The fate of methylmercury through the formation of bismethylmercury sulfide as an intermediate in mice.

A previous study by our group indicated that methylmercury (MeHg) is biotransformed to bismethylmercury sulfide [(MeHg)2S)] by interaction with reactive sulfur species (RSS) produced in the body. In the present study, we explored the transformation of MeHg to (MeHg)2S in the gut and the subsequent fate of (MeHg)2S in vitro and in vivo. An ex vivo experiment suggested the possibility of the extracellular transformation of MeHg to (MeHg)2S in the distal colon, and accordingly, the MeHg sulfur adduct was detected in the intestinal contents and feces of mice administered MeHg, suggesting that (MeHg)2S is formed through reactions between MeHg and RSS in the gut. In a cell-free system, we found that (MeHg)2S undergoes degradation in a time-dependent manner, resulting in the formation of mercury sulfide and dimethylmercury (DMeHg), as determined by X-ray diffraction and gas chromatography/mass spectrometry, respectively. We also identified DMeHg in the expiration after the intraperitoneal administration of (MeHg)2S to mice. Thus, our present study identified a new fate of MeHg through (MeHg)2S as an intermediate, which leads to conversion of volatile DMeHg in the body.

A population approach for the estimation of methylmercury ToxicoKinetics in red mullets.

It is known that, as the vast majority of the anthropogenically emitted mercury can be found in aquatic ecosystems, where several methylating bacteria are present, fish consumption represents the most critical intake source of the most toxic form of mercury, the methylmercury (MeHg). The aim of this work is to predict MeHg levels in the fish muscles which, being the edible portion, are part of the human diet. A physiologically based toxicokinetics model was developed to evaluate the kinetics of MeHg in red mullets. Fishes were described by means of a multi-compartment model including stomach, gut, blood, muscles and an additional compartment virtually encompassing all the remaining organs. Absorption, distribution and excretion were modelled considering different MeHg routes of administration and excretion: intake by ingestion of contaminated food, intake and elimination through inhalation-exhalation and excretion through feces. The model has been firstly validated on Terapon jarbua fish (using the weighted least squares method for parameter estimation) to be subsequently readapted to predict methylmercury concentrations in the muscle of red mullets (using an approximate Bayesian computation approach). This simple multicompartmental model could be considered part, a link in the chain, of a wider more complex project aiming at tracking the fate of MeHg from polluted seawater to the human end consumer. The present study could be useful to surveillance organizations in order to carry out a more comprehensive and informed risk assessment analysis and to take appropriate preventive measures by evaluating possible new MeHg concentration thresholds to minimize public health hazards.

Determination of spatial mercury concentration by laser ablation-inductively coupled plasma mass spectrometry.

Laser ablation-inductively coupled plasma mass spectrometry (LA-ICP-MS) is capable of metal imaging by acquiring local spatial information. However, the preparation of an appropriate standard for quantitative analysis is difficult because the matrices between the standard and the sample should match, and homogeneity of metal concentration in the standard is required. Hence, the aim of this study was to establish a highly quantitative mercury imaging method that utilizes LA-ICP-MS and an appropriate mercury standard consisting of rat tissue. Our standard showed homogeneous mercury concentration and good linearity between concentration and signal intensity, and met the qualifications for quantitative imaging by LA-ICP-MS. Mercury concentration in MeHg-exposed rat kidneys obtained by LA-ICP-MS measurement of the standard (7.84 ± 0.57 µg/g) was comparable to that obtained by cold vapor atomic absorption spectrophotometry (AAS, 7.27 ± 0.46 µg/g). The results indicate that LA-ICP-MS enabled quantitative imaging with the appropriate standard.

Dietary Fructooligosaccharides Reduce Mercury Levels in the Brain of Mice Exposed to Methylmercury.

Methylmercury (MeHg) exposure during pregnancy is a concern because of its potential health risks to fetuses. Intestinal microbiota has important roles in the decomposition and fecal excretion of MeHg. We investigated the effect of nondigestible saccharides on the accumulation and excretion of Hg after MeHg exposure. Female BALB/cByJ mice were fed a basal diet or the same diet supplemented with 5% fructooligosaccharides (FOS) or 2.5% glucomannan. Six weeks after feeding, mice were administered MeHg chloride (4 mg Hg/kg, per os (p.o.)), and urine and feces were collected for 28 d. FOS-fed mice had lower total Hg levels in all tissues (including the brain) compared with that of controls. The glucomannan diet had no effect on tissue Hg levels. No differences in tissue concentrations of inorganic Hg among groups were found. Fecal Hg excretion was markedly higher in FOS-fed mice than that in controls, but urinary Hg excretion was similar. FOS-fed mice had a higher proportion of inorganic Hg in feces than that of controls, with a significant increase in fecal Hg excretion. Analysis of fecal bacterial population showed the relative abundance of Bacteroides in FOS-fed mice to be higher than that in controls. The results suggest that FOS enhanced fecal Hg excretion and decreased tissue Hg levels after MeHg administration, possibly by accelerating MeHg demethylation by intestinal bacteria (the candidate genus Bacteroides). This demethylation also reduces MeHg absorption in the large intestine. In conclusion, daily FOS intake may decrease tissue Hg levels in animals and humans exposed to MeHg.

Cellular and Molecular Mechanisms Mediating Methylmercury Neurotoxicity and Neuroinflammation.

Methylmercury (MeHg) toxicity is a major environmental concern. In the aquatic reservoir, MeHg bioaccumulates along the food chain until it is consumed by riverine populations. There has been much interest in the neurotoxicity of MeHg due to recent environmental disasters. Studies have also addressed the implications of long-term MeHg exposure for humans. The central nervous system is particularly susceptible to the deleterious effects of MeHg, as evidenced by clinical symptoms and histopathological changes in poisoned humans. In vitro and in vivo studies have been crucial in deciphering the molecular mechanisms underlying MeHg-induced neurotoxicity. A collection of cellular and molecular alterations including cytokine release, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate dyshomeostasis, and cell death mechanisms are important consequences of brain cells exposure to MeHg. The purpose of this review is to organize an overview of the mercury cycle and MeHg poisoning events and to summarize data from cellular, animal, and human studies focusing on MeHg effects in neurons and glial cells. This review proposes an up-to-date compendium that will serve as a starting point for further studies and a consultation reference of published studies.

Toxicokinetics of methylmercury in diabetic KK-Ay mice and C57BL/6 mice.

We compared the toxicokinetics of methylmercury (MeHg) in KK-Ay type 2 diabetic mice and C57BL/6J mice to evaluate how metabolic changes associated with diabetes affect MeHg toxicokinetics. A single dose of MeHg (0.2, 1, or 5 mg mercury/kg) was administered orally to 12-week-old KK-Ay and C57BL/6J male mice. Total mercury concentrations in plasma, blood cells, whole blood, and tissues (brain, kidneys, liver, and pancreas) were measured after 4, 7, 11, and 14 days. The volume of distribution/bioavailability and the elimination rate constant per day were higher in KK-Ay mice, while the terminal elimination half-life was lower in almost all samples of KK-Ay mice. The area under the curve was lower in all blood and almost all tissue samples from KK-Ay mice. Total clearance/bioavailability was lower in all blood and tissue samples of KK-Ay mice at all MeHg doses. These results indicate that MeHg is more rapidly absorbed by, and eliminated from, the blood cells, brain, liver, kidney, and pancreas of KK-Ay mice under the experimental conditions. Different patterns of tissue-to-plasma and tissue-to-whole blood partition coefficients suggest that notable differences in MeHg transfer between plasma and blood cells affect its distribution in tissues of the two mouse strains. These findings are useful to understand the selective distribution of MeHg to target organs and the sensitivity to MeHg in pathological states.

Chronic exposure to methylmercury enhances the anorexigenic effects of leptin in C57BL/6J male mice.

Several studies have demonstrated that heavy metals disrupt energy homeostasis. Leptin inhibits food intake and decreases body weight through activation of its receptor in the hypothalamus. The impact of heavy metals on leptin signaling in the hypothalamus is unclear. Here, we show that the environmental pollutant, methylmercury (MeHg), favors an anorexigenic profile in wild-type males. C57BL/6J mice were exposed to MeHg via drinking water (5 ppm) up to 30 days. Our data shows that MeHg exposure was associated with changes in leptin induced activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in the hypothalamus. In males, the activation of JAK2/STAT3 signaling pathway was sustained by an increase in SOCS3 protein levels. In females, MeHg-activated STAT3 was inhibited by a concomitant increase in PTP1B. Taken together, our data suggest that MeHg enhanced leptin effects in males, favoring an anorexigenic profile in males, which notably, have been shown to be more sensitive to the neurological effects of this organometal than females. A better understanding of MeHg-induced molecular mechanism alterations in the hypothalamus advances the understanding of its neurotoxicity and provides molecular sites for novel therapies.

Chronic exposure to methylmercury disrupts ghrelin actions in C57BL/6J mice.

Methylmercury (MeHg) is a neurotoxic pollutant widely present in the environment. Initial symptoms of MeHg may include loss of body weight. However, the mechanisms by which MeHg induces body weight changes have yet to be fully elucidated. Body weight is regulated by multiple mechanisms. Whereas multiple peripheral peptides lead to food intake cessation, ghrelin is the only recognized peripheral hormone that stimulates food intake. It exerts its action on Neuropeptide Y/Agouti-related peptide neurons in the hypothalamus. To test if MeHg affects ghrelin signaling C57BL/6J mice (males and females) were exposed to 5 ppm MeHg via drinking water during a month. On days 15 and 30 of MeHg exposure ghrelin was administered intraperitoneally and changes in body weight and food intake were recorded. In addition, changes in ghrelin-induced signaling pathways in hypothalamus were also analyzed. Here, we show that in males, MeHg enhanced ghrelin-induced body weight gain by activating the AMP-activated Kinase (AMPK)/Uncoupled protein 2 (UCP2) signaling pathway. In contrast, in females, MeHg inhibited ghrelin-induced mTOR signaling activation and decreased Npy mRNA expression, thus mitigating the ghrelin-induced weight gain. Combined, our novel results demonstrate, for the first time, that MeHg disrupts the physiological functions of ghrelin differently in males and females.

Uptake, efflux, and toxicity of inorganic and methyl mercury in the endothelial cells (EA.hy926).

Cardiovascular disease (CVD) is the major cause of morbidity, mortality, and health care costs in the United States, and possibly around the world. Among the various risk factors of CVD, environmental and dietary exposures to mercury (Hg), a highly toxic metal traditionally regarded as a neurotoxin, has been recently suggested as a potential contributor towards human atherosclerotic development. In this study, we investigated the toxicity, type of cell death, dose-dependent uptake, and efflux of inorganic HgII (as HgCl2) and methylmercury or MeHg (as CH3HgCl) in EA.hy926 endothelial cells, as these two forms of Hg are often reported to be present in human blood among the general populations (~20-30% as HgII and ~70-80% as MeHg). Our results showed that HgII is more toxic than MeHg to the endothelial cells, owing to the higher uptake into the cytoplasm and perhaps importantly lower efflux of HgII by the cells, thus the "net" accumulation by the endothelial cells is higher for HgII than MeHg when exposed to the same Hg levels in the media. Furthermore, both HgII and MeHg were found to induce apoptotic and necrotic cell death. This study has important implications for the contributions of these two common Hg species to the development of atherosclerosis, an important process leading to CVD.

Chronic kidney disease in pregnant mothers affects maternal and fetal disposition of mercury.

Chronic kidney disease (CKD) affects over 15 % of the adults in the United States. Pregnant women with CKD present an additional challenge in that they are at increased risk for adverse events such as preterm birth. Exposure to environmental toxicants, such as methylmercury, may exacerbate maternal disease and increase the risk of adverse fetal outcomes. We hypothesized that fetuses of mothers with CKD are more susceptible to accumulation of methylmercury than fetuses of healthy mothers. The current data show that when mothers are in a state of renal insufficiency, uptake of mercury in fetal kidneys is enhanced significantly. Accumulation of Hg in fetal kidneys may be related to the flow of amniotic fluid, maternal handling of Hg, and/or underdeveloped mechanisms for cellular export and urinary excretion. The results of this study indicate that renal insufficiency in mothers leads to significant alterations in the way toxicants such as mercury are handled by maternal and fetal organs.

Does the addition of ingredients affect mercury and cadmium bioaccessibility in seafood-based meals?

Despite the bioaccessibility of nutrients and contaminants present in individual seafood products has been thoroughly studied, information is extremely limited in what concerns complete seafood-based meals, where interactions between ingredients may occur. Hence, this study aimed to evaluate the effect of different ingredients and cooking processes in mercury (Hg) and cadmium (Cd) bioaccessibility in complete meals of tuna (Thunnus spp.) and edible crab (Cancer pagurus), respectively. The addition of ingredients/side dishes decreased Hg levels in cooked tuna meals, but increased Hg bioaccessibility (up to 31% of bioaccessible Hg in complete meals, against 13.5% in stewed tuna alone). Cd levels in edible crab meals were significantly decreased by the addition of ingredients (~36% and ~65% decrease in boiled crab and paté, respectively), but its' bioaccessibility was not significantly affected (>94% in all cases). Results showed that the weekly consumption of 2 complete tuna meals does not exceed MeHg tolerable weekly intake (TWI), whereas Cd's TWI is largely surpassed with the consumption of 50 g/week of edible crab meals. This highlights the importance of determining contaminant levels and bioaccessibility in a whole seafood-based meal context, as such approach enables a more realistic assessment of the risks that seafood can pose to consumers.

Physical, Chemical, and Biological Factors that Contribute to the Variability of Mercury Concentrations in Largemouth Bass Micropterus salmoides from Missouri Reservoirs.

Large-bodied predatory sportfish from Missouri reservoirs can contain elevated methylmercury concentrations that are of concern to the health of consumers. The concentration of total mercury (tHg) in the muscle (which > 95% is in the methylated-Hg form) of harvestable-sized largemouth bass (Micropterus salmoides; LMB) was examined to determine which factors contributed to the variability of tHg concentration in sportfish populations among Missouri reservoirs. Mean tHg concentrations in LMB from each reservoir were compared to physical and chemical characteristics of the reservoir and to biological attributes of each LMB population. Low concentrations of tHg (70-170 ng/g wet weight) in LMB from large reservoirs (surface area ≥ 35,680 acres) were likely related to the dilution of chemical Hg forms with water volume and depth. The highest tHg concentrations in LMB (268-542 ng/g) were from reservoirs with low particulate inorganic material (< 1.5 mg/L) and chlorophyll a concentrations (< 14.6 µg/L), and from LMB populations with a low proportion of large fish (proportional size distribution of LMB > 12 inches was < 33%). These relationships suggest that resource competition among LMB likely contributed to tHg bioaccumulation in reservoirs < 930 acres. Small reservoirs located in northern Missouri also may have greater methylation potential due to warmer water temperatures and anoxic conditions, but more data are needed to confirm these interactions. Fish consumption advisories for reservoirs with large surface area and volume could be reduced from one fish meal per month to one per week. To improve Missouri fisheries and protect consumers, management strategies to limit methylation and improve fish growth should be considered to reduce methylmercury bioaccumulation in small- and medium-sized reservoirs.

Mercury Accumulation and Effects in the Brain of the Atlantic Sharpnose Shark (Rhizoprionodon terraenovae).

Few published studies have examined whether the elevated concentrations of the nonessential toxic metal mercury (Hg) often observed in shark muscle also occur in the shark brain or whether Hg accumulation affects shark neurophysiology. Therefore, this study examined accumulation and distribution of Hg in the shark brain, as well as effects of Hg on oxidative stress in the shark central nervous system, with particular focus on the Atlantic sharpnose shark (Rhizoprionodon terraenovae). Sharks were collected along the southeastern U.S. coast throughout most of this species' U.S. geographical range. Total Hg (THg) concentrations were measured in and compared between shark muscle and brain, whereas known biomarkers of Hg-induced neurological effects, including glutathione depletion, lipid peroxidation, and concentrations of a protein marker of glial cell damage (S100b), were measured in shark cerebrospinal fluid. Brain THg concentrations were correlated with muscle THg levels but were significantly lower and did not exceed most published thresholds for neurological effects, suggesting limited potential for detrimental responses. Biomarker concentrations supported this premise, because these data were not correlated with brain THg levels. Hg speciation also was examined. Unlike muscle, methylmercury (MeHg) did not comprise a high percentage of THg in the brain, suggesting that differential uptake or loss of organic and inorganic Hg and/or demethylation of MeHg may occur in this organ. Although Hg accumulation in the shark brain generally fell below toxicity thresholds, higher THg levels were measured in the shark forebrain compared with the midbrain and hindbrain. Therefore, there is potential for selective effects on certain aspects of shark neurophysiology if brain Hg accumulation is increased.

Mercury and methylmercury bioaccumulation in a contaminated bay.

The bioaccumulation and the main source of total Hg (THg) and methylmercury (MMHg) in the deposit-feeding polychaete Neanthes japonica collected in Jinzhou Bay, China, were investigated. Compared with the historical data, THg bioaccumulation in polychaetes collected in sediment of Jinzhou Bay was distinctly higher due to higher sediment THg concentration, but MMHg bioaccumulation was significantly lower. THg accumulation in polychaetes mainly derived from its accumulation in sediment. However, MMHg bioaccumulation in polychaetes did not correlate with Hg concentration in sediment. Besides sediment ingestion, MMHg accumulation in polychaetes may partially source from the process of in vivo transformation. The in vivo Hg methylation may take place in polychaetes, according to the excellent correlation between MMHg concentration and THg and inorganic Hg concentration in polychaetes. The biochemical characters in polychaete body, the oxidation-reduction environment and the microbial activity in polychaete gut may be beneficial to in vivo Hg methylation.

Marine fog inputs appear to increase methylmercury bioaccumulation in a coastal terrestrial food web.

Coastal marine atmospheric fog has recently been implicated as a potential source of ocean-derived monomethylmercury (MMHg) to coastal terrestrial ecosystems through the process of sea-to-land advection of foggy air masses followed by wet deposition. This study examined whether pumas (Puma concolor) in coastal central California, USA, and their associated food web, have elevated concentrations of MMHg, which could be indicative of their habitat being in a region that is regularly inundated with marine fog. We found that adult puma fur and fur-normalized whiskers in our marine fog-influenced study region had a mean (±SE) total Hg (THg) (a convenient surrogate for MMHg) concentration of 1544 ± 151 ng g-1 (N = 94), which was three times higher (P < 0.01) than mean THg in comparable samples from inland areas of California (492 ± 119 ng g-1, N = 18). Pumas in California eat primarily black-tailed and/or mule deer (Odocoileus hemionus), and THg in deer fur from the two regions was also significantly different (coastal 28.1 ± 2.9, N = 55, vs. inland 15.5 ± 1.5 ng g-1, N = 40). We suggest that atmospheric deposition of MMHg through fog may be contributing to this pattern, as we also observed significantly higher MMHg concentrations in lace lichen (Ramalina menziesii), a deer food and a bioindicator of atmospheric deposition, at sites with the highest fog frequencies. At these ocean-facing sites, deer samples had significantly higher THg concentrations compared to those from more inland bay-facing sites. Our results suggest that fog-borne MMHg, while likely a small fraction of Hg in all atmospheric deposition, may contribute, disproportionately, to the bioaccumulation of Hg to levels that approach toxicological thresholds in at least one apex predator. As global mercury levels increase, coastal food webs may be at risk to the toxicological effects of increased methylmercury burdens.

Co-administration of a Rhododendron tomentosum extract does not affect mercury tissue concentrations and excretion rate in methylmercury-treated adult male rats.

OBJECTIVES: Consumption of fish/seafood is clearly linked to higher mercury levels in human tissue samples. However, correlations between methylmercury (MeHg) intakes calculated from dietary surveys and mercury body burdens are usually weak and can vary across populations. Different factors may affect MeHg absorption, distribution, metabolism and excretion, including co-exposures to phytochemicals and antibiotics, which were shown to affect mercury body burdens in rodents. Based on the observation that rat pups developmentally exposed to MeHg and a Rhododendron tomentosum extract (Labrador Tea) presented significantly higher blood mercury levels at weaning compared to pups exposed to MeHg alone, the modulation of MeHg toxicokinetics by Labrador Tea was further investigated in adult rats. RESULTS: Total mercury levels were quantified in the blood, liver, kidney and feces of adult male rats exposed to MeHg (1.2 mg/kg bodyweight/day, for 3 weeks) administered either alone or in combination with Labrador Tea (100 mg/kg bodyweight/day) or with an antibiotics cocktail (to inhibit MeHg demethylation by gut bacteria). While the reduced fecal excretion and higher blood mercury levels expected from antibiotics-treated rats were observed, mercury levels in samples from Labrador Tea-treated rats were not significantly different from those measured in samples from rats exposed to MeHg alone.

Change in mercury speciation in seafood after cooking and gastrointestinal digestion.

Mercury (Hg) is readily bioaccumulated in seafood, a common ingredient in indigenous cuisines throughout the world. This study investigates Hg speciation in cooked seafood after gastric and intestinal digestion. The results showed that the removal of Hg by washing was negligible. Additionally, the results of our calculations regarding the mass balance of Hg concentration indicated that cooking reduced Hg mainly by means of volatilization and that Hg2+ was more readily reduced than MeHg. Moreover, cooking lowered the bioaccessibility of Hg in seafood: the reduced percent of bioaccessible Hg2+ after cooking ranged from 2 to 35% (on average, 16%). The corresponding numbers were slightly lower compared with those for MeHg (on average, 19%). Furthermore, there might be a chemical transformation of Hg during in vitro gastrointestinal digestion. The results of in vivo tests in laboratory mice suggested that methylation of Hg mainly took place in the gastric tract, whereas demethylation of Hg occurred primarily during intestinal digestion. These findings indicate that the bioaccessibility of Hg2+ and MeHg was not only related to their initial concentrations in the food samples, but also that further studies on the mechanisms of Hg demethylation and methylation during gastrointestinal digestion are essential for more realistic risk assessments.

Effect of lactic acid bacteria on mercury toxicokinetics.

The capacity of two LAB strains to inhibit inorganic [Hg(II)] and organic (methyl-Hg; MeHg) mercury translocation through monolayers of co-cultures of NCM460 and HT29-MTX colonic cells was evaluated. Lactobacillus casei BL23 and Lactobacillus acidophilus ATCC4356 reduced the permeability of Hg(II) and MeHg from aqueous solutions through NCM460/HT29-MTX monolayers (20-94% reduction). However, assays using the bioaccessible (soluble) Hg fraction obtained by in vitro gastrointestinal digestion of Hg-contaminated swordfish only showed a reduction (42%) with the BL23 strain. In vivo experiments carried out in mice receiving an acute dose of Hg(II) or MeHg (0.5 mg/kg body weight/day) with or without lactobacilli resulted in significant decreases of the bioavailability of MeHg with both strains and increased excretion of Hg in feces after treatment with the lactobacilli. However, Hg(II) bioavailability or excretion was not affected. Hg accumulation in liver and kidney remained similar in LAB-treated or non-treated animals. This is the first study of the impact of LAB on Hg(II) and MeHg toxicokinetics and shows that some LAB strains have potential to diminish MeHg bioavailability. Furthermore, it has established the basis for new studies on the protective effect of LAB under conditions resembling subchronic and chronic Hg exposures.

Primary amino acids affect the distribution of methylmercury rather than inorganic mercury among tissues of two farmed-raised fish species.

The distributions of primary amino acids, MeHg and IHg in body tissues of two commonly farm-raised fish species (common carp: Cyprinus carpio; grass carp: Ctenopharyngodon idellus) in Guizhou Province, SW China, were investigated to understand the effects of primary amino acids on MeHg and IHg metabolism in farm-raised fish. The primary amino acids were classified into four groups: (1) essential and polar amino acids; (2) essential and non-polar amino acids; (3) non-essential and polar amino acids; and (4) non-essential and non-polar amino acids. For both fish species, groups (1, 2 and 3) were enriched in muscle and kidney, whereas group (4) was enriched in scale. The two fish species showed low MeHg concentrations (grass carp: 0.5-3.9 ng/g; common carp:1.0-7.4 ng/g) and low MeHg proportions (grass carp: 2-45%; common carp: 6-37%) in their tissues, which are mainly due to the simple food web structures and the fast growth of the farm-raised fish. Positive correlations (r = 0.342 to 0.472; p < 0.01; n = 78) were observed between MeHg and several primary amino acids (cysteine, threonine, phenylalanine, leucine, valine, glutamate serine and tyrosine) in fish tissues, which may be driven by the formation of MeHg-Cys complexes within fish body. However, no significant correlations were observed between IHg and any primary amino acids, indicating the metabolic processes of IHg and MeHg are different. This study advances our understanding that cysteine and its related/derived amino acids may be an important driving force for MeHg distribution and translocation in fish.

Methylmercury intoxication and cortical ischemia: Pre-clinical study of their comorbidity.

Stroke is one of the main causes of human disability worldwide. Ischemic stroke is mostly characterized by metabolic collapse and fast tissue damage, followed by secondary damage in adjacent regions not previously affected. Heavy metals intoxication can be associated with stroke incidence, because of their damaging action in the vascular system. Mercury, in particular, possesses a high tropism by metabolically active regions, such as the brain. In the present study we sought to evaluate whether methylmercury (MeHg) intoxication can aggravate the tissue damage caused by an ischemic stroke induced by microinjections of endothelin-1 (ET-1) into the motor cortex of adult rats. Following MeHg intoxication by gavage (0.04 mg/kg/day) during 60 days, the animals were injected with ET-1 (1 µl, 40 pmol/µl) or vehicle (1 µl). After 7 days, all animals were submitted to behavioral tests and then their brains were processed to biochemical and immunohistochemical analyses. We observed that long-term MeHg intoxication promoted a significant Hg deposits in the motor cortex, with concomitant increase of microglial response, followed by reduction of the neuronal population following ischemia and MeHg intoxication, as well as disturbance in the antioxidant defense mechanisms by misbalance of oxidative biochemistry with increase of both lipid peroxidation and nitrite levels, associated to behavioral deficits. MeHg exposure and cortical ischemia demonstrated that both injuries are able of causing significant neurobehavioural impairments in motor coordination and learning accompanied of an exacerbated microglial activation, oxidative stress and neuronal loss in the motor cortex, indicating that MeHg as a source of metabolic disturbance can act as an important increasing factor of ischemic events in the brain.