Ana Paula Marreilha dos Santos

Rat brain endothelial cells are a target of manganese toxicity

Manganese (Mn) is an essential trace metal; however, exposure to high Mn levels can result in neurodegenerative changes resembling Parkinsons disease (PD). Information on Mns 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.

High-Fish Consumption and Risk Prevention: Assessment of Exposure to Methylmercury in Portugal

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 Caneças, selected as the control population. The average number of fish meals consumed by person was 4.1 and 3 per week in Sesimbra and Caneças, 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 Caneças. Socioeconomic aspects such as relatives 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 μg/g. Dogfish specimens surpassed the legislated limit for predator species and increased the predators mean to 1 μg/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 μg/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.

Putative proteins involved in manganese transport across the blood-brain barrier

Manganese (Mn) is an essential nutrient required for proper growth and maintenance of numerous biological systems. At high levels it is known to be neurotoxic. While focused research concerning the transport of Mn across the blood-brain barrier (BBB) is on-going, the exact identity of the transporter(s) responsible is still debated. The transferrin receptor (TfR) and the divalent metal transporter-1 (DMT-1) have long been thought to play a role in brain Mn deposition. However, evidence suggests that Mn may also be transported by other proteins. One model system of the BBB, rat brain endothelial (RBE4) cells, are known to express many proteins suspected to be involved in metal transport. This review will discuss the biological importance of Mn, and then briefly describe several proteins that may be involved in transport of this metal across the BBB. The latter section will examine the potential usefulness of RBE4 cells in characterizing various aspects of Mn transport, and basic culture techniques involved in working with these cells. It is hoped that ideas put forth in this article will stimulate further investigations into the complex nature of Mn transport, and address the importance as well as the limitation of in vitro models in answering these questions. Human & Experimental Toxicology (2007) 26, 295-302

Chapter 35 – Mercury

Publisher Summary This chapter discusses mercury, which is a well-documented neurotoxicant. Human exposure to mercury is mainly in the form of methylmercury predominantly from the consumption of fish. This chapter aims to outline the kinetics of organic mercury (MeHg) in humans and the toxic effects of MeHg on the developing fetal central nervous system (CNS) as well as on other organ systems. MeHg has been found to bind to protein-SH groups of amino acids, such as cysteine. A brief review outlining the most critical features of the mechanisms involved in MeHg-induced neurotoxicity are explained in this chapter. This chapter describes the differences in MeHg-induced brain damage between the fetus and the adult and highlights several of the proposed mechanisms of MeHg toxicity in the developing organism. The brain is the primary target site for MeHg. Because the vulnerability to MeHg poisoning is age related, the symptoms of mercury poisoning and mercury deposits are quite different depending on the age at the time of exposure. In addition to its effects on brain structure and brain enzymes, MeHg exposure also affects synaptic transmission. The studies have established that prenatal MeHg exposure in both humans and laboratory animals leads to diffuse brain damage including reduced brain size, damage to the cortex and basal ganglia, loss of cells, ventricular dilation, ectopic cells, disorganized brain layers and gliosis. The risk and toxicity of MeHg have also been analyzed.

Biomarkers of exposure and effect in a working population exposed to lead, manganese and arsenic

ABSTRACT Lead (Pb), manganese (Mn) and arsenic (As) are among the major toxicants in mining environments. Miners are commonly and repeatedly exposed to this toxic mixture. Some adverse effects may appear at concentrations below environmental quality guidelines for individual mixture components. Further, Pb, Mn, and As induce common adverse outcomes, such as interferences in the cholinergic system and heme synthesis. It is thus vital to monitor miners through biomarkers (BM), such that subclinical effects may be identified at an early stage. The main objectives of this study were to evaluate the exposure of a mining population to these three metals and determine alterations in cholinergic and heme synthesis parameters. Blood and urine samples of workers (n = 60) were obtained from a Portuguese mining industry and compared with a control population (n = 80). The levels of the metals were determined in biological samples, as well as urinary heme precursor levels, delta aminolevulinic acid (ALA) and porphyrins, and blood acetylcholinesterase (AChE) activity. The miners exhibited significantly higher values of Pb and As in blood and urine compared to control. In the case of Mn near or slightly higher than limit values were found. Our data show that heme precursors may be used simultaneously with metal levels as BMs for multiple metal exposures on an individual basis, resulting in 94.3% and 95.7% accuracy, respectively, in blood and urine, for subjects correctly identified with respect to occupation. This study also revealed that biological monitoring of this working population regarding metal body burden and heme precursor accumulation is advisable.

Chapter 33 – Mercury

Methylmercury (MeHg), an organomercurial, is one of the most prevalent and toxic environmental pollutants. The major route of human exposure occurs via consumption of MeHg-adulterated seafood. Historically, MeHg epidemics in Minamata Bay, Japan, and in Iraq provided evidence of its developmental toxicity and neurological damage. This chapter describes MeHg kinetics in the human body and focuses predominantly on mechanisms involved in neuropathological and reproductive effects. The chapter also discusses the differential susceptibility to MeHg in fetuses and adults, with a special emphasis on its aberrant effects in the developing central nervous system. Discussions on risk assessment, treatment, and future directions are also covered in this chapter.