in vitro.