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.

Docosahexaenoic acid enhances methylmercury-induced endoplasmic reticulum stress and cell death and eicosapentaenoic acid potentially attenuates these effects in mouse embryonic fibroblasts.

Fish consumption has both the risk of methylmercury (MeHg) poisoning and the benefit of obtaining n-3 polyunsaturated fatty acids (n-3 PUFAs), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). However, the cellular interaction between MeHg and PUFAs remains unknown. Therefore, the aim of this study was to investigate the effects of MeHg and n-3 PUFA exposure on mouse embryonic fibroblasts (MEFs). The results showed that EPA had a negligible effect on MeHg-induced cell death, whereas DHA promoted it. Thiobarbituric acid reactive substance (TBARS) concentrations in cells exposed to DHA and MeHg were higher than in those exposed to EPA and MeHg. Treatment with DHA and MeHg markedly induced the expression of endoplasmic reticulum (ER) stress (CHOP and DNAJB9) and Nrf2 target gene (p62 and HMOX-1) mRNA levels. Unexpectedly, EPA supplementation in addition to DHA and MeHg attenuated DHA- and MeHg-induced cell death and suppressed ER stress and expression of Nrf2 target genes. Our results revealed a differential impact of DHA and EPA on MeHg-induced cell death, and combined treatment with DHA and EPA along with MeHg attenuated MeHg-induced toxicity.

Neuroprotective Effect of Portulaca oleraceae Ethanolic Extract Ameliorates Methylmercury Induced Cognitive Dysfunction and Oxidative Stress in Cerebellum and Cortex of Rat Brain.

Methylmercury (MeHg) is highly toxic, and its principal target tissue in human is the nervous system, which has made MeHg intoxication a public health concern for many decades. Portulaca oleraceae (purslane), a member of the Portulacaceae family, is widespread as a weed and has been ranked the eighth most common plant in the world. In this study, we sought for potential beneficial effects of Portulaca oleracea ethanolic extract (POEE) against the neurotoxicity induced by MeHg in cerebellum and cortex of rats. Male Wistar rats were administered with MeHg orally at a dose of 5 mg/kg b.w. for 21 days. Experimental rats were given MeHg and also administered with POEE (4 mg/kg, orally) 1 h prior to the administration of MeHg for 21 days. After MeHg exposure, we determine the mercury concentration by atomic absorption spectroscopy (AAS); mercury content was observed high in MeHg-induced group. POEE reduced the mercury content. We also observed that the activities of catalase, superoxide dismutase, glutathione peroxidase, and the level of glutathione were reduced. The levels of glutathione reductase and thiobarbituric acid reactive substance were found to be increased. The above biochemical changes were found to be reversed with POEE. Behavioral changes like decrease tail flick response, longer immobility time, and decreased motor activity were noted down during MeHg exposure. POEE pretreatment offered protection from these behavioral changes. MeHg intoxication also caused histopathological changes in cerebellum and cortex, which was found to be normalized by treatment with POEE. The present results indicate that POEE has protective effect against MeHg-induced neurotoxicity.

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.

Response inhibition is impaired by developmental methylmercury exposure: acquisition of low-rate lever-pressing.

Developmental methylmercury (MeHg) exposure produces response perseveration on discrimination reversal procedures, disrupts sensitivity to reinforcement, and enhances sensitivity to dopamine agonists - a profile suggesting a deficit in behavioral inhibition. To examine inhibition, we examined MeHg's effects on the acquisition and persistence of low-rate lever-pressing following a history of high-rate responding. Additionally, we examined whether chronic exposure to selenium protects against MeHg's developmental neurotoxicity. Female rats were exposed in utero via maternal exposure to drinking water containing 0ppm, 0.5ppm or 5ppm of Hg as MeHg, producing approximately 0µg/kg/day, 40µg/kg/day, or 400µg/kg/day of Hg. The mothers (during gestation) and the offspring (throughout life) consumed a purified diet containing 0.06ppm or 0.6ppm of Se (as sodium selenite), forming a 2 (lifespan diet)×3 (developmental MeHg) factorial design. Adult offspring lever-pressed under two schedules of reinforcement. A differential reinforcement of high-rate (DRH) schedule imposed rigid response requirements that remained constant through the study. A high-rate percentile schedule (PCNT-H) incorporated a flexible criterion that reinforced short interresponse times using an adjusting criterion that was sensitive to recent performance. After high-rate responding stabilized, the PCNT-H schedule was abruptly inverted by reinforcing long interresponse times. Acquisition of low-rate responding was impaired in the MeHg-exposed rats because of intrusions of high-rate response bursts. DRH response rates did not change. Dietary selenium did not influence MeHg's effects. High-rate operant behavior perseverated, suggesting that gestational MeHg exposure impairs response inhibition - an effect that extends results previously reported using choice procedures or spatial and visual discrimination reversals.

Dietary selenium (Se) and vitamin E (V(E)) supplementation modulated methylmercury-mediated changes in markers of cardiovascular diseases in rats.

Epidemiological studies demonstrated that human exposure to methylmercury (MeHg) may contribute to the development and progression of metabolic and cardiovascular disorders. However, the mechanisms involved and the role of selenium (Se) and vitamin E (V(E)) supplementation in modulating MeHg cardiovascular toxicities remain unclear. This study examined the effects of Se and V(E) supplementation on MeHg-mediated systemic oxidative stress, antioxidant defense, inflammation, and endothelial dysfunction in an animal model. Male Sprague-Dawley rats were fed a starch-based casein diet or the same diet supplemented with 1 or 3 mg Se/kg diet and with or without 250 or 750 mg V(E)/kg diet. After 28 days of dietary treatment, rats were gavaged with 0 or 3 mg MeHg/kg BW for 14 consecutive days. Results suggested that exposure to MeHg may increase the risk of cardiovascular disease by decreasing circulating paraoxonase-1 activities, increasing serum oxidized low density lipoprotein levels, and associated systemic inflammation and endothelial dysfunction as reflected by increased leukocyte counts and serum levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1. Se and V(E) supplementation may either alleviate or augment the effects of MeHg, depending on their doses and combinations.

Antagonistic interaction of mercury and selenium in a marine fish is dependent on their chemical species.

It is well-known that selenium (Se) shows protective effects against mercury (Hg) bioaccumulation and toxicity, but the underlying effects of Se chemical species, concentration, and administration method are poorly known. In this study, we conducted laboratory studies on a marine fish Terapon jurbua to explain why Hg accumulation is reduced in the presence of Se observed in field studies. When Se and Hg were administrated concurrently in the fish diets, different Se species including selenite, selenate, seleno-dl-cystine (SeCys), and seleno-dl-methionine (SeMet) affected Hg bioaccumulation differently. At high concentration in fish diet (20 µg g(-1) normally), selenate and SeCys significantly reduced the dietary Hg(II) assimilation efficiency (AE) from 38% to 26%. After the fish were pre-exposed to dietary selenite or SeMet (7 µg g(-1) normally) for 22 days with significantly elevated Se body concentrations, the Hg(II) AEs were pronouncedly reduced (from 41% to 15-26%), whereas the dissolved uptake rate constant and elimination rate constant were less affected. In contrast to Hg(II), all the MeHg biokinetic parameters remained relatively constant whether Se was administrated simultaneously with the fish diet or when the fish were pre-exposed to Se with elevated body concentrations. Basic biokinetic measurements thus revealed that Se had direct interaction with Hg(II) during dietary assimilation rather than with MeHg and that different Se species had variable effects on Hg assimilation.

Allium sativum L. extract prevents methyl mercury-induced cytotoxicity in peripheral blood leukocytes (LS).

Adenosine deaminase (ADA) is involved in purine metabolism and plays a significant role in the immune system. The focus of this investigation was to examine the effects of low concentrations of organic mercury on ADA activity in human leukocytes and to investigate the relationship between these effects and cell death. We have examined the protective potential effects of Allium sativum extract (GaE) against Methylmercury (MeHg)-induced cytotoxic effects on human leucocytes under in vitro conditions. MeHg (0.05-10 microM) significantly decreased leukocyte viability (58.97% for MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) and 51.67% for Alamar Blue (AB) and this decrease was positively correlated to the MeHg-induced inhibition of ADA activity. N-acetylcysteine (NAC) and GaE prevented both the MeHg-induced cytotoxic effects on leukocytes according to MTT and AB assays and the effects on the ADA activity. The present results suggest that the protective effects of GaE against MeHg-induced leukocyte damage is related to the removal of oxidant species generated in the presence of MeHg due to the antioxidant efficacy of garlic constituents. It is important to point out that the intense presence of ADA in Leukocyte suspension (LS) highlights the relevant effects in the immune system and in vitro cytotoxicity of MeHg exposure.

Effects of chelators on mercury, iron, and lead neurotoxicity in cortical culture.

Chelation therapy for the treatment of acute, high dose exposure to heavy metals is accepted medical practice. However, a much wider use of metal chelators is by alternative health practitioners for so called "chelation therapy". Given this widespread and largely unregulated use of metal chelators it is important to understand the actions of these compounds. We tested the effects of four commonly used metal chelators, calcium disodium ethylenediaminetetraacetate (CaNa2EDTA), D-penicillamine (DPA), 2,3 dimercaptopropane-1-sulfonate (DMPS), and dimercaptosuccinic acid (DMSA) for their effects on heavy metal neurotoxicity in primary cortical cultures. We studied the toxicity of three forms of mercury, inorganic mercury (HgCl2), methyl mercury (MeHg), and ethyl mercury (thimerosal), as well as lead (PbCl2) and iron (Fe-citrate). DPA had the worst profile of effects, providing no protection while potentiating HgCl2, thimerosal, and Fe-citrate toxicity. DMPS and DMSA both attenuated HgCl2 toxicity and potentiated thimerosal and Fe toxicity, while DMPS also potentiated PbCl2 toxicity. CaNa2EDTA attenuated HgCl2 toxicity, but caused a severe potentiation of Fe-citrate toxicity. The ability of these chelators to attenuate the toxicity of various metals is quite restricted, and potentiation of toxicity is a serious concern. Specifically, protection is provided only against inorganic mercury, while it is lacking against the common form of mercury found in food, MeHg, and the form found in vaccines, thimerosal. The potentiation of Fe-citrate toxicity is of concern because of iron's role in oxidative stress in the body. Potentiation of iron toxicity could have serious health consequences when using chelation therapy.

Cipura paludosa extract prevents methyl mercury-induced neurotoxicity in mice.

Cipura paludosa (Iridaceae), a native plant widely distributed in the north of Brazil, is used in traditional medicine as an anti-inflammatory and analgesic agent, against tuberculosis and gonorrhoea and for regulation of menstrual flow. However, scientific studies on the pharmacological properties of C. paludosa are scarce. We have examined the potential protective effects of the ethanolic extract of C. paludosa against methyl mercury (MeHg)-induced neurotoxicity in adult mice. MeHg was diluted in drinking water (40 mg/l, freely available) and the ethanolic C. paludosa extract (CE) was diluted in a 150 mM NaCl solution and administered by gavage (10 and 100 mg/kg body weight, respectively, twice a day). Because treatment lasted for 14 days and each animal weighed around 40 g, the total dosage of plant extract given to each mouse was 5.6 and 56 g, respectively. After the treatment period, MeHg exposure induced a significant deficit in the motor coordination, which was evident by a reduction (90%) in the falling latency in the rotarod apparatus. Interestingly, this phenomenon was completely recovered to control levels by CE co-administration, independent of dosages. MeHg exposure inhibited cerebellar glutathione peroxidase (mean percentage inhibition of 42%) - an important enzyme involved in the detoxification of endogenous peroxides - and this effect was prevented by co-administration of CE. Conversely, MeHg exposure increased cerebellar glutathione reductase activity (mean percentage inhibition of 70%), and this phenomenon was not affected by C. paludosa co-administration. Neither MeHg nor CE changed the cerebellar glutathione levels. This study has shown for the first time, the in vivo protective effects of CE against MeHg-induced neurotoxicity. In addition, our findings encourage studies concerning the beneficial effects of C. paludosa on neurological conditions related to excitotoxicity and oxidative stress.

Co-consumption of selenium and vitamin E altered the reproductive and developmental toxicity of methylmercury in rats.

Methylmercury (MeHg), an environmental contaminant primarily found in fish and seafood, may pose long-term health risks to pregnant women and their developing children. The objective of this study was to determine whether co-consumption of nutritional supplements would alter the effects of MeHg on reproductive and developmental toxicity using a rodent model. Adult female rats were fed a diet containing additional selenium (1 ppm), additional vitamin E (225 IU/kg) or a combination of the two for 4 weeks before oral dosing of MeHg (1.25 mg/kg/day). Treatment with MeHg and dietary supplementation continued throughout pregnancy after which the dams were allowed to deliver their offspring. In addition to routine evaluations including periodic body weight measurements and daily clinical signs observations, dams and pups were evaluated for auditory startle habituation and pups were evaluated for developmental landmarks and reflexology. The dams and offspring were euthanized approximately 4 weeks after birth of the offspring. Results indicated that treatment with MeHg caused adverse effects on both reproduction of the dams and decreased progeny survival. However, the dams showed significant improvement in body weight gain during lactation and average auditory startle response time when the diet was enriched with both selenium and vitamin E. The combination of both vitamin E and Se also resulted in a significant increase in post-natal survival when compared to MeHg-treated group. There was no nutrient effect on the MeHg toxicity shown in offspring physical landmarks, performance in reflex tests and assessment of simple auricular startle response. Also, accelerated development as indicated by earlier opening in the pups of the supplemental diet groups was observed. These results suggest that antioxidant nutrients in the diet may alter MeHg reproductive and developmental toxicity. The underlying and human health implications warrant further investigations.

Modification of mercury toxicity by selenium: practical importance?

The interaction between mercury and selenium may involve a variety of toxicologically and biochemically distinct processes. In this paper, the interaction between inorganic mercury and sodium selenite, the interaction most extensively studied, as well as the interaction between methylmercury (MeHg) and selenium, the interaction perhaps most significant for non-occupational human populations, will be discussed. It has been shown that the former interaction can be understood as a modification of the kinetic behavior of inorganic mercury by selenite, but this interaction may occur only under very limited conditions. On the other hand, the mechanism of the latter interaction is largely unknown, and kinetic modification appears to play only a minor role. An interaction between MeHg and seleno-proteins or a possible interaction between the inorganic mercury, resulting from the demethylation of MeHg, and the selenium may be important. Compared to the experimental findings, little evidence of the toxicological modification of MeHg by selenium was obtained in epidemiological studies.

Selenite or selenomethionine interaction with methylmercury on uptake and toxicity showing a weak selenite protection: studies on cultured K-562 cells.

Selenium and methylmercuric chloride (MMC) interactions regarding cellular uptake and selenium protection on MMC toxicity have been studied. Human K-562 cells were pretreated or simultaneously treated with either selenite (5 or 50 microM) or selenomethionine (10 or 50 microM) together with (3.5 or 5 microM) MMC. Cells simultaneously treated with selenite or selenomethionine and 3.5 microM MMC showed a decreased mercury concentration with increased selenium dose especially seen in the selenite combinations. The simultaneous selenite and MMC 3.5 microM combinations showed growth curves with an increasing number of viable cells with increased selenite dose. All combinations with 5 microM MMC were toxic to the cells. Interactions between selenite or selenomethionine and MMC regarding cellular uptake of mercury and selenium were observed and indications of selenite protection against MMC toxicity in human K-562 cells were noticed.

Inhibitory effect of selenium on biliary secretion of methyl mercury in rats.

The inhibitory effect of sodium selenite on biliary secretion of methyl mercury was examined in rats. The biliary secretion of methyl mercury in rat treated with 1 mumol/kg of methyl mercury was significantly decreased by administration of selenite at doses of 0.05 mumol/kg or higher. In rats given 10 mumol/kg of methyl mercury, marked depression of biliary secretion of mercury was observed when selenite was injected at a dose of 0.2 mumol/kg. On the other hand, secretion of substantial amounts of selenium was observed when biliary secretion of mercury was depressed. When the concentration of selenium in the bile was higher than 5 nmol/ml, biliary secretion of mercury was markedly depressed independently of the dose of methyl mercury administered (1 mumol/kg or 10 mumol/kg). These results suggest that the degree of inhibitory effect of selenite may be determined by the selenium concentration in the liver or the bile after treatment with selenite rather than the molar ratio of the dose of methyl mercury and selenite. We concluded that the decrease in biliary secretion of methyl mercury induced by selenite may result from inhibition of pathway for secretion of methyl mercury from liver to bile rather than the direct formation of a complex between methyl mercury and selenium. Methyl mercury has been considered to be secreted from liver to bile as a complex with glutathione (GSH). However, administration of selenite did not affect biliary secretion of GSH or hepatic glutathione S-transferase activity. Moreover, gel filtration of liver cytosol demonstrated that the distribution pattern of hepatic methyl mercury between macromolecules and GSH was not significantly changed by administration of selenite. These results suggest that selenite does not affect complex formation of methyl mercury with GSH at least in the liver. Selenite might specifically inhibit the activity of the canalicular transporter(s) which transport complexes of methyl mercury and GSH from the liver to bile.

Protective effects of Ca2+ channel blockers against methyl mercury toxicity.

The protective effects of Ca2+ channel blockers against the toxicity of methyl mercury were examined by both in vivo and in vitro experiments. In the in vivo study we first examined the effects of the Ca2+ channel blockers (20 mg/kg/day), flunarizine, nifedipine, nicardipine, and verapamil against the toxic level of methyl mercury treatment (5 mg/kg/day of methyl mercuric chloride for 12 consecutive days). However, there was a difference in potency of the effects among the reagents. All the Ca2+ channel blockers prevented a decrease in body weight and/or the appearance of the symptoms of neurological disorders in the rats treated with methyl mercury. In the next experiment, we examined flunarizine at different levels of supplementation (1, 25 and 50 mg/kg/day). Flunarizine in a dose-dependent manner prevented a decrease in body weight, appearance of the symptoms of neurological disorder and mortality in the rats treated with methyl mercury. Flunarizine treatment (25 mg/kg/day) for the first 5 days did not affect mercury distribution among the tissues, suggesting that the mechanism of protection against methyl mercury-induced toxicity may be attributed to its own pharmacological effect. In the in vitro study we examined the effect of flunarizine (0, 0.5, 5 and 50 microM) using primary cultures of cerebellar granular cells in 96-well culture plates. Viable cell numbers were estimated 1 and 3 days after treatment with methyl mercury. The estimated 50% lethal concentration (LC50) of methyl mercury was higher in plates treated with 5 and 50 microM of flunarizine both on days 1 and 3, indicating that flunarizine protected the primary cultured cerebellar granular cells against the toxicity of methyl mercury. As such, Ca2+ channel blockers protected against the toxicity of methyl mercury both in vivo and in vitro, suggesting that Ca2+ plays an important role in the mechanisms of methyl mercury toxicity.

Effects of maternal dietary supplementation with selenite on the postnatal development of rat offspring exposed to methyl mercury in utero.

Female Sprague-Dawley rats were fed a control standard diet or a selenite (Se) supplemented diet (1.3 p.p.m. Se) for 8 weeks before mating and during gestation and lactation. Blood glutathione peroxidase activity (GSH-Px) was measured as a biomarker of Se in dames. After mating, the females from two dietary groups were divided into three subgroups (6 groups with 10 animals in each) given 0 (vehicle), 2 or 6 mg/kg methyl mercury (MeHg) by gavage on days 6-9 of gestation. Day 2 post parturition all litters were standardized to 6 pups per litter and remaining pups were used for determination of blood and brain total Hg contents. Behavioural testing was performed at two months of age. The results of the study showed that supplementing the diet with Se partly antagonized some adverse effects of the MeHg such as hypoactivity especially in the high MeHg dose group. There were no changes in physical development or body weight except a tendency to decreased body weight in offspring of mothers exposed to 6 mg Hg/kg. The GSH-Px activity was significantly increased in animals fed on Se supplemented diet. The dietary Se supplementation resulted in considerably increased concentrations of mercury in the blood of the offspring despite milder signs of CNS toxicity and no increase in brain concentrations of mercury.

Effect of organic and inorganic mercury on human sperm motility.

The effects of mercuric chloride and methyl mercuric chloride on the motility of human spermatozoa in vitro were investigated. Organic as well as inorganic mercury compounds decreased the percentage of motile spermatozoa. After 15 min. incubation with 40 microM mercuric chloride a significant decrease in sperm motility was observed. Less than 5% of spermatozoa were motile after 30 min. of exposure to 20 microM methyl mercuric chloride. These effects could not be attenuated by addition of 5 microM sodium selenite. The ultrastructural localization of mercury was demonstrated by autometallography. Silver-enhanced mercury deposits could be demonstrated only in spermatozoa exposed to inorganic mercury. In these cells mercury grains were most abundant in membranes of midpiece and tail.

Development of reflexes in neonatal mice prenatally exposed to methylmercury and selenite.

The development of reflexes in neonates exposed prenatally to methylmercury and selenite was investigated. Pregnant mice were assigned to one of 4 treatments; methylmercury (MeHg), selenite(Se), combination of 2 compounds (MeHg X Se) and saline control (NaCl). Mice were injected subcutaneously (s.c.) on day 9 of gestation. The dose of each compound was 30 mumol/kg. Mercury (Hg) concentrations in the neonatal brain and liver of the MeHg X Se group were slightly lower than in the MeHg group. The results of behavioral examination revealed that the MeHg X Se group showed significantly improved development compared with the MeHg group. These facts suggest the possibility that selenium compounds have protective effects against methylmercury neurotoxicity in fetuses and neonates.