Effects of Vitamin D Receptor, Metallothionein 1A, and 2A Gene Polymorphisms on Toxicity of the Peripheral Nervous System in Chronically Lead-Exposed Workers.

Chronic exposure to lead is neurotoxic to the human peripheral sensory system. Variant vitamin D receptor (VDR) genes and polymorphisms of metallothioneins (MTs) are associated with different outcomes following lead toxicity. However, no evidence of a relationship between lead neurotoxicity and polymorphisms has previously been presented. In this study, we investigated the relationship between the polymorphisms of VDR, MT1A, and MT2A genes and lead toxicity following chronic occupational lead exposure. We measured vibration perception thresholds (VPT) and current perception thresholds (CPT) in 181 workers annually for five years. The outcome variables were correlated to the subject's index of long-term lead exposure. Polymorphisms of VDR, MT1A, and MT2A were defined. The potential confounders, including age, sex, height, smoking, alcohol consumption, and working life span, were also collected and analyzed using linear regression. The regression coefficients of some gene polymorphisms were at least 20 times larger than regression coefficients of time-weighted index of cumulative blood lead (TWICL) measures. All regression coefficients of TWICL increased slightly. MT1A rs11640851 (AA/CC) was associated with a statistically significant difference in all neurological outcomes except hand and foot VPT. MT1A rs8052394 was associated with statistically significant differences in hand and foot CPT 2000 Hz. In MT2A rs10636, those with the C allele showed a greater effect on hand CPT than those with the G allele. Among the VDR gene polymorphisms, the Apa rs7975232 (CC/AA) single nucleotide polymorphism was associated with the greatest difference in hand CPT. MT2A rs28366003 appeared to have a neural protective effect, whereas Apa (rs7975232) of VDR and MT2A rs10636 increased the neurotoxicity as measured by CPT in the hands. MT1A rs8052394 had a protective effect on large myelinated nerves. MT1A rs11640851 was associated with susceptibility to neurotoxicity.

Effects of Zinc and N-Acetylcysteine in Damage Caused by Lead Exposure in Young Rats.

This study investigated the toxicity of rats exposed to lead acetate (AcPb) during the second phase of brain development (8-12 days postnatal) in hematological and cerebral parameters. Moreover, the preventive effect of zinc chloride (ZnCl2) and N-acetylcysteine (NAC) was investigated. Pups were injected subcutaneously with saline (0.9% NaCl solution), ZnCl2 (27 mg/kg/day), NAC (5 mg/kg/day) or ZnCl2 plus NAC for 5 days (3rd-7th postnatal days), and with saline (0.9% NaCl solution) or AcPb (7 mg/kg/day) in the five subsequent days (8th-12th postnatal days). Animals were sacrificed 21 days after the last AcPb exposure. Pups exposed to AcPb presented inhibition of blood porphobilinogen-synthase (PBG-synthase) activity without changes in hemoglobin content. ZnCl2 pre-exposure partially prevented PBG-synthase inhibition. Regarding neurotoxicity biomarkers, animals exposed to AcPb presented a decrease in cerebrum acetylcholinesterase (AChE) activity and an increase in Pb accumulation in blood and cerebrum. These changes were prevented by pre-treatment with ZnCl2, NAC, and ZnCl2 plus NAC. AcPb exposure caused no alteration in behavioral tasks. In short, results show that AcPb inhibited the activity of two important enzymatic biomarkers up to 21 days after the end of the exposure. Moreover, ZnCl2 and NAC prevented the alterations induced by AcPb.

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.

GRIN2A polymorphisms and expression levels are associated with lead-induced neurotoxicity.

Lead acts as an antagonist of the N-methyl-d-aspartate receptor (NMDAR). GRIN2A encodes an important subunit of NMDARs and may be a critical factor in the mechanism of lead neurotoxicity. Changes in GRIN2A expression levels or gene variants may be mechanisms of lead-induced neurotoxicity. In this study, we hypothesized that GRIN2A might contribute to lead-induced neurotoxicity. A preliminary HEK293 cell experiment was performed to analyze the association between GRIN2A expression and lead exposure. In addition, in a population-based study, serum GRIN2A levels were measured in both lead-exposed and control populations. To detect further the influence of GRIN2A gene single nucleotide polymorphisms (SNPs) in lead-induced neurotoxicity, 3 tag SNPs (rs2650429, rs6497540, and rs9302415) were genotyped in a case-control study that included 399 lead-exposed subjects and 398 controls. Lead exposure decreased GRIN2A expression levels in HEK293 cells ( p < 0.001) compared with lead-free cells. Lead-exposed individuals had lower serum GRIN2A levels compared with controls ( p < 0.001), and we found a trend of decreasing GRIN2A level with an increase in blood lead level ( p < 0.001). In addition, we found a significant association between rs2650429 CT and TT genotypes and risk of lead poisoning compared with the rs2650429 CC genotype (adjusted odds ratio = 1.42, 95% confidence interval = 1.01-2.00]. Therefore, changes in GRIN2A expression levels and variants may be important mechanisms in the development of lead-induced neurotoxicity.

Attenuation of lead neurotoxicity by supplementation of polyunsaturated fatty acid in Wistar rats.

BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65-fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead-induced neurotoxicity and associated human health risk.

Lead poisoning in a calf from the mining area of Sierra Madrona and Alcudia Valley / Intoxicación por plomo en un ternero de la zona minera de Sierra Madrona y el Valle de Alcudia

We notify the first reported case of lead (Pb) poisoning in a calf from the old mining district of Sierra Madrona and Alcudia Valley (Spain), which appeared in a farm with visible signs of historic mining activity in the surrounding land. The blood Pb level found in this calf was 311 μg/dL, and was associated to several symptoms of clinical Pb poisoning, including severe paralysis, loss of sensitivity from hip to the hind legs and incoordination. Soils, plants and water points inside the farm showed Pb levels above the threshold values to be classified as highly polluted soils, toxic pastures for livestock and non-potable water for humans. This report indicates that Pb pollution denotes a health risk for cattle reared in the mining area of Sierra Madrona and Alcudia Valley (AU)

Se notifica el primer caso registrado de intoxicación por plomo (Pb) en un ternero del antiguo distrito minero de Sierra Madrona y el Valle de Alcudia (España), que apareció en una finca ganadera con restos visibles de antiguas activides mineras en los terrenos circundantes. El nivel de Pb en sangre detectado en el animal fue de 311 μg/dL, y estuvo asociado a diversos síntomas de intoxicación clínica por Pb, que incluyen parálisis severa, pérdida de sensibilidad en los cuartos traseros e incoordinación. Los suelos, las plantas y los puntos de agua presentes en la finca mostraron niveles de Pb por encima de los valores umbral, siendo considerados como suelos altamente contaminados, pastos tóxicos para el ganado y agua no potable para el consumo humano. Estos datos indican que la contaminación por Pb implica un riesgo para la salud del ganado criado en la zona minera de Sierra Madrona y el Valle de Alcudia (AU)

Effects of occupational lead exposure on renal and nervous system of workers of traditional tile factories in Mashhad (northeast of Iran).

Occupational lead poisoning is a health problem in Iran. Renal and neuropsychiatric complications of occupational lead poisoning are the main concerns for the workers and their employers. It was thus aimed to investigate the renal and neurotoxic effects of lead poisoning in the workers of two traditional-tile-factories. Researchers visited the workers in the factories and collected data by taking direct history and physical examinations in summer of 2005. Data were recorded in previously designed forms. Blood and urine lead concentrations were measured by an atomic absorption technique. A neurologist examined all workers and electrophysiological investigations were undertaken as clinically indicated. Data were analyzed by SPSS software and chi-square, student t test and Pearson correlation tests were used accordingly. The numerical data were expressed as mean ± standard deviation and p < 0.05 was considered as the significant level. Overall, 108 male subjects aged 37 ± 7.8 years were studied. Duration of lead exposure was 9.8 ± 6 years. Lead concentration in 2005 was 361.5 ± 176.9 µg/L. The main objective clinical findings were lead line (64.8%), peripheral neuropathy of upper limb (37%), suppression of deep tendon reflexes (DTR) in upper limbs (25.7%), tremor (23.3%), peripheral neuropathy of lower limbs (17%) and abdominal tenderness (15.1%). The subjective findings were mainly on the central nervous system, such as loss of memory (57%), moodiness (56.1%), agitation (47.7%), drowsiness (36.4%), and headache (29.9%). There was no significant correlation between blood lead concentration and glomerular filtration rate (GFR). But there were significant correlations between the blood lead concentrations and urine lead concentration (p < 0.001). This study showed that lead had toxic effects on the teeth (bone), central and peripheral nervous system, more than renal function. Prophylactic and treatment measures were performed.

Neurotoxic effects and biomarkers of lead exposure: a review.

Lead, a systemic toxicant affecting virtually every organ system, primarily affects the central nervous system, particularly the developing brain. Consequently, children are at a greater risk than adults of suffering from the neurotoxic effects of lead. To date, no safe lead-exposure threshold has been identified. The ability of lead to pass through the blood-brain barrier is due in large part to its ability to substitute for calcium ions. Within the brain, lead-induced damage in the prefrontal cerebral cortex, hippocampus, and cerebellum can lead to a variety of neurologic disorders. At the molecular level, lead interferes with the regulatory action of calcium on cell functions and disrupts many intracellular biological activities. Experimental studies have also shown that lead exposure may have genotoxic effects, especially in the brain, bone marrow, liver, and lung cells. Knowledge of the neurotoxicology of lead has advanced in recent decades due to new information on its toxic mechanisms and cellular specificity. This paper presents an overview, updated to January 2009, of the neurotoxic effects of lead with regard to children, adults, and experimental animals at both cellular and molecular levels, and discusses the biomarkers of lead exposure that are useful for risk assessment in the field of environmental health.

Avaliação dos efeitos tóxicos sobre o sistema nervoso periférico, decorrentes da exposição ocupacional ao chumbo / Evaluation of toxic effects on the peripheral nervous system, as a consequence of the occupational exposure to lead

Após descrever a interação do homem com meio ambiente, em particular nas atividades laborativas, se destaca a extração e o processamento dos minérios de chumbo como importante fonte de exposição ocupacional a este metal, que gerou no passado grandes casuísticas de intoxicação. Em seguida é feito um relato de como ocorreu a exposição ocupacional ao chumbo em Santo Amaro da Purificação na Bahia, e uma revisão da toxicologia deste metal, identificando-se a necessidade de se trabalhar com indicadores, parâmetros, que melhor reflitam os efeitos cumulativos, como os que ocorrem no sistema nervoso periférico. Analisar e discutir as alterações do sistema nervoso periférico pós exposição ocupacional, em um grupo de ex-empregados de uma metalurgia primária de chumbo; e identificar marcadores que melhor reflitam os efeitos da bioacumulação deste metal. A partir de dados secundários, foi construída uma serie de casos, na qual se analisou o passado clínico e toxicológico, e a relação com os achados neurofisiológicos. Os dados analisados, demonstraram a ocorrência, de um leque de neuropatias periféricas em todo o grupo, mas as alterações da condução motora em membros superiores, que tem sido melhor relacionadas aos efeitos tóxicos do chumbo, não foram tão consistentes. Ficou comprovado ser a media acumulada do chumbo no sangue um marcador biológico mais fidedigno, para avaliações de efeitos de longo prazo como as alterações sobre o sistema nervoso periférico.

The influence of milk intake on the lead toxicity to the sensory nervous system in lead workers.

The dietary calcium supplement has been suggested to children and pregnant women for prevention of lead toxicity, because of lead-calcium interaction. Lead workers were supplied free milk in Taiwan; however, part of workers did not drink milk due to lactose intolerance. The goal of this study is to evaluate the effects of milk-intake on the peripheral nervous system in workers with long-term lead exposure. We measured 181 workers' current perception thresholds (CPT) as neurological outcomes. The outcome variables were then correlated to the subject's milk intake, blood lead levels, and index of long-term lead exposure that was calculated by the subject's serial blood lead data in a period of working duration. The potential confounders, including age, gender, body height, smoking and alcohol consumption, were also collected and analyzed in multiple regressions. 23 workers who reported never or rarely drinking milk, which meant that they have suffered from diarrhea or abdomen discomfort after drinking milk since childhood, had higher blood lead parameters but not statistically significant, and higher thresholds in sensory nerve tests, especially, statistically significance on 5 and 250 Hz of hand CPTs, which represent C fiber and A-delta fiber. In multiple regression models with control of potential confounders, significant protective effects of milk intake were found on reducing hand CPTs, but not on foot CPTs. Our study, using measurement of sensory nerve CPTs, revealed that drinking milk (two bottles a day, about 700 g per day) might have an effect to protect lead peripheral neurotoxicity. The detail biochemical mechanisms need further investigations. However, reduction of occupational lead exposure is the essential way to protect lead neuropathy. The authors did not emphasize that offers of milk to workers could be instead of occupational hygiene efforts. Furthermore, lead workers with lactose intolerance might be more susceptible, and need more industrial hygiene interventions.

Erythrocyte aminolevulinate dehydratase activity as a lead marker in patients with chronic renal failure.

BACKGROUND: Overexposure to lead may result in an increased risk for developing chronic renal failure (CRF) and hypertension. Subclinical lead poisoning is difficult to identify. Because the heme biosynthetic pathway is highly sensitive to lead, we considered the study of enzymes involved in this pathway as a method to detect an excessive body lead burden. METHODS: Main concerns in assessing the heme pathway in patients with CRF were related to aminolevulinate dehydratase (ALAD) activity. We first selected a number of patients with CRF at a predialysis stage, subsequently dividing them into two groups after the EDTA mobilization test had determined whether lead pools were expanded. The study included 24 healthy controls, 12 patients with clinical plumbism and biochemical demonstration of lead poisoning (Pb-CONT), 18 patients with CRF with no evidence of high lead storage (CRF/-), and 8 patients with CRF with high urinary excretion of lead in contrast to normal blood lead levels (CRF/+). RESULTS: As expected, symptoms of plumbism (Pb-CONT) were accompanied by an increased erythrocyte zinc-protoporphyrin-free protoporphyrin ratio and high urine coproporphyrin excretion, whereas both these values were within the normal range in all patients with CRF. CRF/- patients showed minor abnormalities of erythrocyte heme metabolism, such as low ALAD activity, both baseline and in vitro restored. The ALAD-restored ALAD ratio correlated closely with urine lead excretion; it was normal in healthy controls and CRF/- patients and significantly reduced in Pb-CONT and CRF/+ patients. CONCLUSION: The erythrocyte ALAD-restored ALAD ratio may be a useful tool to show otherwise subclinical lead poisoning in patients with CRF.

Past adult lead exposure is associated with longitudinal decline in cognitive function.

OBJECTIVE: To determine whether adults with past exposure to neurotoxicants have progressive declines in cognitive function years after exposure has ceased, and whether tibia lead is a predictor of the magnitude of change. METHODS: A total of 535 former organolead manufacturing workers with a mean age of 55.6 years, a mean duration of 16 years since last occupational lead exposure, and low blood lead levels at the first study visit and 118 controls were evaluated with neurobehavioral tests two to four times over 4 years. "Peak" tibia lead levels, estimated from current levels measured by X-ray fluorescence, were used to predict changes in cognitive function over time. RESULTS: In former lead workers, peak tibia lead ranged from -2.2 to 98.7 microg Pb/g bone mineral. Compared to controls, former lead workers performed worse over time for three tests of visuo-constructive ability and verbal memory and learning (p < 0.05). In former lead workers, peak tibia lead predicted declines for six tests of verbal memory and learning, visual memory, executive ability, and manual dexterity (p < 0.05 for four tests and < 0.10 for two additional tests). On average, for these six tests, an increase of 15.7 microg/g of peak tibia lead was equivalent in its effects on annual test decline to 5 more years of age at baseline. CONCLUSIONS: These are the first data to suggest that cognitive function can progressively decline due to past occupational exposures to a neurotoxicant.