Neuro- and nephrotoxicity of subchronic cadmium chloride exposure and the potential chemoprotective effects of selenium nanoparticles.

Cadmium (Cd) exposure leads to production of reactive oxygen species (ROS), which are associated with Cd-induced neurotoxicity and nephrotoxicity. Selenium nanoparticles (Se-NPs) have high bioavailability and antioxidant activities so it attracted wide spread attention. The present study examined the possible ameliorative effect of Se-NPs with diameters of 3-5 nm and 10-20 nm against cadmium chloride (CdCl2)-induced neuro- and nephrotoxicity in rats. Rats were treated with Se-NPs (0 or 0.5 mg/kg BW, s.c.) one hour prior to the CdCl2 (0 or 5 mg/kg BW, p.o.). Pretreatment with Se-NPs significantly decreased CdCl2-induced elevation of serum kidney and brain damage biomarkers; lipid peroxidation; the percent of DNA fragmentation and nearly normalized the activity of acetylcholinesterase (AchE) and significantly increased the activity and expression of antioxidant biomarkers in the RNA and protein levels. Se-NPs also attenuated CdCl2-induced upregulation of kidney and brain pro-apoptotic B-cell CLL/lymphoma 2 associated X (Bax) RNA and protein levels with preventing the increased body burden of Cd and the altered Fe and Cu homeostasis. Histopathological analysis confirmed the biochemical and molecular outcomes. Our data stated that Se-NPs appear to be effective in ameliorating the adverse neurological and nephrotoxic effects induced by CdCl2 partially through the scavenging of free radicals, metal ion chelation, averting apoptosis and altering the cell-protective pathways. The results indicated that Se-NPs could potentially included as an additive to Cd-based industries to control Cd-induced brain and renal injury.

The neuroprotective effect of curcumin against Cd-induced neurotoxicity and hippocampal neurogenesis promotion through CREB-BDNF signaling pathway.

Heavy metal neurotoxicity is one of the major challenges in today's era due to the large scale and widespread mechanisation of the production. However, the causative factors responsible for neurotoxicity are neither known nor do we have the availability of therapeutic approaches to deal with it. One of the major causative agents of neurotoxicity is a non-essential transition heavy metal, Cadmium (Cd), that reaches the central nervous system (CNS) through the nasal mucosa and olfactory pathway causing adverse structural and functional effects. In this study, we explored the neuroprotective efficacy of plant derived Curcumin which is reported to have pleiotropic biological activity including anti-oxidant, anti-inflammatory, anti-apoptotic, anti-carcinogenic and anti-angiogenic effects. Four different concentrations of curcumin (20, 40, 80 and 160 mg/kg of the body weight) were used to assess the behavioural, biochemical, hippocampal proteins (BDNF, CREB, DCX and Synapsin II) and histological changes in Swiss Albino mice that were pre-treated with Cd (2.5 mg/kg). The findings showed that Cd exposure led to the behavioural impairment through oxidative stress, reduction of hippocampal neurogenesis associated proteins, and degeneration of CA3 and cortical neurons. However, treatment of different curcumin concentrations had effectively restored the behavioural changes in Cd-exposed mice through regulation of oxidative stress and up-regulation of hippocampal proteins in a dose-dependent manner. Significantly, a dose of 160 mg/kg body weight was found to be glaringly effective. From this study, we infer that curcumin reverses the adverse effects of neurotoxicity induced by Cd and promotes neurogenesis.

Effects of combined lead and cadmium exposure: changes in schedule-controlled responding and in dopamine, serotonin, and their metabolites.

Adult male rats were maintained on 1 of 4 ad-lib diets: Group Control-Diet received a normal laboratory diet that contained no added chemicals: Group Lead-Diet received a diet containing 500 ppm (parts per million) lead: Group Cadmium-Diet received a diet containing 100 ppm cadmium: and Group Lead-Cadmium-Diet received a diet containing both 500 ppm lead and 100 ppm cadmium. After 60 days of exposure to their respective diets, animals were placed on restricted diets (15 g/day) of the identical food received during the exposure period. Each animal was trained to lever press on a fixed-interval 1-min schedule for 21 sessions (1 session day). The results of schedule training showed that lead alone or cadmium alone was associated with increased lever pressing relative to control diet. However, when lead and cadmium were exposed jointly, performance was not significantly different from control performance. Similar attenuation of effects were observed for central neurotransmitter functions. Specifically disturbances in dopamine and serotonin turnover that were produced by lead alone were attenuated by the cotreatment of cadmium and lead. Possible accounts of the apparent antagonism between cadmium and lead are discussed.

Exposure to cadmium during gestation and lactation decreases cocaine self-administration in rats.

This investigation examined the effects of perinatal cadmium exposure on subsequent self-administration of cocaine during the adult cycle. Female Sprague-Dawley rats were gavaged daily with 0.0 (14% sucrose solution, w/v) or 5.0 mg cadmium chloride (dissolved in 14% sucrose solution, w/v) for 30 days prior to breeding with non-exposed males. Dams continued to experience cadmium exposure through gestation and until pups were weaned at postnatal day (PND) 21. On PND 70, offspring were anesthetized and chronic indwelling jugular catheters were implanted. Following recovery, test subjects were trained in operant chambers to self-administer 0.500 mg/kg infusion (inf) intravenous cocaine on a fixed-ratio (FR) 2 schedule of reinforcement. Following acquisition, self-administration rates were tested for saline, 0.030, 0.060, 0.125, 0.250, and 0.500 mg/kg inf cocaine. Rats exposed developmentally to cadmium self-administered significantly less than controls at saline, 0.030, and 0.060 mg/kg inf cocaine. These data indicate that early-life cadmium exposure, a common exposure vector of which is the use of tobacco products, may affect cocaine sensitivity.

Dietary cadmium exposure alters characteristics of training, substitution, and tolerance when morphine is used as a discriminative stimulus.

This study examined the possibility that cadmium, a toxicant in high concentration in all tobacco products, may alter the stimulus properties of morphine. Adult male rats were exposed to regular laboratory chow (Group Control) or chow containing 100 ppm added cadmium chloride (Group Cadmium). Following an initial 30 day exposure period, control and cadmium-exposed animals were trained to discriminate between i.p. injections of 3.00 mg/kg morphine sulfate and vehicle (distilled water) in a two-choice drug discrimination task. Subsequently, the morphine dose-effect generalization function (0.75-6.00 mg/kg) was determined for control and cadmium-exposed animals. Additional substitution tests were conducted with increasing doses of the high efficacy mu agonist fentanyl (0.0016-0.04 mg/kg), the intermediate efficacy mu agonist (-)-metazocine (0.60-5.00 mg/kg), and the kappa agonist (+/-)-bremazocine (0.03-0.12 mg/kg). Also, increasing doses of the selective mu antagonist naloxone (0.0008-0.50 mg/kg) were presented against the training dose of morphine (3.00 mg/kg) and 0.02 mg/kg fentanyl. Finally, training was discontinued, and control and cadmium-exposed animals were injected with 8.00 mg/kg morphine in the home cage every 12 hr for 2 weeks, prior to redetermining the morphine dose effect function. Following a 1 week recovery period where morphine injections were discontinued, a final determination of the morphine dose-effect function was made. The results of the investigation indicated that cadmium exposure, without affecting the rate-changing properties of the drugs, slowed initial acquisition of the morphine discrimination, decreased the potency of selective doses of naloxone with respect to antagonizing the stimulus effects of morphine and fentanyl, and blocked the development of tolerance to morphine. Morphine, fentanyl, and (-)-metazocine generalized (substituted) equally across both groups, while (+/-)-bremazocine failed to substitute for the morphine stimulus in either group. These findings add to the growing literature on the interaction between metal poisoning and drug selection/abuse.

Social memory deficits in adult male rats exposed to cadmium in infancy.

In two experiments infant rats were injected subcutaneously with 0, 1, or 2 mg Cd/kg on Day 5 or 6 after birth. In adulthood (150 days of age) subjects in both experiments who received the 2 mg/kg dose failed to learn the identity of a strange rat in a social recognition test. Cadmium-treated rats investigated familiar and strange rats equally, whereas control subjects investigated familiar rats much less than unfamiliar individuals. Results with rats in the 1 mg/kg group were less consistent; in Experiment 1 they failed to learn the identity of a stranger, in Experiment 2 they behaved like controls. The level of investigation of a strange rat did not differ among the experimental groups, indicating cadmium did not cause a performance deficit. The 2 mg/kg dose of cadmium had no effect on body weight in Experiment 1 and a small (6.98%), but significant, depressant effect on body weight in Experiment 2. Cadmium exposure in infancy appears to affect social memory processes long after the treatment period.

Effects of inhalation of cadmium on the rat olfactory system: behavior and morphology.

To investigate the effects of cadmium on olfaction, two separate studies were conducted in which male adult rats were exposed to CdO, via inhalation, for 5 h per day, 5 days a week for 20 weeks. Target exposure values of 250 and 500 micrograms/m3 were measured at 200 and 325 micrograms/m3 for the low concentration in two experiments, and 550 and 660 micrograms/m3 for the high concentration. Prior to exposure, olfactory thresholds were obtained using a conditioned suppression technique. After 20 weeks of cadmium exposure, there was no evidence of anosmia in any of the rats nor were there any significant changes observed in olfactory thresholds. Although olfaction was not impaired, cadmium levels in the olfactory bulbs of exposed rats were significantly elevated compared to controls. Cardiac and respiratory histopathology were observed at all exposure levels, but there was no evidence of nasal pathology related to exposure to cadmium. Failure of cadmium to produce olfactory dysfunction may be due to the protective effects of metallothionein and/or to the highly resilient nature of the rodent olfactory system.

Behavioural and functional neurotoxicological changes caused by cadmium in a three-generational study in rats.

1. Three consecutive generations of Wistar rats were orally treated by gavage with 3.5, 7.0 or 14.0 mg/kg cadmium (in form of cadmium chloride diluted in distilled water) over the period of pregnancy, lactation and 8 weeks after weaning. 2. Behavioural (open field behaviour) and electrophysiological (spontaneous and evoked cortical activity, etc.) parameters of male rats from each generation were investigated at the age of 12 weeks. 3. The main behavioural outcomes were change in vertical exploration activity (rearing) and increased exploration of an open field centre. The spontaneous and evoked electrophysiological variables showed dose- and generation-dependent changes (increased frequencies in the electrocorticogram, lengthened latency and duration of evoked potentials, etc.) signalling a change in neural functions. 4. The data show that low-level, multigeneration exposure to inorganic cadmium can affect functions of the nervous system. This suggests that cadmium exposed human populations may be at risk of developing nervous system disorders.

Low lead and cadmium levels and childhood visual-perception development.

This study investigated possible relationships of lead and cadmium levels to childhood visual-perceptual development. Hair-metal concentrations of lead and cadmium were analyzed in 25 children who were having learning problems. They were also administered the Bender Visual-motor Gestalt Test. Lead and cadmium levels correlated significantly and negatively with age-deviations of Bender errors. A continuing reexamination of lead and cadmium levels is needed because levels previously thought harmless may be associated with decrements in childhood visual-perceptual development.

Lead and cadmium levels in violent criminals.

Two groups of violent incarcerated male criminals and 30 nonviolent criminals were compared for element content of hair by atomic absorption spectroscopy. Groups did not differ in age, socioeconomic status, or months institutionalized. The groups did differ significantly in lead and cadmium levels. The importance of cadmium in affecting reactivity to stimuli is discussed.

The effects of chronic cadmium exposure on schedule controlled responding and conditioned suppression in the adult rat.

Adult rats fed daily rations of laboratory chow with added CdCl2 were tested for schedule controlled responding and conditioned suppression (conditioned emotional response-CER). Determinations of tissue Cd, levels of metallothionein, and the ratio of Cd in the tissue to the Cd-binding capacity of metallothionein also were made. Animals were exposed daily to either 5 mg/kg Cd (Group Cd-5), 1 mg/kg Cd (Group Cd-1), or no Cd (Group Control). An initial phase of training on a variable interval 2 min (VI-2) food reinforcement schedule lasting 40 sessions (1 session/day) was followed by CER training and then an interpolated period (100 days) of continued exposure but with no training. Schedule retraining was introduced for 21 sessions (1 session/day). The results showed no group differences during original schedule training. On the CER test, Group Cd-1 was found to exhibit less suppression (defined in terms of lever press rates) than controls to preaversive stimuli. Group Cd-5 showed significantly greater suppression to the primary aversive stimulus (shock) than the other two groups. Both treatment groups showed significantly lower lever press rates than controls on the schedule retraining task. These behavioral disturbances occurred commensurate with increases in non-metallothionein bound Cd in the liver, kidney, and small intestine.

Prenatal exposure to lead and cadmium and psychomotor development of the child at 6 years.

In 1977, a hair sample was taken from 26 newborn babies and their mothers and analysed for lead and cadmium. Six years later, each of these 26 children was given a psychometric test (McCarthy Scales of Children's Abilities). Statistical analysis shows a significant negative relationship between the degree of in utero exposure to cadmium and lead and the child's motor and perceptual abilities. Any effect on memory or verbal skills was not statistically significant. Allowing for the confounding variables does not consistently affect these results.

Neuropsychological effects of occupational exposure to cadmium.

Neuropsychological functioning was measured in 31 male workers exposed to cadmium in a refrigerator coil manufacturing plant. Workers with high urinary cadmium levels performed less well than did those with low urinary cadmium levels on measures of attention, psychomotor speed, and memory. There were modest correlations between one of two biologic measures of cadmium exposure and neuropsychological performance. The neuropsychological impairments cannot readily be attributed to exposure to other neurotoxins, alcohol intake, CNS effects of renal dysfunction, or psychological distress. Cadmium body burden has previously been related to intelligence and school achievement of children; this study would appear to be the first to suggest that occupational exposure to cadmium is associated with cognitive impairment in adults. Cadmium interferes with several important nervous system functions, but the mechanisms of neurotoxicity remain uncertain.

Behavioral consequences of chelator administration in acute cadmium toxicity.

The conditioned flavor-aversion paradigm was used to assess the toxicity of acutely administered cadmium and the interaction of cadmium with the heavy-metal chelating agents dimercaprol (BAL) and dimercaptosuccinic acid (DMSA). Shortly after consuming saccharin, rats received ip administration of cadmium either alone or in combination with sc administration of BAL or DMSA. Three days later they were given the choice between consuming saccharin or water, and saccharin preferences were recorded. When compared to rats receiving either nothing or the vehicle, rats receiving cadmium displayed significant reductions in saccharin preference (i.e., conditioned flavor aversions). BAL and DMSA were also capable of producing conditioned flavor aversions when given alone. Rats receiving cadmium in combination with either BAL or DMSA displayed significant, but not complete attenuations of conditioned flavor aversions when compared to the flavor aversions of rats receiving cadmium alone. Chelator-induced blockade of cadmium-induced flavor-aversion conditioning was not obtained when BAL or DMSA administration was delayed by 4 hr. Attenuation of cadmium-induced aversions by BAL and DMSA extends earlier findings of an attenuation of lead-induced flavor-aversion conditioning by these complexing agents, and thus demonstrates further the utility of the flavor-aversion conditioning paradigm in characterizing metal-chelator interactions.