Low level and sub-chronic exposure to methylmercury induces hypertension in rats: Nitric oxide depletion and oxidative damage as possible mechanisms

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP 14040-903, Brazil.
Archives of Toxicology (Impact Factor: 5.98). 06/2009; 83(7):653-62. DOI: 10.1007/s00204-009-0437-8
Source: PubMed

ABSTRACT Increased risk of hypertension after methylmercury (MeHg) exposure has been suggested. However, the underlying mechanisms are not well explored. In this paper, we have analyzed whether sub-chronic exposure to MeHg increases systolic blood pressure even at very low levels. In addition, we analyzed if the methylmercury-induced hypertension is associated with a decreased plasmatic nitric oxide levels and with a dysregulation of the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), as well as the levels of MDA and glutathione. For this study, Wistar rats were treated with methylmercury chloride (100 microg/kg per day) or vehicle. Total treatment time was 100 days. Malondialdehyde (MDA) and circulating NOx levels and superoxide dismutase (SOD) and catalase (CAT) activities were determined in plasma, whereas glutathione levels were determined in erythrocytes. Our results show that long-term treatment at a low level of MeHg affected systolic blood pressure, increasing and reducing the levels of plasmatic MDA and NOx, respectively. However, the activity of SOD did not decrease in the MeHg exposed group when compared to the control. We found a negative correlation between plasmatic nitrite/nitrate (NOx) levels and systolic blood pressure (r = -0.67; P = 0.001), and a positive correlation between MDA and systolic blood pressure (r = 0.61; P = 0.03), thus suggesting increased inhibition of NO formation with the increase of hypertension. In conclusion, long-term exposure to a low dose of MeHg increases the systolic pressure and is associated, at least in part, with increased production of ROS as judged by increased production of malondialdehyde and depressed NO availability.

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Available from: Gustavo Rafael Mazzaron Barcelos, Feb 24, 2015
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    • "In contrast, methylmercury exposure in rats (0.5 mg MeHg/kg-bw oral gavage for 23–28 days or a 10-fold higher dose) led to latent increases in systolic blood pressure either at 42 days or immediately after exposure, respectively (Wakita, 1987). In another study, rats gavaged with 100 mg/kg-bw/d methylmercury for 100 days also had significantly increased systolic blood pressure after four weeks (Grotto et al., 2009). Therefore, animal studies are highly suggestive of a causative association between methylmercury exposure and adverse cardiovascular effects, while the relationship between inorganic mercury and cardiovascular effects are unclear. "
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    ABSTRACT: Cardiovascular diseases, such as heart attack and stroke, are the major cause of death worldwide. It is well known that a high number of environmental and physiological risk factors contribute to the development of cardiovascular diseases. Although risk factors are additive, increased blood pressure (hypertension) is the greatest risk factor. Over the last two decades, a growing number of epidemiological studies associate environmental exposure to lead or mercury species with hypertension. However, cardiovascular effects beyond blood pressure are rarely studied and thresholds for effect not yet clear. To explore effects of lead or mercury species on the cardiovascular system, normal male Wistar rats were exposed to a range of doses of lead, inorganic mercury or methylmercury through the drinking water for four weeks. High-resolution ultrasound was used to measure heart and vascular function (carotid artery blood flow) at baseline and at the end of the exposure, while blood pressure was measured directly in the femoral artery at the end of the 4-week exposure. After 4 weeks, blood pressure responses to lead were biphasic. Low lead levels decreased blood pressure, dilated the carotid artery and increased cardiac output. At higher lead doses, rats had increased blood pressure. In contrast, methylmercury-exposed rats had increased blood pressure at all doses despite dilated carotid arteries. Inorganic mercury did not show any significant cardiovascular effects. Based on the current study, the Benchmark Dose Level 10% (BMDL10s) for systolic blood pressure for lead, inorganic mercury and methylmercury are 1.1, 1.3 and 1.0 μg/kg-bw/d, respectively. However, similar total mercury blood levels attributed to inorganic mercury or methylmercury produced strikingly different results with inorganic mercury having no observable effect on the cardiovascular system but methylmercury increasing systolic and pulse pressures. Therefore, adverse cardiovascular effects cannot be predicted by total blood mercury level alone and the mercury species of exposure must be taken into account.
    Toxicology 12/2014; DOI:10.1016/j.tox.2014.11.009 · 3.62 Impact Factor
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    • "Mercury vapor doses from dental amalgam fillings by industrial standards are considered to be small at any given point in time, but given that exposure to amalgams is essentially lifelong it can be argued that the current thresholds for mercury exposure should be lowered [22]. Recent research on rats has speculated on particular mechanisms through which low, constant exposure to mercury negatively affected body systems [23,24]. A review on the health of humans and low levels of mercury concluded that the evidence base was too small to quantify the risk of chronic exposure to mercury [25]. "
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    ABSTRACT: The objective of this study was to quantify the relationship between number of dental amalgam surfaces and urinary mercury levels. This study uses participant data from a large philanthropic chronic disease prevention program in Calgary, Alberta, Canada. Urine samples were analysed for mercury levels (measured in mug/g-creatinine). T-tests were used to determine if differences in urine mercury were statistically significant between persons with no dental amalgam surfaces and one or more dental amalgam surfaces. Linear regression was used to estimate the change in urinary mercury per amalgam surface. Urinary mercury levels were statistically significantly higher in participants with amalgam surfaces, with an average difference of 0.55 mug/g-creatinine. Per amalgam surface, we estimated an expected increase of 0.04 mug/g-creatinine. Measured urinary mercury levels were also statistically significantly higher in participants with dental amalgam surfaces following the oral administration of 2,3-dimercaptopropane-l-sulfonate (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) which are used to mobilize mercury from the blood and tissues. Our estimates indicate that an individual with seven or more dental amalgam surfaces has 30% to 50% higher urinary mercury levels than an individual without amalgams. This is consistent with past literature that has identified seven amalgam surfaces as an unsafe level of exposure to mercury vapor. Our analysis suggests that continued use of silver amalgam dental fillings for restorative dentistry is a non-negligible, unnecessary source of mercury exposure considering the availability of composite resin alternatives.
    Journal of Occupational Medicine and Toxicology 08/2013; 8(1):22. DOI:10.1186/1745-6673-8-22 · 1.62 Impact Factor
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    • "One of the main mechanisms responsible for the toxicity of Hg is the induction of oxidative stress [4] [5] [6]. In several in vitro and in vivo studies, genotoxic effects of inorganic and organic forms of the metal were detected [7] [8] [9] and it is possible that its DNA-damaging properties are related to its adverse health effects in humans such as induction of cancer, neurological disorders and cardiovascular diseases [10] [11] [12]. Consumption of foods that contain antioxidants is known to counteract the toxic effects of certain metals including Hg [13] [14] [15] [16]. "
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    ABSTRACT: Aim of this study was to investigate the cytotoxic and genotoxic properties of inorganic and organic mercury compounds, i.e., HgCl(2) and methylmercury (MeHg). In addition, the DNA-protective and antioxidant effects of the flavonoid quercetin (QC) were studied. All experiments were conducted with human-derived liver cells (HepG2), which possess antioxidant and drug-metabolizing enzymes in an inducible form. 8-Hydroxydeoxyguanosine (8-OHdG) and comet formation were monitored as endpoints of DNA damage. The impact of the metal compounds on the redox status was also investigated, since it is assumed that their toxic effects are due to oxidative damage. A number of biochemical parameters related to oxidative stress, namely glutathione, malondialdehyde, protein carbonyl and formation of reactive oxygen species (ROS) were measured after treatment of the cells with the mercury compounds in the presence and absence of quercetin. To elucidate the mechanisms that underlie the effects of QC, three protocols (pre-, simultaneous and post-treatment) were used. Both mercury compounds (range 0.1-5.0μM) caused induction of DNA migration and formation of 8-OHdG. In combination with the flavonoid (range 0.1-5.0μM), DNA-protective effects of QC were observed after pre- and simultaneous treatment but not when the flavonoid was added after treatment with the metal compounds. Exposure to the metal compounds led also to substantial changes of all parameters of the redox status and co-treatment experiments with QC showed that these alterations are reversed by the flavonoid. Taken together, the results of our experiments indicate that these two mercury compounds cause DNA damage and oxidative stress in human-derived liver cells and that the flavonoid reduces these effects. Since the concentrations of the metals and of the flavonoids used in the present work reflect human exposure, our findings can be taken as an indication that QC may protect humans against the adverse effects caused by the metal.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 07/2011; 726(2):109-15. DOI:10.1016/j.mrgentox.2011.05.011 · 3.68 Impact Factor
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