Pb exposure reduces the expression of SNX6 and Homer1 in offspring rats and PC12 cells.

Lead (Pb) is a widespread environmental heavy metal toxicant and chronic Pb exposure can have irreversible effects on memory and cognitive function, which is closely related to dendritic spines. Studies have shown that SNX6 and Homer1 can regulate the growth of dendritic spines. We aimed to investigate the effect of Pb exposure on the dendritic spines in hippocampus, the expression of SNX6 and Homer1 in rats and PC12 cells. The animals were randomly divided to three groups: control group, low lead group and high lead group. PC12 cells were divided into 3 groups: 0 µM, 1 µM and 100 µM Pb acetate. The results showed that the Pb levels in blood and hippocampus of all exposure groups were significantly higher than that of the control group. The morphology of dendritic spines in hippocampus after Pb treatment was changed and the density of dendritic spines was reduced. The expression of SNX6 and Homer1 was decreased in Pb exposed groups compared with the control group. Furthermore, up-regulation of SNX6 expression could reverse the down-regulation of Pb exposure on Homer1. These results indicate that Pb exposure can reduce the expression of SNX6 and lead to a decrease in Homer1 expression, which affects the changes in dendritic spines causing learning and memory impairment.

Neuroprotective effect of morin on lead acetate- induced apoptosis by preventing cytochrome c translocation via regulation of Bax/Bcl-2 ratio.

Lead (Pb) intoxication is a prevalent type of environmental toxicity as well as minimal amount of lead exposure is liable for neurobehavioral or perhaps intelligence defects. The present study was undertaken to investigate the beneficial effects of morin in protecting the lead acetate (PbAc)-induced oxidative stress in rat brain. PbAc intoxication resulted in motor deficit, memory impairment and oxidative stress Further, PbAc administration alters Bax/Bcl-2 expression thereby increases cytochrome c release from the mitochondria. Treatment with morin at a dose of 40 mg/kg b.wt. significantly restored back the abnormal changes that were noticed in PbAc intoxicated rats. Histopathological sections of cortex, cerebellum and hippocampus showed the extent of neuronal loss in PbAc induced rats and its restoration upon administration of morin. These outcomes imply that morin might be employed therapeutically to chelate toxic metals like Pb, thus possibly lowering PbAc-induced neurotoxicity and tissue damage.

Ascorbic Acid Ameliorates Gestational Lead Exposure-Induced Developmental Alteration in GAD67 and c-Kit Expression in the Rat Cerebellar Cortex.

In the present study, we investigated the effects of ascorbic acid on lead-exposed developing cerebellum. Female rats were divided into the following three groups: control (distilled water), lead (0.2% lead acetate), and lead plus ascorbic acid (100 mg/kg/day, 10% solution). To evaluate the effect of lead exposure and ascorbic acid treatment accurately on the cerebellar development for the gestational period, we halted further treatment with lead and ascorbic acid in the dams after delivery of the pups. Although the ascorbic acid slightly decreased the lead level in pups, lead level was still high in the group treated with lead plus ascorbic acid group compared with the control group. The blood lead levels indicated that the ascorbic acid could facilitate both the excretion and transfer of lead from a dam to its pups via milk. At postnatal day 21, lead exposure significantly reduced the number of Purkinje cells in the cerebellar cortex of pups. Additionally, lead treatment induced degenerative changes such as reduction of glutamic acid decarboxylase (GAD67) and c-kit expressions are observed in the developing cerebellar cortex. In the cerebellum of the pups from the lead plus ascorbic acid group, reduction of the number of Purkinje cells, GAD67 expression, and c-kit immunopositivity were remarkably restored compared with the lead group. Our present results suggested that ascorbic acid treatment to lead-exposed dam exerted protective effects on the developing cerebellum against lead-induced neurotoxicity.

Glazed clay pottery and lead exposure in Mexico: Current experimental evidence.

OBJECTIVES: Lead exposure remains a significant environmental problem; lead is neurotoxic, especially in developing humans. In Mexico, lead in human blood is still a concern. Historically, much of the lead exposure is attributed to the use of handcrafted clay pottery for cooking, storing and serving food. However, experimental cause-and-effect demonstration is lacking. The present study explores this issue with a prospective experimental approach. METHODS: We used handcrafted clay containers to prepare and store lemonade, which was supplied as drinking water to pregnant rats throughout the gestational period. RESULTS AND DISCUSSION: We found that clay pots, jars, and mugs leached on average 200 µg/l lead, and exposure to the lemonade resulted in 2.5 µg/dl of lead in the pregnant rats' blood. Neonates also showed increased lead content in the hippocampus and cerebellum. Caspase-3 activity was found to be statistically increased in the hippocampus in prenatally exposed neonates, suggesting increased apoptosis in that brain region. Glazed ceramics are still an important source of lead exposure in Mexico, and our results confirm that pregnancy is a vulnerable period for brain development.

Low-level Chronic Lead Exposure Impairs Neural Control of Blood Pressure and Heart Rate in Rats.

Lead (Pb) induces adverse effects when it chronically accumulates in the body, including effects on the nervous and cardiovascular systems. Wistar rats were exposed to lead acetate for 30 days (first dose 4 µg/100 g followed by 0.05 µg/100 g/day, i.m.) to investigate the cardiovascular system impact on the autonomic control. The femoral artery and vein were catheterised to perform hemodynamic evaluations in awake rats: heart rate variability (HRV), baroreflex sensitivity, cardiopulmonary reflex and hemodynamic responses to vagal and sympathetic pharmacological blockade. Rats exposed to Pb exhibited a higher blood pressure and reduced HRV in the time domain when compared to the saline-injected group. Spectral analysis of the HRV in the frequency-domain showed an augmented low-frequency component of the spectrum. Methylatropine and atenolol administration suggest increased sympathetic tone and reduced vagal tone on the control of heart rate. Chronic Pb exposure decreased the sensitivity of the baroreflex without significantly changing the cardiopulmonary reflex. This study demonstrated for the first time in an animal model of a controlled, low-dose chronic lead exposure that cardiovascular changes, such as arterial hypertension, are accompanied by impaired autonomic control of the cardiovascular system, as characterised by reduced baroreflex sensitivity and a sympathovagal imbalance.

Effects of curcumin and tannic acid on the aluminum- and lead-induced oxidative neurotoxicity and alterations in NMDA receptors.

Exposure to aluminum (Al) and lead (Pb) can cause brain damage. Also, Pb and Al exposure alters N-methyl-d-aspartate receptor (NMDAR) subunit expression. Polyphenols such as tannic acid and curcumin are very efficient chelator for metals. The effects of curcumin and tannic acid (polyphenols) on Al(3+)- and Pb(2+)-induced oxidative stress were examined by investigating lipid peroxidation (LPO) levels, antioxidant enzyme activities, acetyl cholinesterase (AChE) activity and also NMDA receptor subunits 2A and 2B concentrations in the brain tissue of rats sub-chronically. Rats were divided into seven groups as control, Al, Pb, aluminum-tannic acid treatment (AlT), aluminum-curcumin treatment (AlC), lead-tannic acid treatment (PbT) and lead-curcumin treatment (PbC). After 16 weeks of treatment, LPO levels in the brain and hippocampus were higher in Al(3+)-exposed rats than that of Pb(2+)-exposed group. Superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in brain tissue of Al- and Pb-exposed rats increased significantly compared with control, while catalase (CAT) and AChE activities decreased. It was observed that metal exposure affected NR2A concentrations more than NR2B concentrations and also that polyphenol treatments increased these receptor protein concentrations.

Occupational and environmental lead exposure to adolescent workers in battery recycling workshops.

Lead (Pb), as other environmental neurotoxicant substances, has the capability to interfere with many biochemical events present in cells throughout the body. In the present study, the environmental and occupational exposure to Pb has been assessed by analyzing the scalp hair samples of male adolescents aged 12-15 years, who have worked for the last 12-36 months in Pb battery recycling workshops (BRWs). For comparative purposes, gender and age-matched subjects living in the vicinity of recycling workshops as well as in areas without industrial activity were used as controls. The scalp hair samples were oxidized by acid in a microwave oven prior to determination of Pb by electrothermal atomic absorption spectrometry. The results indicated that both workers and nonworking exposed subjects had higher levels of Pb than nonexposed controls. The contents of Pb in scalp hair of adolescent workers in the present study were compared with those reported in other studies.

Lead induces COX-2 expression in glial cells in a NFAT-dependent, AP-1/NFκB-independent manner.

Epidemiologic studies have provided solid evidence for the neurotoxic effect of lead for decades of years. In view of the fact that children are more vulnerable to the neurotoxicity of lead, lead exposure has been an urgent public health concern. The modes of action of lead neurotoxic effects include disturbance of neurotransmitter storage and release, damage of mitochondria, as well as induction of apoptosis in neurons, cerebrovascular endothelial cells, astroglia and oligodendroglia. Our studies here, from a novel point of view, demonstrates that lead specifically caused induction of COX-2, a well known inflammatory mediator in neurons and glia cells. Furthermore, we revealed that COX-2 was induced by lead in a transcription-dependent manner, which relayed on transcription factor NFAT, rather than AP-1 and NFκB, in glial cells. Considering the important functions of COX-2 in mediation of inflammation reaction and oxidative stress, our studies here provide a mechanistic insight into the understanding of lead-associated inflammatory neurotoxicity effect via activation of pro-inflammatory NFAT3/COX-2 axis.

Continuous exercise training and curcumin attenuate changes in brain-derived neurotrophic factor and oxidative stress induced by lead acetate in the hippocampus of male rats.

CONTEXT: For many years it has been known that lead is life-threatening, not only as an air pollutant but also because of it has been associated with several conditions including neurodegenerative disease. Curcumin (the principal curcuminoid found in turmeric) has demonstrated potent antioxidant properties. OBJECTIVE: We investigated neuroprotective effects of endurance exercise and/or curcumin on lead acetate-induced neurotoxicity in the rat hippocampus. MATERIALS AND METHODS: Forty male Wistar rats were randomly divided into five groups: 1) lead acetate, 2) curcumin, 3) training, 4) training + curcumin, and 5) control. The rats in the training groups performed treadmill running five times a week for 8 weeks (15-22 m/min, 25-64 min). All groups except control received lead acetate (20 mg/kg), whereas the control group received curcumin solution (ethyl oleate). In addition, the curcumin and training + curcumin groups received curcumin solution (30 mg/kg) intraperioneally. RESULTS: Lead acetate resulted in a significantly increase in the malondialdehyde (MDA) in plasma (72%), but not significant in hippocampus (59%). In addition, it led to significantly decreased brain-derived neurotrophic factor in hippocampus (17%) and total antioxidant capacity (27%), as compared to control group. Treadmill running, curcumin supplementation or both resulted in a significant decrease in hippocampus MDA (17, 20, 31%, respectively) and plasma MDA (60, 22, 71%) and also, significantly increased brain-derived neurotrophic factor (76, 45, 94%) and total antioxidant capacity (47.13, 47.11, 61%) levels, as compared to lead acetate group. DISCUSSION AND CONCLUSION: These results provide a rationale for an inhibitory role of curcumin and regular exercise in the attenuation of lead-induced neurotoxicity.

Early postnatal lead exposure induces tau phosphorylation in the brain of young rats.

Cognitive impairment is a common feature of both lead exposure and hyperphosphorylation of tau. We, therefore, investigated whether lead exposure would induce tau hyperphosphorylation. Wistar rat pups were exposed to 0.2% lead acetate via their dams' drinking water from postnatal day 1 to 21. Lead in blood and brain were measured by atomic absorption spectrophotometry and the expression of tau, phosphorylated tau and various serine/threonine protein phosphatases (PP1, PP2A, PP2B and PP5) in the brain was analyzed by Western blot. Lead exposure significantly impaired learning and resulted in a significant reduction in the expression of tau but increased the phosphorylation of tau at Ser199/202, Thr212/Ser214 and Thr231. PP2A expression decreased, whereas, PP1 and PP5 expression increased in lead-exposed rats. These results demonstrate that early postnatal exposure to lead decrease PP2A expression and induce tau hyperphosphorylation at several serine and threonine residues. Hyperphosphorylation of tau may be a mechanism of Pb-induced deficits in learning and memory.

Over activation of hippocampal serine/threonine protein phosphatases PP1 and PP2A is involved in lead-induced deficits in learning and memory in young rats.

Serine/threonine protein phosphatases regulate several key cellular events in the brain, including learning and memory. These enzymes, when over-activated, are known to function as a constraint on learning and memory. We investigated whether these phosphatases are implicated in lead (Pb)-induced deficits in learning and memory. Wistar rat pups were exposed to 0.2% Pb-acetate via their dams' drinking water from postnatal day (PND) 1-21 and directly in drinking water until PND 30. Pb levels in blood, brain and hippocampus were measured and expression of PP1, PP2A, PP2B and PP5 in hippocampus was analyzed. Total phosphatase activity, and PP1 and PP2A activities were determined. Tau phosphorylation at various epitopes was determined by Western blot. Spatial learning and memory was determined by Morris water maze test. Pb exposure significantly increased levels of Pb in blood, brain and hippocampus, reduced the number of synapses in hippocampus and impaired learning and long-term memory (LTM). Short-term memory (STM) was only affected in rats at PND21. Pb exposure increased the expression and activity of PP1 and decreased phosphorylation of tau at threonine-231 in hippocampus at both PND21 and PND30. Pb-induced phosphorylation of tau at serine-199/202 (AT8) paralleled with PP2A activity; at PND21 PP2A activity increased and AT8 phosphorylation decreased; at PND30 PP2A activity decreased and AT8 phosphorylation increased. Increased PP1 activity in hippocampus by Pb is associated with learning and LTM impairment, whereas, increased PP2A activity is associated with STM impairment. These findings suggest the overactivation of PP1 and PP2A, together with changes in tau phosphorylation, as a potential mechanism of lead-induced deficits in learning and memory.

The protective effect of green tea extract on lead induced oxidative and DNA damage on rat brain.

The role of green tea in protection against neurotoxicity induced by lead acetate was investigated in rats. Five equal groups, each of ten rats were used. The first group was served as control, the second, third, and fourth groups were given lead acetate, lead acetate and green tea, and green tea only, respectively, for one month, the fifth group was administered lead acetate for one month followed by green tea for 15 days. Lead acetate was given orally at a dose of 100 mg/kg b. wt, while green tea was given in drinking water at a concentration of 5 g/L. Lead acetate administration induced loss of body weight and decreased concentration of reduced glutathione and SOD activity in brain tissues as well as significantly high DNA fragmentation and pathological changes. Co-administration of green tea with lead acetate significantly alleviated these adverse effects.

Is lead exposure in early life an environmental risk factor for Schizophrenia? Neurobiological connections and testable hypotheses.

Schizophrenia is a devastating neuropsychiatric disorder of unknown etiology. There is general agreement in the scientific community that schizophrenia is a disorder of neurodevelopmental origin in which both genes and environmental factors come together to produce a schizophrenia phenotype later in life. The challenging questions have been which genes and what environmental factors? Although there is evidence that different chromosome loci and several genes impart susceptibility for schizophrenia; and epidemiological studies point to broad aspects of the environment, only recently there has been an interest in studying gene × environment interactions. Recent evidence of a potential association between prenatal lead (Pb(2+)) exposure and schizophrenia precipitated the search for plausible neurobiological connections. The most promising connection is that in schizophrenia and in developmental Pb(2+) exposure there is strong evidence for hypoactivity of the N-methyl-d-aspartate (NMDA) subtype of excitatory amino acid receptors as an underlying neurobiological mechanism in both conditions. A hypofunction of the NMDA receptor (NMDAR) complex during critical periods of development may alter neurobiological processes that are essential for brain growth and wiring, synaptic plasticity and cognitive and behavioral outcomes associated with schizophrenia. We also describe on-going proof of concept gene-environment interaction studies of early life Pb(2+) exposure in mice expressing the human mutant form of the disrupted in schizophrenia 1 (DISC-1) gene, a gene that is strongly associated with schizophrenia and allied mental disorders.

Galantamine rescues lead-impaired synaptic plasticity in rat dentate gyrus.

Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead.

Protective antioxidant effect of Centella asiatica bioflavonoids on lead acetate induced neurotoxicity.

Lead (Pb) is a neurotoxic heavy metal and children in the developmental stage are particularly susceptible to toxic effects of lead exposure. The brain is the key organ involved in interpreting and responding to potential stressors. Epidemiological investigations have established the relationship between chronic lead exposure and cognitive impairments in young children. Excessive production of radical species plays an important role in neuronal pathology resulting from excitotoxic insults, therefore one plausible neuroprotective mechanism of bioflavonoids is partly relevant to their metal chelating and antioxidant properties. Centella asiatica (CA) is a tropical medicinal plant enriched with bioflavonoids and triterpenes and selenium, reported to rejuvenate the cells and promote physical and mental health. Bioflavonoids are claimed to be exert antimutagenic, neurotrophic and xenobiotics ameliorating and membrane molecular stabilizing effects. The objective of the present work is to study the protective antioxidant effect of pretreatment of CA extract (CAE) on lead acetate induced changes in oxidative biomarkers in the central nervous system (CNS) of mice.

Lead encephalopathy due to traditional medicines.

Traditional medicine use is common in developing countries and increasingly popular in the western world. Despite the popularity of traditional medicines, scientific research on safety and efficacy is limited. However documented fatalities and severe illness due to lead poisoning are increasingly recognized to be associated with traditional medicine use. As society becomes more globalized, it is imperative for pharmacists and health care providers to learn about the safety of traditional medical practices. The information presented educates and alerts pharmacists and health care providers about the potential of traditional medicines to cause lead encephalopathy. Case reports were located through systematic literature searches using MEDLINE, CINAHL, AMED, CISCOM, EMBASE and The Cochrane library from 1966 to the February 2007. Reference lists of identified articles and the authors' own files were also searched. Inclusion criteria were cases of human lead encephalopathy associated with traditional medical practices. There were no restrictions regarding the language of publication. Data were subsequently extracted and summarized in narrative and tabular form. We found 76 cases of lead encephalopathy potentially associated with traditional medicine. Ayurvedic medicines were associated with 5 cases (7%), Middle eastern traditional medicines with 66 cases (87%) and 5 cases (7%) with other traditional medicines. Of the 76 cases, 5% were in adults and 95% were in infants and young children. Of the 4 adult cases, at least one was left with residual neurological impairment. In infants and young children, among 72 cases 8 (11%) were fatal, and at least 15 (21%) had residual neurological deficits. Traditional medicine users should be screened for lead exposure and strongly encouraged to discontinue metal-containing remedies. Therefore, the United States Food and Drug Administration and corresponding agencies in other countries should require and enforce heavy metal testing for all imported traditional medicines and "dietary supplements".

Postnatal lead poisoning impairs behavioral recovery following brain damage.

Lead is a potent environmental toxicant with well-known effects on intelligence, school achievement and behavior. Lead exposure is also associated with an increased risk of a variety of health problems including cancer, hypertension, cardiovascular disease, and renal disease. Considering the risk of hypertension, cardiovascular problems, and stroke following lead exposure, the current research assessed the extent to which postnatal exposure to environmentally relevant levels of lead could impair the recovery from a later occurring brain injury. Using a photochemical thrombotic stroke model we found that postnatal lead exposure significantly impaired post-stroke recovery of beam walking ability and proprioceptive limb placing. Considering the increased risk for hypertension and cardiovascular disease in lead-exposed humans, diminished capacity for repair or adaptation following lead exposure needs to now be examined in greater detail.

Lead toxicity.

Lead is one of the oldest known and most widely studied occupational and environmental toxins. Despite intensive study, there is still vigorous debate about the toxic effects of lead, both from low-level exposure in the general population owing to environmental pollution and historic use of lead in paint and plumbing and from exposure in the occupational setting. The majority of industries historically associated with high lead exposure have made dramatic advances in their control of occupational exposure. However, cases of unacceptably high exposure and even of frank lead poisoning are still seen, predominantly in the demolition and tank cleaning industries. Nevertheless, in most industries blood lead levels have declined below levels at which signs or symptoms are seen and the current focus of attention is on the subclinical effects of exposure. The significance of some of these effects for the overt health of the workers is often the subject of debate. Inevitably there is pressure to reduce lead exposure in the general population and in working environments, but any legislation must be based on a genuine scientific evaluation of the available evidence.