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Lead (Pb) continues to be a major toxic metal in the environment. Pb exposure frequently occurs in the presence of other metals, such as arsenic (As) and manganese (Mn). Continued exposure to low levels of these metals may lead to long-term toxic effects due to their accumulation in several organs. Despite the recognition that metals in a mixture may alter each other's toxicity by affecting deposition, there is dearth of information on their interactions in vivo. In this work, we investigated the effect of As and Mn on Pb tissue deposition, focusing on the kidney, brain, and liver. Wistar rats were treated with eight doses of each single metal, Pb (5 mg/Kg bw), As (60 mg/L), and Mn 10 mg/Kg bw), or the same doses in a triple metal mixture. The kidney, brain, liver, blood, and urine Pb, As, and Mn concentrations were determined by graphite furnace atomic absorption spectrophotometry. The Pb kidney, brain, and liver concentrations in the metal-mixture-treated group were significantly increased compared to the Pb-alone-treated group, being more pronounced in the kidney (5.4-fold), brain (2.5-fold), and liver (1.6-fold). Urinary excretion of Pb in the metal-mixture-treated rats significantly increased compared with the Pb-treated group, although blood Pb concentrations were analogous to the Pb-treated group. Co-treatment with As, Mn, and Pb alters Pb deposition compared to Pb alone treatment, increasing Pb accumulation predominantly in the kidney and brain. Blood Pb levels, unlike urine, do not reflect the increased Pb deposition in the kidney and brain. Taken together, the results suggest that the nephro- and neurotoxicity of "real-life" Pb exposure scenarios should be considered within the context of metal mixture exposures.

Manganese (Mn) is an essential metal for biological systems; however, occupational or clinical exposure to high levels of Mn can produce a neurological disorder called manganism. Oxidative stress and neuroinflammation play major roles in the Mn-induced neurodegeneration leading to dysfunction of the basal ganglia. We investigated the toxic effects of MnCl2 in an immortalized rat brain endothelial cell line (RBE4) and the protective effects of the radical scavenging aminosalicylic acids, 5-aminosalicylic acid (5-ASA) and 4-aminosalicylic acid (4-PAS). Mn cytotoxicity was determined with 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) activity. A significant decrease in MTT reduction concomitant with increased LDH release was noted in RBE4 cells exposed for 24 h to MnCl2 (600 and 800 μM; p < 0.0001). Our results establish that compared to 4-PAS, 5-ASA has greater efficacy in protecting RBE4 cells from Mn-induced neurotoxicity after preexposure to MnCl2 800 μM (p < 0.0001).

Manganese (Mn) is an essential element and it acts as a cofactor for a number of enzymatic reactions, including those involved in amino acid, lipid, protein, and carbohydrate metabolism. Excessive exposure to Mn can lead to poisoning, characterized by psychiatric disturbances and an extrapyramidal disorder. Mn-induced neuronal degeneration is associated with alterations in amino acids metabolism. In the present study, we analyzed whole rat brain amino acid content subsequent to four or eight intraperitoneal injections, with 25 mg MnCl₂/kg/day, at 48-h intervals. We noted a significant increase in glycine brain levels after four or eight Mn injections (p < 0.05 and p < 0.01, respectively) and arginine also after four or eight injections (p < 0.001). Significant increases were also noted in brain proline (p < 0.01), cysteine (p < 0.05), phenylalanine (p < 0.01), and tyrosine (p < 0.01) levels after eight Mn injections vs. the control group. These findings suggest that Mn-induced alterations in amino acid levels secondary to Mn affect the neurochemical milieu.

Background: Manganese (Mn) is a naturally occurring element and an essential nutrient for humans and animals. However, exposure to high levels of Mn may cause neurotoxic effects. The pathological mechanisms associated with Mn neurotoxicity are poorly understood, but several reports have established it is mediated, at least in part, by oxidative stress., Objectives: The present study was undertaken to test the hypothesis that a decrease in acetylcholinesterase (AChE) activity mediates Mn-induced neurotoxicity., Methods: Groups of 6 rats received 4 or 8 intraperitoneal (i.p.) injections of 25mg MnCl(2)/kg/day, every 48 h. Twenty-four hours after the last injection, brain AChE activity and the levels of F(2)-isoprostanes (F(2)-IsoPs) and F(4)-neuroprostanes (F(4)-NPs) (biomarkers of oxidative stress), as well as prostaglandin E(2) (PGE(2)) (biomarker of neuroinflammation) were analyzed., Results: The results showed that after either 4 or 8 Mn doses, brain AChE activity was significantly decreased (p<0.05), to 60 ± 16% and 55 ± 13% of control levels, respectively. Both treated groups exhibited clear signs of neurobehavioral toxicity, characterized by a significant (p<0.001) decrease in ambulation and rearings in open-field. Furthermore, Mn treatment caused a significant increase (p<0.05) in brain F(2)-IsoPs and PGE(2) levels, but only after 8 doses. In rats treated with 4 Mn doses, a significant increase (p<0.05) in brain F(4)-NPs levels was found. To evaluate cellular responses to oxidative stress, we assessed brain nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and Mn-superoxide dismutase (Mn-SOD, SOD2) protein expression levels. A significant increase in Mn-SOD protein expression (p<0.05) and a trend towards increased Nrf2 protein expression was noted in rat brains after 4 Mn doses vs. the control group, but the expression of these proteins was decreased after 8 Mn doses. Taken together, these results suggest that the inhibitory effect of Mn on AChE activity promotes increased levels of neuronal oxidative stress and neuroinflammatory biomarkers., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Chronic, excessive exposure to manganese (Mn) may induce neurotoxicity and cause an irreversible brain disease, referred to as manganism. Efficacious therapies for the treatment of Mn are lacking, mandating the development of new interventions. The purpose of the present study was to investigate the efficacy of ebselen (Ebs) and para-aminosalicylic acid (PAS) in attenuating the neurotoxic effects of Mn in an in vivo rat model. Exposure biomarkers, inflammatory and oxidative stress biomarkers, as well as behavioral parameters were evaluated. Co-treatment with Mn plus Ebs or Mn plus PAS caused a significant decrease in blood and brain Mn concentrations (compared to rats treated with Mn alone), concomitant with reduced brain E₂ prostaglandin (PGE₂) and enhanced brain glutathione (GSH) levels, decreased serum prolactin (PRL) levels, and increased ambulation and rearing activities. Taken together, these results establish that both PAS and Ebs are efficacious in reducing Mn body burden, neuroinflammation, oxidative stress and locomotor activity impairments in a rat model of Mn-induced toxicity., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Manganese (Mn) is an essential trace metal; however, exposure to high Mn levels can result in neurodegenerative changes resembling Parkinson's disease (PD). Information on Mn's effects on endothelial cells of the blood-brain barrier (BBB) is lacking. Accordingly, we tested the hypothesis that BBB endothelial cells are a primary target for Mn-induced neurotoxicity. The studies were conducted in an in vitro BBB model of immortalized rat brain endothelial (RBE4) cells. ROS production was determined by F(2)-isoprostane (F(2)-IsoPs) measurement. The relationship between Mn toxicity and redox status was investigated upon intracellular glutathione (GSH) depletion with diethylmaleate (DEM) or L-buthionine sulfoximine (BSO). Mn exposure (200 or 800 microM MnCl(2) or MnSO(4)) for 4 or 24h led to significant decrease in cell viability vs. controls. DEM or BSO pre-treatment led to further enhancement in cytotoxicity vs. exposure to Mn alone, with more pronounced cell death after 24-h DEM pre-treatment. F(2)-IsoPs levels in cells exposed to MnCl(2) (200 or 800 microM) were significantly increased after 4h and remained elevated 24h after exposure compared with controls. Consistent with the effects on cell viability and F(2)-IsoPs, treatment with MnCl(2) (200 or 800 microM) was also associated with a significant decrease in membrane potential. This effect was more pronounced in cells exposed to DEM plus MnCl(2) vs. cells exposed to Mn alone. We conclude that Mn induces direct injury to mitochondria in RBE4 cells. The ensuing impairment in energy metabolism and redox status may modify the restrictive properties of the BBB compromising its function., (Copyright 2010 Elsevier B.V. All rights reserved.)

The aim of this study was to evaluate the exposure to methylmercury (MeHg) of potential populations at risk living in Portugal. To ascertain youth exposure, a questionnaire was distributed to 300 students of a middle secondary school in Sesimbra and to 429 students studying in Canecas, selected as the control population. The average number of fish meals consumed by person was 4.1 and 3 per week in Sesimbra and Canecas, respectively. The subpopulations of high intake (PHI) corresponding to those ingesting 7 or more fish meals per week were also analyzed separately, with 17% of the students belonging to the PHI of Sesimbra versus 6.1% in Canecas. Socioeconomic aspects such as relative's professional involvement with fisheries correlated with the higher intakes in Sesimbra. Fish samples were collected in the dock of Sesimbra and total mercury (Hg) was determined by flow injection cold vapor atomic fluorescence spectroscopy (FI-CV-AFS). The mean value found for nonpredators was 0.035 microg/g. Dogfish specimens surpassed the legislated limit for predator species and increased the predators mean to 1 microg/g. The cross-sectional data were integrated with the fish analysis results to estimate the population exposure to MeHg. The indices of risk calculated for youth reached values of 4.5, demonstrating the existence of risk to a part of the population exceeding the provisional tolerable weekly intake (PTWI) level mandated by WHO (1.6 microg/kg bw). The results indicate that monitoring of Hg levels in fish is mandatory and counseling should be provided to populations at risk, encouraging them to prevent the risk.

The protective role of zinc against the toxic effects of 2, 5-hexanedione (2,5-HD), the main neurotoxic metabolite of n-hexane, was investigated by studying the interference of zinc on the toxicokinetics of 2,5-HD. Six groups of Wistar rats were exposed for 3 days to diets containing 2,5-HD, zinc chloride and 2,5-HD+zinc chloride. The amounts of pyrroles and free and total 2,5-HD in urine were determined using Ehrlichs's reagent and gas chromatography/flame ionization detection, respectively. The results show that after the first day of co-exposure (ZnCl(2)+2,5-HD) there was a significant decrease in the excretion of pyrroles and free 2, 5-HD in rats exposed to the chemical mixture when compared to the pyrroles and free 2,5-HD excreted in rats exposed to 2,5-HD alone. However, no significant decrease was observed in the urinary excretion of total 2,5-HD (free 2,5-HD + preformed 2,5-HD). Suggestions are made about the role played by this metal ion in inhibiting pyrrole formation., (Copyright 2000 John Wiley & Sons, Ltd.)