Effects of oral,subchronic cadmium administration on fertility,prenatal and postnatal progeny development in rats

Cadmium chloride was administered by gavage to female rats 5 days a week for 5 weeks, then during mating and gestation periods at doses of 0.04, 0.4, and 4 mg Cd/kg/day. Treatment with cadmium neither affected the survival and fertility of females, nor produced overt fetotoxic effects. Fetal cadmium concentration was not related to the level of exposure. Litter size, body weight gain and viability of offspring during 2 months after parturition were similar in all groups. The exploratory locomotor activity of 2-month-old males and females born to rats given 0.4 and 4 mg Cd/kg/day was significantly reduced. The progeny of cadmium-treated females showed decreased performance in the rotarod test. In general, the degree of behavioral impairment was dose-related.     

The influence of maternal cadmium exposure or fetal cadmium injection on hepatic metallothionein concentrations in the fetal rat

The ability of Cd to induce the synthesis of fetal hepatic metallothionein (MT) was investigated in rat fetuses exposed to Cd throughout gestation via the mother's drinking water or injected directly with Cd through the uterine wall on Day 18 of gestation. On Day 21 all dams were killed and fetal and maternal tissues were removed. Tissue MT, Zn, Cu, and Cd concentrations were measured. Fetal hepatic Cd concentration was increased only at the high maternal Cd exposure, whereas Zn concentration was significantly reduced by Cd exposure. Both fetal liver and kidney MT were reduced following maternal Cd exposure. Unlike maternal hepatic MT, fetal hepatic MT was not increased after maternal Cd exposure nor did the direct injection of Cd into the 18 days of gestation fetus induce fetal MT synthesis. These data suggest that fetal rat liver is incapable of synthesizing MT in response to Cd, possibly because Cd is not transported to the site of MT synthesis in the fetal system. Furthermore, neither the route of exposure, the duration of prenatal Cd exposure, nor the stage of gestation appear to account for the differences observed between fetal and adult hepatic MT induction by Cd.     

Developmental and sex differences in cadmium distribution and metallothionein induction and localization

Age- and sex-related differences in hepatic and renal distribution of cadmium (Cd) and the effect of Cd injection (10 mumol/kg) on tissue zinc (Zn), copper (Cu) and metallothionein (MT) levels were investigated in 2- to 84-day old rats. Renal Cd accumulation increased with age of the animal. Sex differences in renal Cd accumulation were noted in young animals where the 2- and 8-day old males had significantly greater concentration than the females. There were no clear effects of Cd on renal Zn. Renal Cu levels, however, were elevated in the adults. The adult females contained about twice as much MT as the adult males. Cd treatment had no effect on renal MT levels of 8- to 84-day old animals but depressed the levels in 2-day old. Age-related increase in hepatic Cd accumulation was also found; the pattern was more clear cut in females than in males. In addition, in the females the hepatic Cd concentration was significantly higher than in the males. Cd-injection significantly increased hepatic Zn and MT concentrations only in weaned animals. While there were no sex differences in MT levels in the young animals, the weaned females had significantly more MT than the corresponding males. Immunohistochemical staining for MT showed positive staining in both cytoplasm and nuclei of the parenchymal cells. The number of MT-positive nuclei was dependent on the relative MT concentration of the liver. In spite of the intense nuclear staining in 2-day old controls and 84-day old Cd-injected rats, less than 1% of the hepatic MT was present in the nuclear fraction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral alterations in offspring of female rats repeatedly exposed to cadmium oxide by inhalation

Prolonged exposure of female rats to cadmium oxide aerosols (0.02 and 0.16 mg Cd/m3) in air had no effect on fertility. Viability and postnatal growth of the offspring of dams that were exposed to 0.16 mg Cd/m3 before and during gestation, however, were depressed. Forepaw muscular strength and endurance of pups in all groups were similar. Maternal Cd exposure resulted in reduction of exploratory motor activity in 3-month-old pups from the 0.16 mg Cd/m3 group and male offspring from the 0.02 mg Cd/m3 group. Dose-dependent decreases of avoidance acquisition were seen in female offspring but not in males. In the open-field test, the ambulation of 5-month-old males from the 0.16 mg Cd/m3 was lowered, whereas in females from the 0.02 mg Cd/m3 group it was enhanced. The results indicate central nervous system (CNS) dysfunction in offspring of female rats exposed to low concentrations of cadmium oxide by inhalation.     

Influence of cadmium and copper on tissue element levels of pregnant rats

In the current study, we examined the effects of Cd on Cd, Cu, Zn and Fe levels in placenta and maternal and fetal plasma and tissues, the placental weight, total fetal and maternal body weights, and fetal and maternal tissue weights during pregnancy. A total of 21 adult female rats were treated during gestation with drinking water containing one of the following: 70 mg/L of CdCl₂, a combination of 70 mg/L of CdCl₂ and 70 mg/L of CuSO₄, or no addition (control). Placenta Cu and Fe levels, fetal liver and kidney Cu levels, and fetal liver tissue weights were lower in the group administered Cd than in the control group. Also, Cd levels in the placenta, maternal and fetal liver, and maternal kidney were higher in the group treated with Cd than in controls. In the group administered both Cd and Cu, fetal body and tissue weights did not change, but Cd levels in the placenta, maternal and fetal liver, and maternal kidneys were higher than in controls. Zn and Fe levels in the maternal kidney and fetal liver were also lower in this group. Cd exposure during pregnancy resulted in Cd accumulation in maternal and fetal tissues during pregnancy and a decrease in the total weight of fetuses, and the combination of Cd and Cu caused some changes in the both maternal and fetal levels of Cu, Zn, and Fe, but it did not cause changes in the total fetal body weight or the weights of individual tissues.     

Effects of low-dose perinatal cadmium exposure on tissue zinc and copper concentrations in neonatal mice and on the reproductive development of female offspring

It has been suggested that the toxic effects of cadmium (Cd) are the result of interactions with essential metals, such as zinc (Zn) and copper (Cu). Previous studies have shown altered Zn and/or Cu levels in the tissues of rodents that drank water supplemented with >50 ppm Cd. To evaluate the effects of lower level Cd exposure on maternal and neonatal Zn and Cu levels and on the reproductive organs of female offspring, mice were exposed to 0, 1 and 10 ppm Cd in the drinking water from conception to 10 days after birth. The Cd concentrations in the brains of the offspring were higher in the exposed group than in the control group at birth. In the kidneys and livers, the Cd concentrations were higher in the Cd-exposed group 10 days after birth. At birth, increased Zn concentrations were observed in the kidneys and livers of the Cd-exposed offspring, although the Cd concentrations in these tissues did not differ between the exposed and non-exposed groups. The hepatic Cu concentrations of the exposed mice tended to be lower than those of the control mice at birth and were significantly lower 10 days after birth. In addition, Cd exposure tended to delay the timing of vaginal opening and perturbed the estrous cycles of the female offspring. These findings suggest that perinatal Cd exposure, even at low levels, affects the Zn and Cu concentrations of neonates and the reproductive functions of female offspring.     

Prenatal cadmium exposure alters postnatal immune cell development and function

Cadmium (Cd) is generally found in low concentrations in the environment due to its widespread and continual use, however, its concentration in some foods and cigarette smoke is high. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports of immunomodulatory effects of prenatal exposure to Cd. This study was designed to investigate the effects of prenatal exposure to Cd on the immune system of the offspring. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl₂ (10 ppm) and the effects on the immune system of the offspring were assessed at two time points following birth (2 and 7 weeks of age). Thymocyte and splenocyte phenotypes were analyzed by flow cytometry. Prenatal Cd exposure did not affect thymocyte populations at 2 and 7 weeks of age. In the spleen, the only significant effect on phenotype was a decrease in the number of macrophages in male offspring at both time points. Analysis of cytokine production by stimulated splenocytes demonstrated that prenatal Cd exposure decreased IL-2 and IL-4 production by cells from female offspring at 2 weeks of age. At 7 weeks of age, splenocyte IL-2 production was decreased in Cd-exposed males while IFN-γ production was decreased from both male and female Cd-exposed offspring. The ability of the Cd-exposed offspring to respond to immunization with a S. pneumoniae vaccine expressing T-dependent and T-independent streptococcal antigens showed marked increases in the levels of both T-dependent and T-independent serum antibody levels compared to control animals. CD4⁺FoxP3⁺CD25⁺ (nTreg) cell percentages were increased in the spleen and thymus in all Cd-exposed offspring except in the female spleen where a decrease was seen. CD8⁺CD223⁺ T cells were markedly decreased in the spleens in all offspring at 7 weeks of age. These findings suggest that even very low levels of Cd exposure during gestation can result in long term detrimental effects on the immune system of the offspring and these effects are to some extent sex-specific.     

Antioxidant enzymes activity and lipid peroxidation in liver and kidney of rats exposed to cadmium and ethanol.

The oxidative status of liver and kidney of rats co-exposed to cadmium (50 mg Cd/l in drinking water) and ethanol (5 g EtOH/kg body weight/24 h, intragastrically) for 12 weeks was studied. The activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) as well as the concentration of malondialdehyde (MDA), as an indicator of lipid peroxidation, were measured in homogenates of the liver and kidney. Concentrations of zinc (Zn), copper (Cu), iron (Fe) and Cd in the serum or blood, and their content in the liver and kidney as well as EtOH concentration in the whole blood were assayed. Daily Cd intake in the Cd and Cd+EtOH groups was similar and ranged from 2.39 to 4.88 mg/kg body weight/24 h and from 2.64 to 4.14 mg/kg body weight/24 h, respectively. After the administration of EtOH alone, the activity of SOD increased in the kidney and decreased in the liver, whereas the activity of CAT decreased in both these organs, and MDA concentration increased in the liver and was unchanged in the kidney. The exposure to 50 mg Cd/l led to a decrease in the activities of SOD in the liver and CAT in the liver and kidney, and an increase in the kidney activity of SOD and MDA concentration in both these organs. In the rats co-exposed to Cd and EtOH, the kidney activity of SOD and the liver concentration of MDA were lower, whereas the kidney activity of CAT was higher compared to the Cd group. The concentration of Fe in the serum and its content in the liver of rats treated with EtOH increased, whereas the concentrations of Zn and Cu in the serum and the content of Zn, Cu and Fe in the kidney and that of Zn and Cu in the liver were unchanged. In the liver and kidney of rats treated with Cd alone, the content of Fe was decreased and that of Zn and Cu was enhanced. After EtOH administration to Cd-exposed rats, a decrease in Cu serum concentration and its liver content and an increase in Fe concentration in the serum and its content in the liver and kidney, compared to the group exposed to Cd alone, were noted. Moreover, EtOH decreased the blood Cd concentration and its accumulation in the liver and kidney of these animals. EtOH alone decreased Cd content in the liver and increased in the kidney, however the whole content of Cd in these organs was unchanged compared with control. The results of this study indicate that despite the ability of Cd and EtOH to induce the oxidative stress the effect in the liver and kidney is not intensified at simultaneous exposure to both substances. The changes in the studied indicators of oxidative stress (SOD, CAT and MDA) observed in the kidney and especially in the liver of the rats co-exposed to Cd and EtOH may result from an independent effect of Cd and/or EtOH and also from their interaction. The interactive effect may involve, among others, changes in Cd accumulation and content of Zn, Cu and Fe in these organs and their concentration in serum. Since the rats treated with Cd and Cd+EtOH had reduced drinking fluids intake that might result in dehydratation, the effect of the both xenobiotics on the oxidative status of the body may be not solely due to Cd and/or EtOH, but also the modyfing influence of accompanying alterations such as reduced water intake and dehydratation. The results of the study allow us to hypothesize that Cd-exposed alcohol misusers are not at enhanced risk of liver and kidney damage due to lipid peroxidation.     

Embryotoxic and long-term effects of cadmium exposure during embryogenesis in rats

The present study was performed to evaluate the long-term behavioral effect in offspring of a subteratogenic Cd dose administered by the oral route to Wistar rat during organogenesis. First, the teratogenic Cd dose was determined by treating pregnant rats with 20 mg/kg Cd from Day 6 to Day 14 of pregnancy and by visceral and skeletal analysis of their fetuses. In a second experiment, pregnant rats treated with this Cd dose were allowed to give birth and nurture their offspring. The physical and behavioral parameters of the offspring were analyzed in infancy and during adulthood. Results showed that Cd treatment during organogenesis (1) was not able to induce maternal toxicity; (2) induced external malformations; (3) increased significantly fetus anomalies and malformations, with reduced metacarpus ossification, cleft palate and right or left renal cavitation being observed in these animals; (4) did not modify pup body weight or weight gain during the lactation period; (5) improved testis descent and delayed the vaginal opening of pups; (6) did not modify ear unfolding, incisor eruption, eye opening, negative geotaxis or palmar grasp; (7) did not modify the open-field parameters and the stereotyped behavior of male or female pups; and (8) modified male sexual behavior and (9) reduced female sexual behavior. We conclude that prenatal exposure to a teratogenic Cd dose induced in the survivor animals several deleterious effects in their development as well as in adult behaviors, mainly in the sexual sphere.     

The interaction of zinc and cadmium in the synthesis of hepatic metallothionein in rats

The interaction of injected zinc salts (Zn) and cadmium salts (Cd) with regard to the synthesis of metallothionein (MT) in adult rat liver was investigated. Male rats received an i.p. injection of Zn (20 mg/kg) or Cd (0.6 mg/kg) with or without pretreatment with Zn (20 mg/kg 16 h prior to the second injection). It was found that both metals, when administered singly, induced the synthesis of significant levels of hepatic MT, but that, when the Cd injection followed the Zn injection, synthesis of MT was not additive. When Zn pretreatment was followed by a second Zn injection, MT accumulation was additive (approx. 2-fold of that observed after a single Zn injection). Also, a highly significant positive correlation, (r = 0.97, P less than 0.01) was noted between hepatic Zn concentration and hepatic MT concentration, a relationship which was independent of the mode of MT induction. The results of the investigation indicate that: (1) in the presence of pre-existing hepatic Zn--MT, the ability of Cd to induce new MT synthesis is greatly reduced; rather, Cd is sequestered by the pre-existing MT; and (2) Zn may play a major role in the induction of MT synthesis both after Zn administration and after Cd administration.     

Stimulation of cadmium uptake by estradiol in the kidney of male rats treated with cadmium

The present study was carried out to analyze the sex differences in the retention of Cd in rats treated with a small amount of Cd, and its mechanisms. Cd and Zn concentrations in the kidney and liver of female rats treated with 28 nmol Cd or 1 nmole Zn were significantly higher than those in male rats. Pretreatment with estradiol (1.8 mumol/kg of b.w., twice a day, 6 consecutive days) increased the Cd and Zn concentrations in the kidney of male rats treated with Cd or Zn. Incubation of MDCK cells with 10(-5) M estradiol, 10(-5) M stilboestrol and 10(-5) M progesterone caused a significant increase in Cd uptake. These results suggest that endogenous female sex hormones may play a role in a higher concentration of Cd and Zn in the kidney of female rats than that in male rats. The basal level of metallothionein (MT) in the liver and kidney of control female rats was within the same range as that in the control male rats. Cd and Zn accumulations caused by pretreatment with estradiol in the kidney of male rats treated with Cd or Zn were so low (Cd: 38 ppb, Zn: 1.0 ppb) as to be probably unable to induce the synthesis of MT. An increase in the concentration of Cd in the cultured renal cells occurred 1 hr after treatment with estradiol and Cd. Pretreatment with estradiol alone also resulted in a modification of the concentration of Na and K, which cannot be bound to MT. Together, all of the above findings suggest that estradiol directly increases the accumulation of Cd into the renal cells without inducing the synthesis of MT.     

Effect of dimercaptosuccinate on the accumulation and distribution of cadmium in the liver and kidney of the rat

The effect of dimercaptosuccinic acid (DMSA) on the tissue distribution, renal and hepatic subcellular localization of Cd2+, Zn2+ and Cu2+ in Cd(2+)-pretreated male rats and on the tissue distribution of Zn2+ and Cu2+ in the normal rat was studied. Cd(2+)-pretreated rats which received 3 x 1 mg Cd2+/kg body wt s.c. at 48 hr intervals followed after 7 days by DMSA (50 mg/kg body wt i.p.) daily for 17 days had total hepatic Cd2+ concentrations 25 per cent lower than Cd(2+)-pretreated controls (P < 0.01). DMSA did not influence the concentration or distribution of Cd2+ in the liver cytosol whereas in the mitochondrial-lysosomal and nuclei + cell debris fractions the Cd2+ concentration was reduced by 54 and 48 per cent respectively. Total renal and hepatic Cu2+ concentrations were increased by Cd2+ treatment and reduced by treatment of the Cd(2+)-exposed animal with DMSA. In the liver cytosol Cu2+, Zn2+ and Cd2+ accumulated in the metallothionein fraction and none was mobilized from the cytosol by DMSA. In the kidney cytosol Cu2+ accumulated in fractions in addition to metallothionein and was eliminated from each of these fractions following treatment with DMSA. It is concluded that the high affinity of metallothionein for these cations prevented their elimination from the cytosol and that the interaction of Cd2+ and Cu2+ with DMSA occurred in the particulate fraction and therefore delayed the response to DMSA treatment. It is suggested that long term treatment with DMSA, although ineffective in mobilizing Cd2+ from the kidney may provide a useful therapeutic measure to reduce the liver burden of Cd2+ and the high renal Cu2+ concentrations in the Cd(2+)-exposed animal.     

Effects of maternal cadmium administration on development of monoaminergic, GABAergic and glutamatergic systems

The effects of maternal exposure to 10mgCd/l (as cadmium acetate) in drinking water during gestation and lactation on the development of monoaminergic and aminoacidergic systems were studied in discrete brain areas of the pups: striatum, cerebral cortex, dorsal hippocampus and basal-medial hypothalamus. Hippocampal levels of serotonin and 5-hydroxyindolacetic acid were significantly reduced in rats exposed to Cd whereas the dopamine content was not significantly affected by Cd. Glutamate concentration decreased in hypothalamus and increased in hippocampus, while gamma-aminobutiric acid content decreased only in cerebral cortex. The present results demonstrate that maternal exposure to 10mg/l of Cd leads to neurochemical disturbances on serotoninergic and aminoacidergic systems during development.     

Impaired maternal behaviour and altered central serotonergic activity in the adult offspring of chronically ethanol treated dams

Female rats were given 16% ethanol solution as the sole liquid during the entire period of gestation. At birth the offspring was removed and reared by foster dams consuming normal tap water. At adult age the female offspring showed deficiencies in their maternal behaviour; they built nests of poor quality and they displayed prolonged times for retrieving pups placed outside the nest. In the whole brains of the prenatally ethanol-exposed females a decreased serotonin synthesis was observed. The offspring of the prenatally ethanol exposed mothers did not show any signs of disturbances in physical or behavioural development.     

Protective role of zinc against the toxicity induced by exposure to cadmium during gestation and lactation on testis development

To assess the effects of exposure to Cd and Zn on rat testicular development, offspring, from mothers receiving either tap water, Cd, Zn or Cd + Zn during gestation and lactation periods, were observed on gestational day (GD) 20 and on postnatal days (PND) 12, 21 and 35. During gestation, Cd induced maternal hypozincemia and less transfer of Zn to the fetus. During lactation, progressive Cd accumulation and Zn depletion in testis at PND12 and PND21 were noted. An increase of abnormal seminiferous tubules and a decrease in testis weight and plasmatic testosterone concentration were also observed at PND21 and PND35 respectively. Interestingly, Zn supply induced a significant protection against Cd toxicity. These results suggest that the toxic effects of Cd observed during development are mediated by the disruption of Zn metabolism, which is established in mothers during pregnancy causing Zn deficiency in fetuses and continues to become more pronounced during lactation.     

Prenatal Exposure to Nicotine: Effects on Prepulse Inhibition and Central Nicotinic Receptors

The present experiment examined effects of prenatal nicotine exposure (6 mg/kg/day via osmotic minipump) throughout gestation on prepulse inhibition of the acoustic startle response (PPI) and on the density of nicotinic acetylcholine receptors (nAchRs) in the brains of 5-week-old Sprague–Dawley rats. A total of 117 male and 103 female offspring were used. Prenatal nicotine reduced subsequent percent PPI to a 98 dB stimulus in female but not in male offspring. There was an inverse correlation between the percent of PPI and nAchR density in the cortex of male rats and the striatum of female rats.     

Protective role of zinc against the neurotoxicity induced by exposure to cadmium during gestation and lactation periods on hippocampal volume of pups tested in early adulthood

The present study was conducted to assess the possible effect of cadmium (Cd) throughout gestation and lactation on the volume of the subregion of the hippocampus as well as the potential protective role of zinc (Zn) against Cd neurotoxicity. For this purpose, female rats received either tap water, Cd, Zn or Cd?+?Zn in their drinking water during gestation and lactation. At postnatal day 35 (PND35), the male pups were sacrificed, and their brains were taken for histologic, chemical, and biochemical analysis. Hippocampal volume was measured in histologic brain slices using Cavalieri’s principle. Zn depletion was observed in the brains of pups issued from mothers exposed to Cd. Biochemical analysis further revealed that Cd exposure significantly increases the superoxide dismutase (SOD) activity, as well as the metallothionein (MT) level. During histologic investigation, our results showed that gestational and lactational exposure to Cd significantly altered and decreased the volume of CA1, CA3 pyramidal cell layer and the dentate gyrus. However, there were no marked differences shown in CA2 subfield. Compared to Cd group, co-treatment with Cd and Zn provided correction of the changes induced by the Cd exposure. These results highlight the protective role of Zn against Cd-induced alteration in the hippocampus which is a crucial structure implicated in learning and memory processes.     

Acute cadmium exposure and ovarian steroidogenesis in cycling and pregnant rats

The purpose of this study was to evaluate the effect(s) of acute in vivo cadmium (Cd) exposure on steroidogenesis in rat ovaries during different reproductive states. Sprague-Dawley rats were injected subcutaneously on the day of diestrus, or on day 7 or 16 of gestation with a single dose of 0, 3, or 5 mg Cd/ kg bw, and evaluated 24 h later. Serum progesterone and estradiol concentrations were determined. Whole-ovary culture was used to evaluate Cd effects on the production of progesterone, testosterone, and estradiol. Liver, kidney, spleen, ovary, placenta, and blood were analyzed for Cd and iron (Fe) concentrations. No general toxic effects, no disruption of estrous cyclicity, and no change in fetal viability were seen. Histologic evaluation revealed moderate Cd-related thecal congestion in ovaries of pregnant rats. The highest Cd concentrations, except for liver, were found in the fetal portion of the placenta. Interestingly, Cd-related decreases in Fe concentration were found in several tissues from rats in proestrus and on gestation day 8, and in fetal placenta from rats on gestation day 17. Cadmium appears to interfere with normal steroidogenesis at a number of sites in the biosynthetic pathway with serum estradiol concentration and ovarian estradiol production the most affected. Acute Cd effects on steroidogenesis are most severe in rats evaluated in proestrus or in early pregnancy, while in late pregnancy steroidogenesis is relatively unaffected.     

Prenatal programming of hepatic monoamine oxidase by 5,5-diphenylhydantoin

During ontogeny, rat liver monoamine oxidase gradually increased in activity in both sexes until the pubertal period when female activity rose 1.5- to 2.0-fold higher than male activity. Oral administration of 5,5-diphenylhydantoin (10 mg/kg body wt) to pregnant rats on days 7,9, 12, 14and 16 of gestation had no effect on the monoamine oxidase activity of immature male or female offspring. The enzyme activity in adult male offspring, from females prenatally treated with diphenylhydantoin, was elevated to a level similar to that of adult females. Subcutaneous injection of diphenylhydantoin (10 mg/kg body wt) for 5 days prior to death failed to induce changes in monoamine oxidase activity in either pre- or postpubertal males or females. Thus, prenatal administration of diphenylhydantoin can program changes in adult male monoamine oxidase activity. The serum levels of testosterone in the male offspring of prenatally treated females, on days 5 and 63 postpartum, were the same as those of their respective controls, demonstrating that the changes caused by diphenylhydantoin are not due to diminished levels of testosterone.     

Sex-specific effects of neonatal exposures to low levels of cadmium through maternal milk on development and immune functions of juvenile and adult rats

Cadmium (Cd) is a major environmental contaminant. Although immunotoxic effects have been associated with Cd exposure, the inconsistency of experimental results underlines the need of an experimental approach more closely related to environmental conditions. We investigated the effects of exposing neonatal Sprague-Dawley rats to environmentally relevant doses of Cd through maternal milk. Dams received 10 parts per billion (ppb) or 5 parts per million (ppm) Cd chloride (CdCl2) in drinking water from parturition until the weaning of the pups. Half of the offspring was sampled at weaning time. The remaining juvenile rats received water without addition of Cd until adulthood. Cd accumulation in kidneys of juvenile rats fed from dams exposed to Cd indicated the transfer of the metal from mother to pups through maternal milk. This neonatal exposure resulted in decreased body, kidney and spleen weights of just weaned females but not of males. This effect was more pronounced in the less exposed females fed from dams exposed to 10 ppb Cd, which also displayed lower hepatic metallothionein-1 (MT-1) mRNA levels. The effect of Cd exposure on body and organ weights did not persist to adulthood. In contrast, we observed gender-specific effects of neonatal Cd exposure on the cytotoxic activity of splenic NK-cells of both juvenile and adult rats. Cd also strongly inhibited the proliferative response of Con A-stimulated thymocytes in both male and female adult rats 5 weeks after the cessation of Cd exposure. These immunotoxic effects were observed at doses much lower than those reported to produce similar effects when exposure occurred during adulthood. In conclusion, neonatal exposures to environmentally relevant levels of Cd through maternal milk represent a critical hazard liable to lead to both transitory and persistent immunotoxic effects.