Evaluation of cytoprotective effects of compounds isolated from Copaifera langsdorffii Desf. against induced cytotoxicity by exposure to methylmercury and lead.

Copaifera langsdorffii L. is one of the most known medicinal species in Brazil. Its leaves are rich in phenolic compounds with potential biological activities as an antioxidant and chelating agent. This paper reports the isolation of four compounds from the hydroalcoholic extract of the leaves of C. langsdorffii and the investigation of their possible cytoprotective effects against heavy metal poisoning. Quercitrin (1), afzelin (2), 3,5-di-O-(3-O-methyl galloyl) quinic acid (3) and 4,5-di-O-(3-O-methyl galloyl) quinic acid (4), were associated with toxic doses of methylmercury and lead and evaluated by Alamar blue cell viability assays in HepG2 and PC12. The compounds displayed significant cytoprotective effect for the HepG2 cell line against both metals. Compounds 1-4 did not protect PC12 cells against methylmercury induced-cytotoxicity, but at lower concentrations, they protected against lead induced-cytotoxicity. The evaluated compounds showed a promising cytoprotection effect against exposure to heavy metals and should be further investigated as protective agents.

Selenium protection against mercury neurotoxicity: Modulation of apoptosis and autophagy in the anterior pituitary.

AIMS: The aim of the present study is to shed light on the modulating action of selenium on two of the most crucial cellular pathways; apoptosis and autophagy and the possible interplay between them in determining the pituitary fate in the context of mercury intoxication through demonstration of the molecular, histopathological, immunohistochemical, and ultrastructural features of selenium mercury-treated adenohypophysis. METHODS: Thirty adult Sprague Dawley male albino rats were assigned into control group, mercury-treated group and mercury­selenium concomitantly-treated group. The adenohypophysis was subjected to structural, molecular and protein expression assessment of autophagy and apoptotic markers and western blotted analysis of Beclin 1 as a key cross-regulator of autophagy and apoptosis. KEY FINDINGS: Selenium treatment ameliorated the mercury-induced apoptosis detected by improvement in PCR and immunohistochemical expression of the apoptotic markers Bax, Bcl-2 and Caspase-3. Selenium also improved mercury-induced autophagic dysfunction with statistically significant improvement in western blotted levels of the autophagy markers LC3I, LC3II and Beclin1. The histopathological and ultrastructural studies strongly confirmed those findings. SIGNIFICANCE: The crosstalk between the apoptotic Bcl-2 family of proteins and the autophagic Beclin-1LC3 pathway in the context of mercury intoxication paves the way for developing novel effective treatment strategies for several mercury-induced pituitary diseases.

Protective Effect of Leaf Ethanolic Extract Etlingera hemisphaerica Blume Against Mercuric Chloride Toxicity in Blood of Mice.

This research was intended to investigate the protective effect of leaf ethanolic extract Etlingera hemisphaerica Blume (LE3H) against mercuric chloride (HgCl2) toxicity in blood of mice (Mus musculus). The experimental animals, 95 male M. musculus, received drink and food ad libitum. Three materials were tested: LE3H (0.13, 0.26, 0.39 mg/g body weight [bw]) was administered by gavage; HgCl2 (5 mg/kg bw) was administrated by gavage or intraperitoneal injection; and Imunos (the nutritional supplement to stimulate the immune system; 0.2 mg/g bw), as a positive control for LE3H treatment, was given by gavage. Blood samples were taken from the tails for determining number of blood cells. The animals were killed by cervical dislocation (CD), and then blood samples were collected from the hearts for protein electrophoresis. Results revealed the same number of leukocytes with LE3H (0.39 mg/g bw) treatment as with the Imunos treatment. HgCl2 administration increased leukocytes and decreased erythrocytes; HgCl2 administration followed by LE3H (0.39 mg/g bw) treatment protected the amount of blood cells as well as the control. HgCl2 administration showed a new 125 kDa protein and caused overexpression of 48 kDa protein; this protein profile could be protected by LE3H (0.39 mg/g bw) treatment as in the control condition. We conclude that LE3H provides a protective effect against HgCl2 toxicity in blood of M. musculus.

Folic acid supplementation enhances arsenic methylation: results from a folic acid and creatine supplementation randomized controlled trial in Bangladesh.

Background: Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. Objective: This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. Design: In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 µg per day), 3 g creatine per day, 400 µg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12-24, half of the participants receiving FA received placebo. Results: Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P < 0.05). In the creatine group, the mean decrease in %MMAs exceeded that of the placebo group at wk 6 and 12 (P < 0.05); creatine supplementation did not affect change in %InAs or %DMAs. The decrease in %MMAs at wk 6 and 12 was larger in the 800 µg FA than in the 400 µg FA group (P = 0.034). There were no differences in treatment effects between the 400 µg FA and creatine + FA groups. Data suggest a rebound in As metabolite proportions after FA cessation; at wk 24, log(%InAs) and %DMAs were not significantly different than baseline levels among participants who discontinued FA supplementation. Conclusions: The results of this study confirm that FA supplementation rapidly and significantly increases methylation of InAs to DMAs. Further research is needed to understand the strong cross-sectional associations between urinary creatinine and As methylation in previous studies. This trial was registered at https://clinicaltrials.gov as NCT01050556.

Effects of diphenyl diselenide diet on a model of mercury poisoning.

This work investigated the preventive effect of diphenyl diselenide [(PhSe)2] against the toxic effects of mercury in silver catfish (Rhamdia quelen). The animals were treated during 30 consecutive days with a (PhSe)2 supplemented feed (3.0 mg kg-1) or commercial feed. During the last 5 days the animals received a daily intraperitoneal dose of HgCl2 (1.7 mg kg-1) or Saline (0.9%). Twenty-four hours after the last HgCl2 injection, the animals were euthanized by spinal cord section to biological material obtainment. Hepatic (AST and ALT) and renal (ammonia and creatinine) toxicity biomarkers, δ-ALA-D activity, TBARS, total and non-protein thiols levels and hepatic, renal and blood mercury (Hg) and zinc (Zn) content were evaluated. Considering renal parameters, HgCl2 exposition increased serum creatinine levels and decreased δ-ALA-D activity, total and non-protein thiols and TBARS levels. HgCl2 exposure also decreased blood δ-ALA-D activity. With exception of blood δ-ALA-D activity and total thiols levels, (PhSe)2 supplementation partially prevented mercury induced alterations. Animals exposed to HgCl2 presented an increase in liver and kidney Hg content and a decrease in liver and blood Zn content. The alteration in blood Zn content was partially prevented with (PhSe)2 supplementation. With the exception of mercury and zinc content, no effects of HgCl2 exposure on hepatic tissue were observed. These results show that (PhSe)2 supplementation can represent a promising alternative to prevent the toxic effects presented by Hg exposure.

Mercuric chloride induced hepatotoxic and hematologic changes in rats: The protective effects of sodium selenite and vitamin E.

This study focuses on investigating the possible protective effect of sodium selenite (Na2SeO3) and/or vitamin E against mercuric chloride (HgCl2)-induced hepatotoxicity in rat. Male rats were given HgCl2 (1 mg/kg body weight (bw)) and HgCl2 plus Na2SeO3 (0.25 mg/kg bw) and/or vitamin E (100 mg/kg bw) daily via gavage for 4 weeks. HgCl2-treated groups had significantly higher white blood cell and thrombocyte counts than the control group. Serum activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, γ-glutamyl-transferase, and lactate dehydrogenase significantly increased and serum levels of total protein, albumin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol significantly decreased in the HgCl2-treated groups compared with control group. Malondialdehyde level significantly increased and superoxide dismutase, catalase, and glutathione peroxidase activities decreased in liver tissue of HgCl2-treated rats. Also, HgCl2 exposure resulted in histopathological changes. Supplementation of Na2SeO3 and/or vitamin E provided partial protection in hematological and biochemical parameters that were altered by HgCl2 As a result, Na2SeO3 and/or vitamin E significantly reduced HgCl2-induced hepatotoxicity, but not protected completely.

Selenium as an antidote in the treatment of mercury intoxication.

Selenium (Se) is an essential trace element for humans. It is found in the enzyme glutathione peroxidase. This enzyme protects the organism against certain types of damage. Some data suggest that Se plays a role in the body's metabolism of mercury (Hg). Selenium has in some studies been found to reduce the toxicity of Hg salts. Selenium and Hg bind in the body to each other. It is not totally clear what impact the amount of Se has in the human body on the metabolism and toxicity of prolonged Hg exposure.

Prenatal exposure to methyl mercury from fish consumption and polyunsaturated fatty acids: associations with child development at 20 mo of age in an observational study in the Republic of Seychelles.

BACKGROUND: Fish is a rich source of n-3 polyunsaturated fatty acids (PUFAs) but also contains the neurotoxicant methyl mercury (MeHg). PUFAs may modify the relation between prenatal MeHg exposure and child development either directly by enhancing neurodevelopment or indirectly through the inflammatory milieu. OBJECTIVE: The objective was to investigate the associations of prenatal MeHg exposure and maternal PUFA status with child development at 20 mo of age. DESIGN: The Seychelles Child Development Study Nutrition Cohort 2 is an observational study in the Republic of Seychelles, a high-fish-eating population. Mothers were enrolled during pregnancy and their children evaluated at 20 mo of age by using the Bayley Scales of Infant Development II (BSID-II), the MacArthur Bates Communicative Development Inventories (CDI), and the Infant Behavior Questionnaire-Revised. There were 1265 mother-child pairs with complete data. RESULTS: Prenatal MeHg exposure had no direct associations with neurodevelopmental outcomes. Significant interactions were found between MeHg and PUFAs on the Psychomotor Developmental Index (PDI) of the BSID-II. Increasing MeHg was associated with lower PDI but only in children of mothers with higher n-6/n-3. Among mothers with higher n-3 PUFAs, increasing MeHg was associated with improved PDI. Higher maternal docosahexaenoic acid (DHA) was associated with improved CDI total gestures (language development) but was significantly adversely associated with the Mental Development Index (MDI), both with and without MeHg adjustment. Higher n-6:n-3 ratios were associated with poorer scores on all 3 CDI outcomes. CONCLUSIONS: We found no overall adverse association between prenatal MeHg exposure and neurodevelopmental outcomes. However, maternal PUFA status as a putative marker of the inflammatory milieu appeared to modify the associations of prenatal MeHg exposure with the PDI. Increasing DHA status was positively associated with language development yet negatively associated with the MDI. These findings may indicate the existence of an optimal DHA balance with respect to arachidonic acid for different aspects of neurodevelopment.

Ameliorative stroke of selenium against toxicological effects of mercuric chloride in liver of freshwater catfish Heteropneustes fossilis (Bloch).

Mercury, a prevalent and unrelenting toxin, occurs in a variety of forms in freshwater as well as, in marine life. Mercury is an important inducer of oxidative stress in fish leading to formation of reactive oxygen species. Selenium is an essential micronutrient for animals and has antagonistic effect against mercuric toxicity in fishes. Present study has been made to evaluate toxic effect of HgCl2 (0.15 mg/L) on liver of freshwater catfish Heteropneustes fossilis (Bl.). Protective ability of selenium has been investigated by simultaneous exposure of fish with sodium selenite (0.15 mg/L) along with mercuric chloride. For present study Fishes were divided into three groups of ten fishes each the first group served as control, while the second group fish were exposed to HgCl2 . Animals of third group were treated with HgCl2 and Na2 SeO3 . Results reveal that mercury induced lipid peroxidation and in response to this, antioxidants reduced glutathione (GSH) and Catalase (CAT) were reduced whereas, Glutathione reductase (GR) level was enhanced. These antioxidants scavenge the reactive oxygen radicals. Hg induced histopathological damage and elevation in alkaline phosphatase (ALP) and transaminases and reduction in protein and glucose contents were evidently seen in catfish liver. Intriguingly, results indicate that under stress of mercury, the fish actively generate oxidative stress and antioxidant responses, which can be used as biomarkers of pollution. Simultaneous exposure to Selenium along with Hg suppressed Hg uptake and lipid peroxidation. Histological architecture and all biochemical parameters were maintained near normal in the presence of selenium in liver of the catfish.

The welfare value of FDA's mercury-in-fish advisory: a dynamic reanalysis.

Assessing the welfare impact of consumer health advisories is a thorny task. Recently, Shimshack and Ward (2010) studied how U.S. households responded to FDA's 2001 mercury-in-fish advisory. They found that the average at-risk household reduced fish consumption by 21%, resulting in a 17%-reduction in mercury exposure at the cost of a 21%-reduction in cardioprotective omega-3 fatty acids. Based on a static assessment of the health costs and benefits Shimshack and Ward concluded that the advisory policy resulted in an overall consumer welfare loss. In this note, we propose a dynamic assessment that links the long-term cardiovascular health effects of the advisory to life-cycle consumption. We find that under reasonable assumptions the welfare loss might be much larger than suggested. Our analysis highlights the importance of accounting for dynamic effects when evaluating persistent changes in exposure to environmental health risks.

Ameliorating effect of ß-carotene on antioxidant response and hematological parameters of mercuric chloride toxicity in Nile tilapia (Oreochromis niloticus).

The impact of different levels of dietary ß-carotene to alleviate the effect of mercuric chloride toxicity in Nile tilapia was assessed. Semi-purified diets containing 0, 40, and 100 mg ß-carotene kg(-1) dry diet were fed for 21 days, which were subjected to sublethal concentration of mercuric chloride (0.05 ppm). Hematological and biochemical parameters, lipid profile, and antioxidant response were examined. All hematological parameters of tilapia fish starting from second week of toxicity were significantly decreased. A significant increasing trend in liver enzymes (ALT and AST) were observed parallel to the time of toxicity and peroxide radicals (MDA) appearing significantly increased in toxicated group without carotene supplement, although carotene supplementation return all parameters within the control levels. Mercury accumulated significantly in fish liver and white muscles in toxicated group while it showed a significant reduction in dietary ß-carotene-treated group. Overall, it can be used as immunostimulant and alleviate the suppression effect resulted from immune depressive stressful condition in farmed Nile tilapia.

[Fish and seafood as a source of human exposure to methylmercury]. / Ryby i owoce morza jako zródlo narazenia czlowieka na metylortec.

Fish and seafood are recommended diet constituents providing high quality protein, vitamins, minerals and omega-3 fatty acids, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, these foodstuffs can also be the major source ofmethylmercury intake in humans. In general, more than 90% of the mercury in fish is found as methylmercury, but contents of methylmercury can vary considerably between species. Predatory species that are at the top of the food chain and live a long time, may accumulate higher levels of methylmercury. This paper contains information about sources of human exposure to organic compounds of mercury, toxicity, metabolism and transformation of mercury in the environment. Assessment of methylmercury by international risk assessment bodies such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and U.S. National Research Council (NRC) were presented. Climate changes and their influence on the mercury cycle in the environment especially mercury methylation and concentrations of methylmercury in marine species were also presented. Consumer advice prepared by European Commission and Member States as regards consumption of predatory fishes such as swordfish, tuna, shark, marlin and pike, taking into account the most vulnerable groups of population e.g. women planning pregnancy, pregnant or breastfeeding women and children were presented. Mercury and methylmercury contamination of fishes and seafood on the basis of the literature references as well as intake of mercury with fish and fish products in Poland and other European country were discussed. The role of selenium as a factor which counteracts methylmercury toxicity and protects against some neurological effects of methylmercury exposure in humans, as well as information on potential etiological factors connected with autism disorder were also described. Attention has also been drawn to increasing number of notifications to Rapid Alert System for Food and Feed (RASFF) concerning the contamination of fish and fish products with total mercury. European and national regulations concerning maximum permissible levels of mercury in food were also presented. Possibility of selection of different fish and seafood species, taking into account low methylmercury contamination and high contents of omega-3 fatty acids e.g. sardine, mackerel, anchovy, salmon, periwinkle, have been discussed.

[Overview of studies on detoxification effect of smilacis glabrae rhizoma on mercury poisoning].

Mercury-containing preparations are widely used in surgery department of traditional Chinese medicine and have made remarkable achievements. But they are toxic to human kidney, nerve, immune, etc. Smilacis Glabrae Rhizoma is sweet, tasteless and neutral in nature and able to enter liver and stomach channels and detoxify mercury poisoning. This article summarizes the mercury poisoning and the detoxification effect of Smilacis Glabrae Rhizoma in ancient records, pharmaceutical studies and clinical application, in order to provide ideas and methods for the safe use of mercury-containing preparations in surgery department of traditional Chinese medicine.

Therapeutic potential of N-acetyl cysteine with antioxidants (Zn and Se) supplementation against dimethylmercury toxicity in male albino rats.

Mercury (Hg) is currently one of the most prevalent pollutants in the environment. Many studies have examined its effects on the health of both humans and animals. Experimental studies have shown that sulfur-containing nutrients play an important role as detoxification and protecting cell against the detrimental properties of mercury. The present study was undertaken to elucidate the toxicity induced by dimethylmercury in male rats through the activities of transaminases, alkaline phosphatase, lactate dehydrogenase in serum and oxidative damage as acetyl cholinesterase activity in different regions of brain and lipid peroxidation, reduced glutathione content, mean DNA damage in liver, kidney and brain of rats given dimethylmercury (10 mg/kg, p.o., once only) along with combination therapy of N-acetyl cysteine (2 mM/kg, i.p.), zinc (2 mM/kg, p.o.) and selenium (0.5 mg/kg, p.o.) for 3 days. In the dimethylmercury group, activities of transaminases, alkaline phosphatase, lactate dehydrogenase in serum, level of lipid peroxidation, mean DNA damage and mercury ion concentration were significantly higher whereas reduced glutathione content and the activity of acetyl cholinesterase were significantly lower compared to controls (P≤0.05). Combined treatment of zinc and selenium with N-acetyl cysteine to dimethylmercury-exposed rats showed a substantial reduction in the levels of DMM-induced oxidative damage and comet tail length. In conclusion, the results of this study support that the supplementation of zinc and selenium with N-acetyl cysteine can improve the DMM induced blood and tissue biochemical oxidative stress and molecular alterations by recoupment in mean DNA damage.

Chlorella suppresses methylmercury transfer to the fetus in pregnant mice.

To investigate the effects of chlorella on methylmercury (MeHg) transfer to the fetus during pregnancy, female C57BL/6N mice (aged 10 weeks) were housed for 7 to 8 weeks, from 4 weeks before mating to birth, with diets containing 0% or 10% chlorella powder (CP) and MeHg-containing drinking water (2 µg Hg/ml). The consumption volume of the MeHg-containing water was limited to 15 ml/mouse/week throughout the experiment. Distilled water and a basal diet (0% CP) was given to control mice. Except for the mating period, during the 5(th) week, mice were housed individually until parturition. Two neonates were randomly selected from each mother mouse within 24 hr after parturition for Hg analysis of the blood, brain, liver, and kidneys. Mother mice were sacrificed on the same day as neonates to obtain tissue samples for Hg analysis. The blood and brain Hg levels of both neonates and mothers in the CP diet group were significantly lower than those in the basal diet group. Although the hepatic and renal Hg levels were not significant in mothers between the two dietary groups, in neonates, the CP diet group showed significantly lower Hg levels in these tissues than the basal diet group. The results obtained here revealed that continuous CP intake suppressed MeHg transfer to the fetus, in addition to effective suppressing MeHg accumulation in brains of the mothers.

Dietary selenium's protective effects against methylmercury toxicity.

Dietary selenium (Se) status is inversely related to vulnerability to methylmercury (MeHg) toxicity. Mercury exposures that are uniformly neurotoxic and lethal among animals fed low dietary Se are far less serious among those with normal Se intakes and are without observable consequences in those fed Se-enriched diets. Although these effects have been known since 1967, they have only lately become well understood. Recent studies have shown that Se-enriched diets not only prevent MeHg toxicity, but can also rapidly reverse some of its most severe symptoms. It is now understood that MeHg is a highly specific, irreversible inhibitor of Se-dependent enzymes (selenoenzymes). Selenoenzymes are required to prevent and reverse oxidative damage throughout the body, particularly in the brain and neuroendocrine tissues. Inhibition of selenoenzyme activities in these vulnerable tissues appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity. Because Hg's binding affinities for Se are up to a million times higher than for sulfur, its second-best binding partner, MeHg inexorably sequesters Se, directly impairing selenoenzyme activities and their synthesis. This may explain why studies of maternal populations exposed to foods that contain Hg in molar excess of Se, such as shark or pilot whale meats, have found adverse child outcomes, but studies of populations exposed to MeHg by eating Se-rich ocean fish observe improved child IQs instead of harm. However, since the Se contents of freshwater fish are dependent on local soil Se status, fish with high MeHg from regions with poor Se availability may be cause for concern. Further studies of these relationships are needed to assist regulatory agencies in protecting and improving child health.

Melatonin protection on mercury-exerted brain toxicity in the rat.

The effect of melatonin on the neurotoxicity induced by mercuric chloride was studied. Adult rats were fed orally with two different doses of mercuric chloride (2 mg; 4 mg/kg body weight) to evaluate brain toxicity with respect to cerebral hemisphere, cerebellum, and medulla oblongata regions for 60 days with or without supplementation with melatonin (5 mg/kg body weight) intraperitoneally. The results suggest that the graded doses of mercury elicit the depletion of enzymatic activities, such as adenosine triphosphatase, succinate dehydrogenase, phosphorylase, alkaline phosphatase, acid phosphatase, altered glycogen, total protein, and lipid peroxidation levels in the cerebral hemisphere, cerebellum, and medulla oblongata of the brain, thereby affecting their respective functions. Blood glucose and mercury levels increased, followed by a reduction in body and organ weights. All these effects seemed to be severe in the cerebral hemisphere of the brain. Further affected indices were, to some extent, maintained in the brain of animals cotreated with melatonin, showing its protective role against mercury-exerted neurotoxicity.