The effects of methylmercury on mitochondrial function and reactive oxygen species formation in rat striatal synaptosomes are age-dependent

New York State Department of Health, Wadsworth Center, Albany, New York, 12201, USA.
Toxicological Sciences (Impact Factor: 3.85). 10/2005; 87(1):156-62. DOI: 10.1093/toxsci/kfi224
Source: PubMed


Methylmercury (MeHg) is especially toxic to the developing central nervous system. In order to understand the reasons for this age-dependent vulnerability, we compared the effects of MeHg on formation of reactive oxygen species (ROS) and mitochondrial function in striatal synaptosomes obtained from rats of various ages. Basal ROS levels were greater, and basal mitochondrial function was lower, in synaptosomes from younger animals, compared to adult animals. MeHg induced ROS formation in synaptosomes from rats of all ages, although the increases were greatest in synaptosomes from the younger animals. MeHg also reduced mitochondrial metabolic function, as assessed by MTT reduction, as well as mitochondrial membrane potential; again, the greatest changes were seen in synaptosomes from early postnatal animals. These age-dependent differences in susceptibility to MeHg are most likely due to a less efficient ROS detoxifying system and lower activity of mitochondrial enzymes in tissue from young animals.

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    • "MeHgCl was sufficient to impede NADH formation by mitochondria . The formation of formazan precipitate as indicated by the MTT assay takes place only in functionally intact mitochondria and provides another measure of mitochondrial metabolic function (Dreiem et al., 2005). In addition, MeHgCl exposure did not induce any observable change in the protein expression of various respiratory complex subunits suggesting that impacts on bioenergetics we observe are not due to changes of protein expression of complexes but of inhibition of complex activity. "
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    ABSTRACT: It has been reported that chronic low dose exposures of methylmercury (MeHg) is associated with cardiovascular diseases in many populations worldwide. The toxic mechanisms through which these adverse effects occur are currently unknown. The objective of this study was to determine the bioenergetic and cytotoxic effects of MeHg on AC16 and H9C2 cardiomyocyte cell lines. Both cell lines exhibit significantly decreased mitochondrial function, cell viability and increased reactive oxygen species (ROS) production. Decreases in maximal respiration and reserve capacity was observed in both cell lines at 1 μM. Bioenergetic profile experiments were also performed in tandem with cells exposed to diamide or menadione, compounds which accumulate in mitochondria and disrupt oxidative phosphorylation. AC16 cells show MeHg dose dependant sensitivities with Stateapparent and ATP production values, but H9C2 cells do not show these trends. H9C2 cells may be more resistant to MeHg toxicity than AC16 cells as reflected in the increases of proton leak and Stateapparent. No changes in expression of respiratory complexes were observed. Results suggest that MeHg has the potential to induce cytotoxicity. Furthermore, MeHg may have differential effects on AC16 and H9C2 cells, derived from human and rat cardiac tissue respectively, suggesting that differences in MeHg toxicity may be species-dependent. Copyright © 2015. Published by Elsevier Ltd.
    Toxicology in Vitro 03/2015; 29(5). DOI:10.1016/j.tiv.2015.03.016 · 2.90 Impact Factor
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    • "Despite these observations, there is evidence that the fetal brain is more susceptible than infantile brain to MeHg toxicity. Differences among gestation stage, exposure duration, and efficacy of antioxidant systems in developing brain might be determinant factors in the age-dependent neuronal vulnerability to MeHg [4, 8–10]. "
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    ABSTRACT: Methylmercury (MeHg) mediated cytotoxicity is associated with loss of intracellular calcium (Ca²⁺) homeostasis. The imbalance in Ca²⁺ physiology is believed to be associated with dysregulation of Ca²⁺ intracellular stores and/or increased permeability of the biomembranes to this ion. In this paper we summarize the contribution of glutamate dyshomeostasis in intracellular Ca²⁺ overload and highlight the mitochondrial dysfunctions induced by MeHg via Ca²⁺ overload. Mitochondrial disturbances elicited by Ca²⁺ may involve several molecular events (i.e., alterations in the activity of the mitochondrial electron transport chain complexes, mitochondrial proton gradient dissipation, mitochondrial permeability transition pore (MPTP) opening, thiol depletion, failure of energy metabolism, reactive oxygen species overproduction) that could culminate in cell death. Here we will focus on the role of oxidative stress in these phenomena. Additionally, possible antioxidant therapies that could be effective in the treatment of MeHg intoxication are briefly discussed.
    BioMed Research International 07/2012; 2012:248764. DOI:10.1155/2012/248764 · 2.71 Impact Factor
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    • "A number of mechanisms have been proposed to be involved in MeHg toxicity, including alterations in calcium homeostasis (Komulainen and Bondy, 1987; Marty and Atchison, 1997) and apoptosis/necrosis (Kunimoto, 1994). Additionally, in the recent years, several studies have implicated the formation of reactive oxygen species (ROS) (Yee and Choi, 1994, 1996; Dreiem et al., 2005) and disruption of mitochondrial function (Hare and Atchison, 1992; Limke and Atchison, 2002) as two key mechanisms in MeHg-induced toxicity. Previously, Ali et al. (1992) reported increased rates of formation of ROS in methylmercury-treated rats. "
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    ABSTRACT: Methylmercury (MeHg) is an environmental contaminant that is found in many ecosystems. Many studies reported that MeHg toxicity is accompanied by increased lipid peroxidation that may lead to oxidative damage to DNA, RNA, and proteins. Vitamin E is considered as the most effective antioxidant preventing lipid peroxidation. The aim of this study was to evaluate the effects of MeHg exposure during pregnancy on the development of the appendicular skeleton in rat fetuses and whether vitamin E administration could reduce this toxicity. Positively mated adult female Sprague-Dawley rats were used and divided into the following experimental groups: control group, received only deionized water, and four MeHg treated groups received 1 mg of MeHg/kg/d, 2 mg of MeHg/kg/d, 1 mg of MeHg/kg/d plus 150 mg of vitamin E/kg/d, and 2 mg of MeHg/kg/d, plus 150 mg of vitamin E/kg/d starting from Day 0 of gestation. On Day 20 of gestation, the fetuses from the pregnant rats were extracted and the fetal growth parameters were evaluated. Skeletal evaluation of ossification of both fore- and hind-limbs, and coxal bones were undertaken. Results showed that treatment with MeHg caused adverse effects on fetal growth parameters and ossification of the bones. The coadministration of vitamin E with MeHg revealed an improvement in these parameters. These results suggest that vitamin E may ameliorate some aspects of MeHg developmental toxicity. The underlying and human health implications warrant further investigations.
    The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 06/2012; 295(6):939-49. DOI:10.1002/ar.22485 · 1.54 Impact Factor
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