Methylmercury (MeHg) is related to several deleterious effects on the vertebrate tissues, mainly on central nervous system, and part of these effects are through of interaction with sulfhydryl group found in cellular proteins. MeHg interacts with low and high molecular weight thiols in the blood and tissues and this fact, in some cases will allow a better absorption and tissue uptake of mercury. In this regard, the purpose of this study was to examine the effect of MeHg-Cysteine (MeHg-Cys) complex administration on cerebral areas, liver and kidney on Hg-uptake and to analyze possible behavioral changes associated with mercury accumulation in adult s mice. Adult male Swiss albino mice were divided into four groups; control (1 mL/Kg distilled water), MeHg (2 mg/kg), Cys (2 mg/kg) and MeHg-Cys complex (2 mg/kg equimolar concentration). All the animals received one injection per day (i.p.), for 60 consecutives days. The initial set of experiments was designed to analyze possible neurobehavioral changes (locomotor performance and/or exploratory activity) caused by treatments. Administration of MeHg or MeHg-Cys complex caused a significant reduction on total locomotor activity in adult s mice, when compared to control group. In contrast to locomotor activity, rearing frequency was decreased only in MeHg group. The final set of experiments was designed to determine the mercury concentration into the brain areas (cortex and cerebellum), liver and kidney in adult s mice. Treatment with MeHg significantly increased mercury concentrations in all tissues analyzed, when compared to control group. The accumulation of mercury on cerebral areas and in liver was further increased in animals treated with MeHg-Cys complex, when compared to MeHg alone group. However, the concentration of mercury found in kidney was lower in the MeHg-Cys treated group, than in the group treated only with MeHg. In conclusion, the present study shows, for the first time, that treatment with MeHg-Cys complex allow better absorption and tissue uptake of mercury than the treatment with MeHg alone, in the cerebral areas and in liver of mice. Furthermore, this study reinforces the view that MeHg causes impairment in motor performance and exploratory activity and suggests that the different forms of MeHg exposure affect its distribution in the tissues of mice, as well as, it can leads to the distinct neurobehavioral consequences. / O metilmercúrio (MeHg) é relatado por ter vários efeitos deletérios sobre tecidos de vertebrados, principalmente no sistema nervoso central, e parte desses efeitos está relacionado a sua capacidade de interagir com grupos sulfidrílicos encontrados em proteínas. O MeHg reage com tióis de baixo e alto peso molecular no sangue e outros tecidos permitindo, em alguns casos uma melhor absorção e captação de mercúrio pelo tecido. Nesse contexto, o objetivo desse trabalho foi examinar os efeitos da administração do complexo MeHg-Cisteína (MeHg-Cys) na captação de mercúrio sobre áreas cerebrais, fígado e rim; e analisar possíveis mudanças comportamentais associadas ao acúmulo de mercúrio em camundongos adultos. Camundongos machos Swiss albino foram divididos em quatro grupos: Controle (1 mL de água destilada), MeHg (2 mg/kg), Cys (2 mg/kg) e Complexo MeHg-Cys (2 mg/kg concentração equimolar). Todos os animais receberam uma injeção (i.p. por dia) durante 60 dias consecutivos. A parte inicial dos experimentos foi designada para analisar possíveis mudanças neuro-comportamentais (desempenho locomotor e/ou atividade exploratória) causadas pelos tratamentos. A administração do MeHg ou do complexo MeHg-Cys reduziu significativamente a atividade locomotora total dos camundongos adultos quando comparado ao grupo controle. Em contraste à atividade locomotora, a freqüência de levantar-se (rearing) diminuiu apenas no grupo que recebeu MeHg. A parte final dos experimentos foi designada para determinar a concentração de mercúrio nas áreas cerebrais (córtex e cerebelo), fígado e rins dos camundongos tratados. O MeHg aumentou significativamente a concentração de mercúrio em todos os tecidos analisados, quando comparado ao grupo controle. O acúmulo de mercúrio sobre as áreas cerebrais e fígado foi acentuadamente aumentado nos animais que receberam o complexo MeHg-Cys, quando comparado ao grupo que recebeu apenas MeHg. Entretanto, a concentração de mercúrio encontrada no rim foi menor no grupo tratado com o complexo MeHg-Cys quando comparado ao grupo tratado apenas com MeHg. Concluindo, o presente estudo mostrou, pela primeira vez, que o tratamento com o complexo MeHg-Cys permite maior absorção e captação de mercúrio pelos tecidos cerebrais e hepático, do que o tratamento apenas com MeHg. Além disso, esse estudo reforça a idéia que o MeHg causa prejuízo na performance motora e atividade exploratória dos animais e também sugere que diferentes formas de exposição ao MeHg afetam a sua distribuição nos tecidos de camundongos, bem como pode levar a conseqüências neuro-comportamentais distintas.

Methylmercury (MeHg) is known predominantly as a neurotoxicant, however emerging experimental and epidemiological evidence has shown associations between MeHg exposure and the potential for increased risks of cardiovascular diseases. This thesis investigated the in vitro cytotoxic effects of MeHg in two cardiomyocyte cell lines, H9C2 rat neonatal cell line and AC16 adult human cell line. We observed significant increases in cell death at concentrations from 1 – 10 µM. ROS production and intracellular calcium concentrations increased dose-dependantly with MeHgCl exposure. Furthermore, while assessing mitochondrial function, a decline in maximal respiration at 1 µM was seen. However, these observations may in turn be a direct consequence of decreased cell numbers following exposures. Additionally, this study highlighted the differences in cellular bioenergetics which may impact how certain cells respond to contaminant stressors. The distribution of MeHg and total Hg in rat heart tissues was also examined and we observed increasing concentrations of MeHg in high and low dosed rat groups as compared to the vehicle controls. No difference was observed in Hg levels between the normal and high fat and sugar diet groups. The urinary isoprostane levels, which are indicative of systemic oxidative stress, showed significant increases in lean rats exposed to the high dose treatment. It was also observed that a high fat and sugar diet in lean and obese rats can contribute to increasing oxidative stress regardless of the level of contaminants they were dosed with. This thesis demonstrated several in vitro effects of MeHg on heart cells as well as determine the distribution of Hg levels in heart tissues and oxidative stress markers from an in vivo study.

Methylmercury (MeHg) production is magnified in the natural environment by geochemical influxes and an active sulfate reducing bacteria community. It has been found that the presence of sulfides, excess nutrients, and the type of depositional environment (normal marine or euxinic) greatly influences MeHg production and degree of pyritization (DOP). The aim of this research is to investigate a possible connection between MeHg accumulation and the DOP in Weeks Bay sediment. Collected sediment samples have confirmed a significant presence of total reduced sulfides, inorganic mercury, reactive iron, and total organic carbon. Pyritization results indicate a normal marine environment and, of the three measured elements (S, Fe, and C,) carbon and sulfur are the dominant limiting factors to the DOP in Weeks Bay. Current geochemical and pH/redox conditions favor MeHg and pyrite production. The quantified pyrite greatly exceeds that of MeHg indicating DOP inhibits MeHg precipitation.

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Early embryo development is one of the most sensitive stages to environmental chemicals during the whole life. Prenatal exposures to many environmental chemicals have been shown to impact fetal development and be associated with adverse health outcomes in later life stages. However, the effects of chemical mixture exposure on developing embryos, especially in early developmental stages, have yet to be fully studied. To fulfill this research gap, my thesis was divided into three data chapters and mainly aimed at investigating the effects of a chemical mixture on human early-stage embryo development. In Chapter 2, I chose methylmercury (MeHg) as the main study toxicant to establish procedures for embryotoxicity testing using human embryonic stem cells (hESCs). I then characterized the effects of low doses of MeHg on this stem cell model by screening a set of cell fate decision-related makers and found MeHg is embryotoxic, which is consistent with epidemiological and in vivo findings. In Chapter 3, I studied the embryotoxicity of a chemical mixture that consists of 23 individual environmental chemicals (including MeHg) detected from the maternal blood samples of pregnant women in Nunavik, labelled as Nunavik Contaminant Mixture (NCM), using the same cell model. The effects of NCM exposure on hESCs were compared to MeHg exposure alone. NCM exposure adversely affected cell viability and adhesion, induced apoptosis, disrupted the cell cycle, altered the expression of cytoskeleton and autophagy proteins, and changed the levels of lineage marker gene and protein expressions in a dose-dependent manner. Some distinct effects on hESCs between NCM exposure and MeHg alone exposure were noticed, and the potential interactions among the chemical components within a chemical mixture were indicated. In Chapter 4, I studied the effects of MeHg exposure during the formation of definitive endoderm (DE) cells from hESCs and compared that to MeHg's effects on undifferentiated hESCs. I found that cell specification towards endoderm could be affected by MeHg exposure, mainly through disrupting calcium homeostasis and over-generating reactive oxygen species, leading to increased ribosome biogenesis and protein synthesis. Moreover, MeHg effects are state-dependent; MeHg enhances pluripotency in undifferentiated hESCs, but it promotes differentiation during DE induction. Taken together, this thesis verifies the value of hESCs in testing the embryotoxicity and developmental toxicity of environmental chemicals, enriches the understanding of the toxicity of MeHg and NCM, emphasizes the necessity of evaluating the effects of chemical mixtures and provides new directions in studying environmental chemical toxicity using stem cells. Findings from my thesis could hopefully contribute to predicting the potential effects of prenatal environmental chemical exposures and aid in developing evidence-based public health policy.

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Inorganic mercury (Hg) is converted to potential neurotoxic methylmercury (MeHg) by a natural process called Hg methylation. MeHg can be biomagnified in the food chain, thus the consumption of Hg-contaminated fish contributes to harmful human health issues. Selenium (Se) inhibits the Hg bioavailability to the methylating bacteria by forming mercuric selenide (HgSe). Pseudodesulfovibrio mercurii, a type of sulfate-reducing bacteria (SRB) cultures were grown in anaerobic environments using an estuarine sulfate lactate growth medium to evaluate the effects of Hg concentrations, bacterial growth phase, and sodium selenate in the Hg methylation process. Bacterial cultures contained two types of mercuric (II) nitrate, dissolved and nanoparticles with 1 nM, 2 nM, and 3 nM concentrations in anoxic conditions. In a different experimental batch, various concentrations of sodium selenate (VI) were added to the Hg-contained medium to evaluate the effect of Se in the Hg methylation process. Dissolved Hg produced higher net MeHg than nanoparticulate Hg throughout the incubation period in the culture medium. Bacterial culture medium stressed with high-level Hg concentrations showed increased MeHg production (pM) but decreased Hg methylation rate (%) for the dissolved Hg. During the methylation process in the presence of Se, net MeHg production was reduced significantly compared to the culture medium solely exposed to Hg. The significant reduction of MeHg generation suggests an interference in the Hg methylation process due to the presence of 50-, 75-, and 100-fold higher Se than Hg. This study reassures the antagonistic effect between Hg and Se at the molecular level. Moreover, this study represents a novel approach when the antagonistic effect of nanoparticulate Hg and selenate is observed at the bacterial level. These interactions between Hg and Se are crucial for a better understanding of the Hg methylation process. This research will help to provide a solid foundation for a better understanding of MeHg generation in anaerobic aquatic conditions.

The threat of environmental mercury (Hg), particularly methylmercury (MeHg), exposure to the health of humans has been well documented. Thus, it is important to monitor exposure and body burden for public health protection. The first objective of this thesis was to characterize the risk of Hg exposure in two Canadian coastal communities: Grand Marian (n = 91) and St. Andrews/St. Stephen (n = 52), New Brunswick, Canada, using dietary questionnaires and hair analysis. Average Hg intakes and body burden were below the most conservative guidelines. We attributed these results to the low Hg concentrations found in the species commonly consumed: haddock, canned tuna, lobster and pollock (all below 0.2 mg/kg). The analytical method employed to determine Hg in hair, cold vapor atomic absorption (CV-AAS), required a bundle of 100-150 hair strands and involved lengthy chemical digestion procedures which reduce throughput. Direct solid introduction techniques minimize these weaknesses. Our second and third objectives were to evaluate two such methods: (1) combustion, gold amalgamation, atomic absorption spectrometry (C-GA-AAS) and (2) laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) for measuring total Hg in single hair strands. Hair samples with a wide range of Hg exposure were obtained from communities. A 1:1 relationship was observed between C-GA-AAS and the established CV-AAS for analysis of 1-cm hair segments. Additionally, the average relative standard deviation (RSD) of Hg between hair strands within an individual was 6.5 +/- 2.8%, thus justifying the use of a single hair strand for biomonitoring. With a limit of quantification of 0.10 ng of total Hg, a single hair strand with average weight of 0.5 mg and Hg concentrations of 0.2 mg/kg can be measured routinely. Using LA-ICP-MS, we showed that a single laser shot can sample hair material within 50 mum along a single hair strand which is equivalent to less than one day of