Several studies have implicated oxidative stress as one of the important mechanisms of toxic effects of lead (Pb). In the present study we tested the beneficial effects of calcium (Ca2+) and zinc (Zn2+) in protecting the Pb-induced oxidative stress in the brains of developing and adult mice. Mice were lactationally exposed to 0.2% Pb and supplemented with either calcium (Ca2+) or zinc (Zn2+) and the mitochondrial antioxidant enzymes [superoxide dismutase (SOD), xanthine oxidase (XO) and catalase (CAT)] and lipid peroxidation (LP) were analyzed in cortex, hippocampus, cerebellum and medulla of brains excised on postnatal day (PND) 14, 21, 28 and 3 months. The levels of free radicals were measured using direct Electron Paramagnetic Resonance (EPR) spectroscopy. Exposure to Pb resulted a significant decrease in the activities of SOD, XO and CAT while the LP levels were significantly increased in different brain regions. Evaluation of EPR signals and g-values showed abundant accumulation of free radicals in different regions of the brain following Pb exposure. Interestingly the supplementation with Ca2+ or Zn2+ reversed the Pb-induced effects on antioxidant enzymes, LP and free radical formation; however Zn2+ supplementation appeared to be more protective. These findings strongly support that zinc and calcium supplementation significantly protect the Pb-induced oxidative stress, a major contributing factor to neurotoxicity.

Rats were lactationally exposed to low- (0.2%) and high-level (1%) lead (Pb) from postnatal day 1 (PND1) through PND21 through the drinking water of the mother. The levels of catecholamines, epinephrine, norepinephrine and dopamine and the activity of the enzyme monoamine oxidase (MAO) were determined in the cerebellum, hippocampus and cerebral cortex in young (1-month-old) and adult (3-month-old) rats. Pb-exposure decreased the activity of mitochondrial MAO in all the brain regions in a dose-dependent manner. The synaptosomal catecholamines (epinephrine, norepinephrine and dopamine), however, increased with low level (0.2%) Pb-exposure and significantly decreased with high level (1%) Pb-exposure in both the age groups. In general, the young rats seem to be more vulnerable to Pb-neurotoxicity. These data suggest that Pb-exposure perturbs the aminergic system in the cerebral cortex, cerebellum and hippocampus and may contribute to the cognitive and behavioural impairments observed in Pb-exposed rats.

Exposure to low-levels of lead (Pb) during early development has been implicated in behavioral abnormalities and cognitive deficits in children. The present study is focused on developmental changes in hippocampus and cerebellum of rats following perinatal exposure to Pb. Pregnant rats were exposed to 0.2% Pb-acetate from gestation day 6 (GD 6) through postnatal day (PND) 21 and the activity levels of acetylcholinesterase (AChE) were estimated in cerebellum and hippocampus of pups at specific time points for 5 weeks. In both the brain regions, Pb-exposure decreased AChE activity with an increase in age. Histochemical observations conducted in 35 days old rat brain showed decreased AChE activity conspicuously in stratum oriens and dentate gyrus of hippocampus, and molecular and granule cell layers of cerebellum. In vitro studies conducted in 35 days old rat brain showed a considerable decrease in the specific activity of AChE at high concentrations (50-100 microM) of Pb in a concentration-dependent manner. However, at low concentrations (5-20 microM), Pb failed to produce such changes. In the presence of eserine (physostigmine), the specific inhibitor of AChE, the inhibitory effect of Pb was potentiated and this was more pronounced at low-concentrations of Pb. The behavioral responses in open-field also showed a significant decrease in both Pb exposed as well as eserine administered rats. These data suggest that low-level perinatal Pb-exposure induces alterations in cholinergic system in the cerebellum and hippocampus of developing brain even after the withdrawal of Pb-exposure, that may contribute to behavioral and learning deficits.

Our earlier studies indicated the role of neurotransmitter systems in lead (Pb) induced behavioral perturbations. In this study, we examined the alterations in synaptosomal acetylcholine (ACh), epinephrine, dopamine, acetylcholinesterase (AChE), and mitochondrial monoamine oxidase (MAO) in the cerebellum and hippocampus of perinatally Pb-exposed rats. Rats (Wistar) were exposed to 0.2% Pb (Pb acetate in drinking water of mother) from gestational day 6 and the pups were exposed lactationally (through mother's milk) to Pb till weaning (postnatal day 21). Studies conducted on different postnatal days (PND 21, 28, 35 and 60) showed significant decreases in synaptosomal AChE and mitochondrial MAO activities, and increases in the levels of ACh, dopamine and epinephrine in the cerebellum and hippocampus of Pb-exposed rats. These alterations were greater at PND 35 and more pronounced in the cholinergic system (ACh and AChE) of hippocampus and the aminergic system (epinephrine, dopamine and MAO) of cerebellum. The total locomotor activity and exploratory behavior were also decreased significantly in Pb-exposed animals corresponding to the alterations observed in cholinergic and aminergic systems. Calcium administration together with Pb, however significantly reversed the Pb-induced alterations in transmitters and enzymes, as well as exploratory and motor behavior suggesting protective effect of calcium in Pb-exposed animals.

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