Toxic Effects Of Methylmercury Research Articles

P01-20 Gender-specific toxic effects of methyl mercury and thimerosal on the SH-SY5Y neuroblastoma cell line

P01-20 Gender-specific toxic effects of methyl mercury and thimerosal on the SH-SY5Y neuroblastoma cell line

In vivo evaluation of the potential protective effects of prolactin against damage caused by methylmercury.

Non-biodegradable metals such as mercury accumulate in living organisms during life (bioaccumulation) and also within trophic webs (biomagnification) and may reach high concentrations in humans. The contamination of humans by mercury in drinking water and food may be common, in particular in riverside communities that have a diet rich in fish. In vitro studies of human cell lines exposed to the cytotoxic and mutagenic effects of methylmercury have shown that prolactin has potential cytoprotective properties and may act as a co-mitogenic factor and inhibitor of apoptosis. The present in vivo study investigated the protective potential of prolactin against the toxic effects of methylmercury in the mammal Mus musculus. Histological and biochemical analyses, together with biomarker of genotoxicity, were used to verify the protective potential of prolactin in mice exposed to methylmercury. The reduction in kidney and liver tissue damage was not significant. However, results of biochemical and genotoxic analyses were excellent. After prolactin treatment, a significant reduction was observed in biochemical parameters and mutagenic effects of methylmercury. The study results therefore indicated that prolactin has protective effects against the toxicity of methylmercury and allowed us to suggest the continuation of research to propose prolactin in the future, as an alternative to prevent the damage caused by mercury, especially in populations that are more exposed.

Methyl mercury: loaves versus fishes

Large numbers of individuals suffered severe neurological effects from poisoning with methyl mercury from the consumption of fish contaminated by industrial discharge in Minamata in the 1950s and 1960s and from bread made from fungicide-treated wheat in the early 1970s in Iraq. In both episodes, infants exposed in utero showed developmental delays. Data from Iraq permitted the estimation of dose-response relationships and provided evidence of greater sensitivity of the foetal brain compared to adult. Studies in a number of communities regularly consuming fish have sought to determine whether and at what level of prenatal exposure neurodevelopment defects may be detected, but the findings do not present a consistent picture. Benchmark analysis using data from Iraq and the three largest studies (New Zealand, Faroes, and Seychelles) suggest an overlap in estimated dose corresponding to a 10% increase in prevalence of adverse effects above background level. However, the Seychelles study, examining children up to 9 years of age, has not found a consistent pattern of adverse developmental effects; a possible explanation may be the presence of micronutrients in the ocean fish diet that enhance brain development and/or counter the toxic effects of methyl mercury.

Effects of Short Term Methylmercury Exposure on Growth and Development of the Large Yellow Croaker Embryos and Larvae

The toxic effects of methylmercury (MeHg) on organisms have caused widespread concerns, but little has been reported on its effects in marine fish. This study investigated the acute and sub-lethal toxicities of MeHg chloride to large yellow croaker (Pseudosciaena crocea) embryos and larvae. Acute toxicity tests showed that the 48-h LC50 values of methylmercury to the embryos and larvae were 28.39 (21.33-33.98) and 18.27 (11.33-29.29) μg L -1 , respectively, while the 96-h LC50 value for larvae was 9.28 (4.41-14.49) μg L -1 , indicating that larvae were more sensitive to MeHg than the embryos. On the other hand, MeHg could cause low hatching success, increase larvae heart rate at concentrations ≥ 20 μg L -1 , as well as delayed hatching process, reduced survival and higher morphological malformations at concentrations ≥ 10 μg L -1 to the embryos and larvae. Results showed that the early life stages of large yellow croaker were sensitive to MeHg exposure.

Bifurcations and global dynamics in a toxin-dependent aquatic population model

The study of effects of environmental toxins on ecosystems is of great interest from both environmental and conservation points of view. In this paper, we present a global stability and bifurcation analysis of a toxin-dependent aquatic population model. Our analytical and numerical results show that both the environmental toxin level and the depuration capability of the population significantly affect the population persistence. The model exhibits a multifarious array of dynamics. While low levels of external toxin allow population persistence and high levels of toxin lead to an extirpation, intermediate toxin concentrations can produce very rich dynamics, such as transient oscillations, hysteresis, heteroclinic orbits, and a codimension-two bifurcation. In particular, a regime of bistability exists where the population is doomed to extinction or survival, depending on initial state of the system. As a practical implication of our study, the toxic effects of methylmercury on rainbow trout are scrutinized. The theory developed here provides a sound theoretical foundation for understanding the population effects of toxicity.

The MARCKS protein amount is differently regulated by calpain during toxic effects of methylmercury between SH-SY5Y and EA.hy926 cells.

Methylmercury (MeHg) is an environmental pollutant that shows severe toxicity to humans and animals. However, the molecular mechanisms mediating MeHg toxicity are not completely understood. We have previously reported that the MARCKS protein is involved in the MeHg toxicity to SH-SY5Y neuroblastoma and EA.hy926 vascular endothelial cell lines. In addition, calpain, a Ca2+-dependent protease, is suggested to be associated with the MeHg toxicity. Because MARCKS is known as a substrate of calpain, we studied the relation between calpain activation and cleavage of MARCKS and its role in MeHg toxicity. In SH-SY5Y cells, MeHg decreased cell viability along with increased calcium mobilization, calpain activation and a decrease in MARCKS amounts. However, pretreatment with calpain inhibitors attenuated the decrease in cell viability and MARCKS amount induced only by 1 µM but not by 3 µM MeHg. In cells with a MARCKS knockdown, calpain inhibitors failed to attenuate the decrease in cell viability caused by MeHg. In EA.hy926 cells, although MeHg caused calcium mobilization and a decrease in MARCKS levels, calpain activation was not observed. These results indicate that the participation of calpain in the regulation of MARCKS amounts is dependent on the cell type and concentration of MeHg. In SH-SY5Y cells, calpain-mediated proteolysis of MARCKS is involved in cytotoxicity induced by a low concentration of MeHg.

Toxic effects of methylmercury, arsanilic acid and danofloxacin on the differentiation of mouse embryonic stem cells into neural cells

This study was performed to assess the neurotoxic effects of methylmercury, arsanilic acid and danofloxacin by quantification of neural-specific proteins in vitro. Quantitation of the protein markers during 14 days of differentiation indicated that the mouse ESCs were completely differentiated into neural cells by Day 8. The cells were treated with non-cytotoxic concentrations of three chemicals during differentiation. Low levels of exposure to methylmercury decreased the expression of GABAA-R and Nestin during the differentiating stage, and Nestin during the differentiated stage. In contrast, GFAP, Tuj1, and MAP2 expression was affected only by relatively high doses during both stages. Arsanilic acid affected the levels of GABAA-R and GFAP during the differentiated stage while the changes of Nestin and Tuj1 were greater during the differentiating stage. For the neural markers (except Nestin) expressed during both stages, danofloxacin affected protein levels at lower concentrations in the differentiated stage than the differentiating stage. Acetylcholinesterase activity was inhibited by relatively low concentrations of methylmercury and arsanilic acid during the differentiating stage while this activity was inhibited only by more than 40 µM of danofloxacin in the differentiated stage. Our results provide useful information about the different toxicities of chemicals and the impact on neural development.

Antagonistic interaction of selenomethionine enantiomers on methylmercury toxicity in the microalgae Chlorella sorokiniana

The protective effect of selenium against mercury toxicity is well known especially between selenomethionine and methylmercury and it has been studied in several living organisms, however information is lacking about the interaction of these species in Chlorella. Investigation into which chiral form of selenomethionine effectively acts against the toxic effects of methylmercury has not previously been carried out. In the present work, two control cultures and two cultures of C. sorokiniana were grown in standard medium with D,L-SeMet, L-SeMet or D-SeMet. After the experiment was started up MeHg(+) was added periodically to the cultures containing D,L-SeMet, L-SeMet, D-SeMet and to one of the control batches. The results show that both SeMet enantiomers counteract the toxicity of MeHg(+), by markedly increasing the total content of chlorophyll, carotenoids, as well as the dry weight and light dependent oxygen production, compared to the culture which is non pre-treated with SeMet and is only exposed to MeHg(+). The levels of MeHg(+) measured in cells are lower in the cultures pre-treated with SeMet indicating that the passage of MeHg(+) into the cells is negligible when carried out in the presence of SeMet, or that SeMet enhances the release of MeHg(+). On the other hand, L-SeMet is directly involved in the detoxification of MeHg(+), but the involvement of D-SeMet occurs only indirectly since it has been neither identified in the medium nor in C. sorokiniana after supplementation with this enantiomer. It may be that D-SeMet is transformed into SeMeSec and L-SeMet. Moreover, SeMeSec is almost totally released from the cells after 72 hours. No mercury-selenium complex was detected but, since the summation of the different species identified accounted only for 77% of the total selenium and mercury measured directly after sample digestion, it is possible that they are present in the form of an undetected Se-Hg complex. This hypothesis is supported by the decrease of inorganic selenium during the experiment. The present paper reports new data about the relationship between the mechanism of detoxification of methylmercury and selenomethionine enantiomers through the study of the metabolic intermediates by means of speciation analysis.

The Nail as a Noninvasive Indicator of Methylmercury Exposures and Mercury/Selenium Molar Ratios in Brain, Kidney, and Livers of Long-Evans Rats

Animal studies indicate that the toxic effects of methylmercury (MeHg) exposures increase when selenium (Se) status is low. Toxicity is directly proportional to Hg/Se molar ratios in critical tissues such as brain and increase dramatically as molar ratios exceed 1:1. In this study, we examined the nail as a biomonitor of Hg/Se molar ratios in kidney, liver, and brain tissues of weanling male Long-Evans rats fed controlled diets containing varying amounts of Se and MeHg. Linear regression analyses indicate that the natural log transform of the Hg/Se ratio in the nails is strongly related to the Hg/Se molar ratio in kidney, liver, and brain (p < 0.01 in all cases). The nail appears to be a reliably accurate noninvasive biomonitor of the Hg/Se molar ratio in tissues and should, therefore, be considered for use in human studies.

Identification of F-box proteins that are involved in resistance to methylmercury in Saccharomyces cerevisiae

We searched for F-box proteins that might be related to the mechanism that protects Saccharomyces cerevisiae against the toxic effects of methylmercury. We found that overexpression of Hrt3 and of Ylr224w rendered yeast cells resistant to methylmercury. Yeast cells that overexpressed Hrt3 and Ylr224w were barely resistant to methylmercury in the presence of a proteasome inhibitor. Our results suggest the existence of some protein(s) that enhances the toxicity of methylmercury in yeast cells and, also, that overexpression of Hrt3 or Ylr224w can confer resistance to methylmercury by enhancing the polyubiquitination of this protein(s) and its degradation in proteasomes.

Methylmercury inhibits the in vitro uptake of the glutathione precursor, cystine, in astrocytes, but not in neurons

Maintenance of adequate intracellular glutathione (GSH) levels is vital for intracellular defense against oxidative damage. The toxic effects of methylmercury (MeHg) are attributable, at least in part, to elevated levels of reactive oxygen species, and thus decreases in GSH synthesis may increase methylmercury toxicity. Astrocytes have recently been proposed to play an essential role in providing GSH precursors to neurons. Therefore, cystine transport, a prerequisite to GSH production, was characterized in cultured astrocytes and neurons, and the effects of methylmercury on this transport were assessed. Astrocytes and neurons both possessed temperature dependent transport systems for cystine. Astrocytes accumulated cystine by Na +-independent (X C−) and -dependent (X AG−) systems while neurons used exclusively Na +-independent systems. Inhibition of the X AG− transport system decreased cystine transport in astrocytes to levels equivalent to those in sodium-depleted conditions, suggesting that cystine is carried by a glutamate/aspartate transporter in astrocytes. Inhibition of the multifunction ectoenzyme/amino acid transporter γ-glutamyltranspeptidase (GGT) decreased cystine transport in both neurons and astrocytes. Inhibition of System X C− with quisqualate also decreased cystine uptake in both astrocytes and neurons. These data demonstrate that cultured astrocytes accumulate cystine via three independent mechanisms, System X AG−, System X C−, and GGT, while cultured hippocampal neurons use System X C− and GGT exclusively. Inhibition of cystine uptake in astrocytes by methylmercury appears to be due to actions on the System X AG− transporter.

Determination of Mercury and Selenium in Hair Samples of Brazilian Indian Populations Living in the Amazonic Region by NAA

Abstract Biomonitoring of mercury contamination of Brazilian Indian population groups living in the Xingu Park, a reservation situated in the Amazonic region, has revealed very high levels of mercury in hair samples as compared to controls. Total mercury was determined by INAA in most of the tribes living in the Park and methylmercury was determined by CVAAS in samples with total mercury above 10 mg/kg. Due to the fact that selenium seems to protect animals against the toxic effects of methylmercury, it was considered also of interest to determine its concentrations in the hair samples with very high mercury levels. Selenium was determined by INAA via the short-lived radionuclide 77mSe (T 1/2 = 17.45 s). The correlations between selenium and mercury concentrations in Brazilian controls and in the Indian population groups are discussed.

Methylmercury Toxicity at Cellular Levels. From Growth Inhibition to Apoptotic Cell Death.

This review describes our studies on the toxic effects of methylmercury (MeHg) at cellular levels using neuroblastoma, PC12, glioma and HeLa cell lines. MeHg specifically disrupted microtubules and inhibited cell growth by halting the cell cycle at the M phase. Effects on DNA, RNA and protein syntheses were not associated with growth inhibition by MeHg. Microtubule disruption by MeHg led to specific inhibition of β-tubulin synthesis with little or no effect on total protein synthesis. This selective reduction in β-tubulin synthesis was caused by post-transcriptional regulation through increased an tubulin pool resulting from depolymerization of microtubules by MeHg. The cells exposed to MeHg proceeded to apoptotic cell death long after growth inhibition. Since the occurrence of apoptosis was preceded by the G2/M phase arrest after MeHg treatment, it is likely that this arrest is an important event in apoptosis induction by MeHg. This apoptosis was induced via a p53-independent pathway in neuronal and nonneuronal cell lines. The study using the MeHg resistant cell line established by us demonstrated that the ability to accumulate MeHg and a low level of intracellular glutathione(GSH) made cells to vulnerable to MeHg.The neuronal cell lines showed a tendency to have a lower GSH level and, consequently, a higher susceptibility to MeHg than nonneuronal cell lines.

Effects of mercury and selenium on glutathione metabolism and oxidative stress in mallard ducks

AbstractEarlier studies have reported on the toxicity and related oxidative stress of different forms of Se, including seleno‐ D,L‐methionine, in mallards (Anas platyrhynchos). This study compares the effects of Se (seleno‐D,L‐methionine) and Hg (methylmercury chloride) separately and in combination. Mallard drakes received one of the following diets: untreated feed (controls), or feed containing 10 ppm Se, 10 ppm Hg, or 10 ppm Se in combination with 10 ppm Hg. After 10 weeks, blood, liver, and brain samples were collected for biochemical assays. The following clinical and biochemical alterations occurred in response to Hg exposure: hematocrit and hemoglobin concentrations decreased; activities of the enzymes glutathione (GSH) peroxidase (plasma and liver), glutathione‐S‐transferase (liver), and glucose‐6‐phosphate dehydrogenase (G‐6‐PDH) (liver and brain) decreased; hepatic oxidized glutathione (GSSG) concentration increased relative to reduced glutathione (GSH); and lipid peroxidation in the brain was detected by increased thiobarbituric reactive substances (TBARS). Effects of Se alone included increased hepatic GSSG reductase activity and brain TBARS concentration. Selenium in combination with Hg partially or totally alleviated effects of Hg on GSH peroxidase, G‐6‐PDH, and GSSG. These findings are compared in relation to field observations for diving ducks and other aquatic birds. It is concluded that since both Hg and excess Se can affect thiol status, measurement of associated enzymes in conjunction with thiol status may be a useful bioindicator to discriminate between Hg and Se effects. The ability of Se to restore the activities of G‐6‐PDH, GSH peroxidase, and glutathione status involved in antioxidative defense mechanisms may be crucial to biological protection from the toxic effects of methylmercury.

Comparison of mercury accumulation among the brain, liver, kidney, and the brain regions of rats administered methylmercury in various phases of postnatal development.

Several animal studies have indicated that a developing organism in its prenatal and early postnatal stage may be at higher risk in toxic metal exposure than in adult stage. Many infants were congenitally affected by methylmercury in the epidemics in Japan and Iraq. The infants reported from Minamata, Japan, had severe cerebral palsy, whereas their mothers had mild or no manifestations of poisoning. Some of the high susceptibility in infants may resulted from the specific features of the methylmercury metabolism in the developing organisms. Prenatal or postnatal development is characterized by functional immaturity of organs, which may affect the mercury (Hg) accumulation among organs. It seems possible that the Hg distribution might, in fact, reflect the toxic effects of methylmercury during a given developing phase. Thus, its distribution deserves closer examination. In our previous study, when a toxic level of methylmercury was administered, the Hg distribution and its effects on body weight gain and neurological disorders were found to be different among the rat postnatal developing phases. In the present study the Hg distribution among organs and brain regions was investigated during the several development phases with a nontoxic level of methylmercury treatment. 24 refs., 1 fig., 2 tabs.

Toxic effects of methylmercury on spermatozoa in vitro

In an in vitro investigation, methylmercury (MeHg) reduced the motility of rat spermatozoa probably by the inhibition of succinate dehydrogenase and ATPase activities. Concomitant morphological changes observed in the spermatozoa were coiled tails and kinks in midpiece and tail regions.

Sexual differences in the distribution and retention of organic and inorganic mercury in methyl mercury-treated rats

At 56 days of age, male and female Long-Evans rats received 1 mumole of 203Hg-labeled methyl mercuric chloride per kilogram sc and total, organic, and inorganic mercury contents and concentrations in tissues were determined for up to 98 days postdosing. Whole body clearance of mercury was faster in females than in males, and females attained higher peak percentages of the methyl mercury dose in kidney and brain than did males. Females had significantly higher mean percentages of the mercury dose present in the kidney and brain as organic or total mercury and in brain as inorganic mercury than did males. Males had significantly higher mean percentages of the dose present as organic or total mercury in pelt and whole body than did females. When expressed on a concentration basis, the only significant sexual difference was in the higher average concentration of organic mercury in the kidneys of females. When expressed on a tissue content basis, significant male-female differences in the kinetics (sex X time interactions) of organic mercury retention were found in kidney, brain, skeletal muscle, pelt, and whole body. Significant sex X time interactions in the concentrations of organic mercury were found in kidney, skeletal muscle, and whole body. Kinetics of retention and concentration of inorganic Hg in the pelt differed significantly for males and females. Discordance in degree of statistical significance of differences in mercury contents and concentrations reflected in part differences in relative body composition of males and females. Integrated exposures of tissues of males and females to organic or inorganic mercury were determined by fitting multiexponential retention functions to retention data. Differences in integrated exposure were estimated by the female-to-male ratio of areas under retention curves. Reconstruction of whole body organic and inorganic mercury burdens from constituent tissues indicated that integrated exposures of males and females to inorganic mercury were equal but females had a lower integrated exposure to organic mercury. Integrated exposure of liver to either form of mercury was about equal in males and females. However, the integrated exposure of the brain of females to inorganic mercury was 2.19 times that of males suggesting a sexual difference in accumulation or retention of inorganic mercury in the nervous system. These sexual differences in distribution and retention of organic and inorganic mercury after methyl mercury exposure may underlie reported sexual differences in sensitivity to the toxic effects of methyl mercury.

Protective effects of freeze dried swordfish on methylmercury chloride toxicity in rats.

This study quantifies selenium in swordfish and examines its prophylactic effect on methylmercury poisoning in rats. It was found that swordfish have twice as much selenium as mercury, and that a diet which included freeze-dried swordfish protected rats from the toxic effects of methylmercury.