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1.  Relationship of Blood Mercury Levels to Health Parameters in the Loggerhead Sea Turtle (Caretta caretta) 
Environmental Health Perspectives  2007;115(10):1421-1428.
Mercury is a pervasive environmental pollutant whose toxic effects have not been studied in sea turtles in spite of their threatened status and evidence of immunosuppression in diseased populations.
In the present study we investigate mercury toxicity in loggerhead sea turtles (Caretta caretta) by examining trends between blood mercury concentrations and various health parameters.
Blood was collected from free-ranging turtles, and correlations between blood mercury concentrations and plasma chemistries, complete blood counts, lysozyme, and lymphocyte proliferation were examined. Lymphocytes were also harvested from free-ranging turtles and exposed in vitro to methylmercury to assess proliferative responses.
Blood mercury concentrations were positively correlated with hematocrit and creatine phosphokinase activity, and negatively correlated with lymphocyte cell counts and aspartate amino-transferase. Ex vivo negative correlations between blood mercury concentrations and B-cell proliferation were observed in 2001 and 2003 under optimal assay conditions. In vitro exposure of peripheral blood leukocytes to methylmercury resulted in suppression of proliferative responses for B cells (0.1 μg/g and 0.35 μg/g) and T cells (0.7 μg/g).
The positive correlation between blood mercury concentration and hematocrit reflects the higher affinity of mercury species for erythrocytes than plasma, and demonstrates the importance of measuring hematocrit when analyzing whole blood for mercury. In vitro immunosuppression occurred at methylmercury concentrations that correspond to approximately 5% of the individuals captured in the wild. This observation and the negative correlation found ex vivo between mercury and lymphocyte numbers and mercury and B-cell proliferative responses suggests that subtle negative impacts of mercury on sea turtle immune function are possible at concentrations observed in the wild.
PMCID: PMC2022655  PMID: 17938730
aspartate aminotransferase (AST); blood; creatine phosphokinase (CPK); hematocrit; immunotoxicity; lymphocytes; loggerhead sea turtles; mercury; methylmercury; toxicity
2.  Differential immunotoxic effects of inorganic and organic mercury species in vitro 
Toxicology letters  2010;198(2):182-190.
Despite the fact that humans are exposed to multiple forms of mercury (elemental, inorganic, and organic), most research on mercury toxicity has focused on methylmercury (MeHg) and on neurotoxic outcomes and mechanisms. Recent work has indicated that the immunotoxic effects of mercury compounds may be significant contributors to human disease as well as mechanistically relevant to other target organ toxicities. In this study, we compared the effects of inorganic Hg (iHg) to organic Hg species (MeHg and ethylmercury, EtHg) in human peripheral blood mononuclear cells (PBMCs) in vitro at sub -cytotoxic concentrations, using methods developed to characterize response of human PBMCs to iHg in vitro. PBMCs were isolated from six volunteer blood donors (3 males, 3 females) and cultured in the presence and absence of lipopolysaccharide (LPS) and low levels (up to 200 nM of each Hg species, separately) for 24 hours in culture. Cell culture supernatants were analyzed for cytokine concentrations with a bead-based multiplex assay.
We report that iHg and MeHg both increase pro-inflammatory cytokine release in LPS-stimulated PBMCs, while EtHg decreases IFN-γ release as well pro-inflammatory cytokine release. IL-17 release is significantly increased only in response to iHg treatment. Levels of anti-inflammatory cytokines (IL-1Ra and IL-10) were not significantly altered by any Hg treatment. These results indicate that both organic and inorganic species of Hg can affect the human immune system, but that they may exert different effects on immune function.
PMCID: PMC4160064  PMID: 20600710
mercury; immunotoxicity; humans; in vitro; cytokines
3.  Impaired immunity in harbour seals (Phoca vitulina) exposed to bioaccumulated environmental contaminants: review of a long-term feeding study. 
Environmental Health Perspectives  1996;104(Suppl 4):823-828.
Mass mortalities among seals and dolphins inhabiting contaminated marine regions have led to speculation about a possible involvement of immunosuppression associated with environmental pollution. To evaluate whether contaminants at ambient environmental levels can affect immune function of seals, we carried out an immunotoxicological study under semifield conditions. Two groups of 11 harbour seals (Phoca vitulina) originating from a relatively uncontaminated area were fed herring from either the highly polluted Baltic Sea or the relatively uncontaminated Atlantic Ocean. Changes in immune function were monitored over a 2 1/2-year period. The seals that were fed contaminated Baltic herring developed significantly higher body burdens of potentially immunotoxic organochlorines and displayed impaired immune responses as demonstrated by suppression of natural killer cell activity and specific T-cell responses. During a 2-week fasting experiment performed at the end of the feeding study, mobilization of organochlorines from the blubber did not lead to a strong increase of contaminant levels in the blood, and no enhancement of the existing immunosuppression was observed. These results demonstrate that chronic exposure to environmental contaminants accumulated through the food chain affects immune function in harbour seals, whereas short-term fasting periods, which are normal for seals, do not seem to pose an additional risk. The seals of this study were not exposed perinatally to high levels of environmental chemicals, and body burdens of organochlorines measured near the end of the study were lower than those generally observed in free-ranging seals inhabiting many contaminated regions. Therefore, it may be expected that environmental contaminants adversely affect immune function of free-ranging seals inhabiting contaminated regions at least as seriously as observed in these studies.
PMCID: PMC1469673  PMID: 8880005
4.  Relation between Methylmercury Exposure and Plasma Paraoxonase Activity in Inuit Adults from Nunavik 
Environmental Health Perspectives  2011;119(8):1077-1083.
Background: Methylmercury (MeHg) exposure has been linked to an increased risk of coronary heart disease (CHD). Paraoxonase 1 (PON1), an enzyme located in the high-density–lipoprotein (HDL) fraction of blood lipids, may protect against CHD by metabolizing toxic oxidized lipids associated with low-density liproprotein and HDL. MeHg has been shown to inhibit PON1 activity in vitro, but this effect has not been studied in human populations.
Objectives: This study was conducted to determine whether blood mercury levels are linked to decreased plasma PON1 activities in Inuit people who are highly exposed to MeHg through their seafood-based diet.
Methods: We measured plasma PON1 activity using a fluorogenic substrate and blood concentrations of mercury and selenium by inductively coupled plasma mass spectrometry in 896 Inuit adults. Sociodemographic, anthropometric, clinical, dietary, and lifestyle variables as well as PON1 gene variants (rs705379, rs662, rs854560) were considered as possible confounders or modifiers of the mercury–PON1 relation in multivariate analyses.
Results: In a multiple regression model adjusted for age, HDL cholesterol levels, omega-3 fatty acid content of erythrocyte membranes, and PON1 variants, blood mercury concentrations were inversely associated with PON1 activities [β-coefficient = –0.063; 95% confidence interval (CI), –0.091 to –0.035; p < 0.001], whereas blood selenium concentrations were positively associated with PON1 activities (β-coefficient = 0.067; 95% CI, 0.045–0.088; p < 0.001). We found no interaction between blood mercury levels and PON1 genotypes.
Conclusions: Our results suggest that MeHg exposure exerts an inhibitory effect on PON1 activity, which seems to be offset by selenium intake.
PMCID: PMC3237359  PMID: 21543280
Inuit; methylmercury; Nunavik; omega-3 polyunsaturated fatty acids; paraoxonase; PON1; selenium
5.  Prenatal methylmercury exposure hampers glutathione antioxidant system ontogenesis and causes long-lasting oxidative stress in the mouse brain 
Toxicology and applied pharmacology  2007;227(1):147-154.
During the perinatal period, the central nervous system (CNS) is extremely sensitive to metals, including methylmercury (MeHg). Although the mechanism(s) associated with MeHg-induced developmental neurotoxicity remains obscure, several studies point to the glutathione (GSH) antioxidant system as an important molecular target for this toxicant. To extend our recent findings of MeHg-induced GSH dyshomeostasis, the present study was designed to assess the developmental profile of the GSH antioxidant system in the mouse brain during the early postnatal period after in utero exposure to MeHg. Pregnant mice were exposed to different doses of MeHg (1, 3 and 10 mg/L, diluted in drinking water, ad libitum) during the gestational period. After delivery, pups were killed at different time points - postnatal days (PNDs) 1, 11 and 21 - and the whole brain was used for determining biochemical parameters related to the antioxidant GSH system, as well as mercury content and the levels of F2-isoprostane. In control animals, cerebral GSH levels significantly increased over time during the early postnatal period; gestational exposure to MeHg caused a dose-dependent inhibition of this developmental event. Cerebral glutathione peroxidase (GPx) and glutathione reductase (GR) activities significantly increased over time during the early postnatal period in control animals; gestational MeHg exposure induced a dose-dependent inhibitory effect on both developmental phenomena. These adverse effects of prenatal MeHg exposure were corroborated by marked increases in cerebral F2-isoprostanes levels at all time points. Significant negative correlations were found between F2-isoprostanes and GSH, as well as between F2-isoprostanes and GPx activity, suggesting that MeHg-induced disruption of the GSH system maturation is related to MeHg-induced increased lipid peroxidation in the pup brain. In utero MeHg exposure also caused a dose-dependent increase in the cerebral levels of mercury at birth. Even though the cerebral mercury concentration decreased to nearly basal levels at postnatal day 21, GSH levels, GPx and GR activities remained decreased in MeHg-exposed mice, indicating that prenatal exposure to MeHg affects the cerebral GSH antioxidant systems by inducing biochemical alterations that endure even when mercury tissue levels decrease and become indistinguishable from those noted in pups born to control dams. This study is the first to show that prenatal exposure to MeHg disrupts the postnatal development of the glutathione antioxidant system in the mouse brain, pointing to an additional molecular mechanism by which MeHg induces pro-oxidative damage in the developing CNS. Moreover, our experimental observation corroborates previous reports on the permanent functional deficits observed after prenatal MeHg exposure.
PMCID: PMC2955629  PMID: 18023834
Methylmercury; prenatal exposure; developmental neurotoxicity; glutathione; oxidative stress; antioxidant enzymes
6.  Mercury in human brain, blood, muscle and toenails in relation to exposure: an autopsy study 
Environmental Health  2007;6:30.
The main forms of mercury (Hg) exposure in the general population are methylmercury (MeHg) from seafood, inorganic mercury (I-Hg) from food, and mercury vapor (Hg0) from dental amalgam restorations. While the distribution of MeHg in the body is described by a one compartment model, the distribution of I-Hg after exposure to elemental mercury is more complex, and there is no biomarker for I-Hg in the brain. The aim of this study was to elucidate the relationships between on the one hand MeHg and I-Hg in human brain and other tissues, including blood, and on the other Hg exposure via dental amalgam in a fish-eating population. In addition, the use of blood and toenails as biological indicator media for inorganic and organic mercury (MeHg) in the tissues was evaluated.
Samples of blood, brain (occipital lobe cortex), pituitary, thyroid, abdominal muscle and toenails were collected at autopsy of 30 deceased individuals, age from 47 to 91 years of age. Concentrations of total-Hg and I-Hg in blood and brain cortex were determined by cold vapor atomic fluorescence spectrometry and total-Hg in other tissues by sector field inductively coupled plasma-mass spectrometry (ICP-SFMS).
The median concentrations of MeHg (total-Hg minus I-Hg) and I-Hg in blood were 2.2 and 1.0 μg/L, and in occipital lobe cortex 4 and 5 μg/kg, respectively. There was a significant correlation between MeHg in blood and occipital cortex. Also, total-Hg in toenails correlated with MeHg in both blood and occipital lobe. I-Hg in both blood and occipital cortex, as well as total-Hg in pituitary and thyroid were strongly associated with the number of dental amalgam surfaces at the time of death.
In a fish-eating population, intake of MeHg via the diet has a marked impact on the MeHg concentration in the brain, while exposure to dental amalgam restorations increases the I-Hg concentrations in the brain. Discrimination between mercury species is necessary to evaluate the impact on Hg in the brain of various sources of exposure, in particular, dental amalgam exposure.
PMCID: PMC2098763  PMID: 17931423
7.  Methylmercury Exposure and Health Effects 
Methylmercury is a hazardous substance that is of interest with regard to environmental health, as inorganic mercury circulating in the general environment is dissolved into freshwater and seawater, condensed through the food chain, ingested by humans, and consequently affects human health. Recently, there has been much interest and discussion regarding the toxicity of methylmercury, the correlation with fish and shellfish intake, and methods of long-term management of the human health effects of methylmercury. What effects chronic exposure to a low concentration of methylmercury has on human health remains controversial. Although the possibility of methylmercury poisoning the heart and blood vessel system, the reproductive system, and the immune system is continuously raised and discussed, and the carcinogenicity of methylmercury is also under discussion, a clear conclusion regarding the human health effects according to exposure level has not yet been drawn. The Joint FAO/WHO Expert Committee on Food Additives proposed to prepare additional fish and shellfish intake recommendations for consumers based on the quantified evaluation of the hazardousness of methylmercury contained in fish and shellfish, methylmercury management in the Korea has not yet caught up with this international trend. Currently, the methylmercury exposure level of Koreans is known to be very high. The starting point of methylmercury exposure management is inorganic mercury in the general environment, but food intake through methylation is the main exposure source. Along with efforts to reduce mercury in the general environment, food intake management should be undertaken to reduce the human exposure to methylmercury in Korea.
PMCID: PMC3514465  PMID: 23230465
Methylmercury; Health effect; Toxicity; Human exposure; Epidemiology
8.  Cardiac autonomic activity and blood pressure among Nunavik Inuit adults exposed to environmental mercury: a cross-sectional study 
Environmental Health  2008;7:29.
Mercury is a contaminant that reaches high levels in Nunavik (North of Quebec). It is transformed into methylmercury (MeHg) and accumulated in marine mammals and predator fish, an important part of the traditional Inuit diet. MeHg has been suggested to affect BP in adults and children while the influence on HRV has only been studied in children. We aimed to assess the impact of MeHg levels on HRV and BP in Inuit adults from Nunavik.
In the fall of 2004, the «Qanuippitaa?» Health Survey was conducted in Nunavik (Quebec, Canada) and information on HRV was collected among 280 adults aged 40 years and older. Indicators of the time and frequency domains of HRV were derived from a 2-hour Holter recording. BP was measured according to the Canadian Coalition for High Blood Pressure technique. Pulse pressure (PP) was the difference between systolic (SBP) and diastolic blood pressure (DBP). Blood mercury concentration was used as exposure biomarker. Statistical analysis was conducted through linear regression and multivariable linear regression was used to control for confounders.
Mercury was negatively correlated with low frequency (LF) (r = -0.18; p = 0.02), the standard deviation of RR intervals (SDNN) (r = -0.14; p = 0.047) and the coefficient of variation of RR intervals (CVRR) (r = -0.18; p = 0.011) while correlations with other HRV parameters did not reach statistical significance. After adjusting for confounders, the association with LF (beta = -0.006; p = 0.93) became non significant. However, the association with SDANN became statistically significant (beta = -0.086; p = 0.026) and CVRR tended to decrease with blood mercury concentrations (beta = -0.057; p = 0.056). Mercury was positively correlated with SBP (r = 0.25; p < 0.0001) and PP (r = 0.33; p < 0.0001). After adjusting for confounders, these associations remained statistically significant (beta SBP = 4.77; p = 0.01 and beta PP = 3.40; p = 0.0036). Moreover, most of the HRV parameters correlated well with BP although SBP the best before adjustment for mercury exposure.
The results of this study suggest a deleterious impact of mercury on BP and HRV in adults. SBP and PP increased with blood mercury concentrations while SDANN decreased with blood mercury concentrations.
PMCID: PMC2443124  PMID: 18538022
9.  Protective Effect of Prolactin against Methylmercury-Induced Mutagenicity and Cytotoxicity on Human Lymphocytes 
Mercury exhibits cytotoxic and mutagenic properties as a result of its effect on tubulin. This toxicity mechanism is related to the production of free radicals that can cause DNA damage. Methylmercury (MeHg) is one of the most toxic of the mercury compounds. It accumulates in the aquatic food chain, eventually reaching the human diet. Several studies have demonstrated that prolactin (PRL) may be differently affected by inorganic and organic mercury based on interference with various neurotransmitters involved in the regulation of PRL secretion. This study evaluated the cytoprotective effect of PRL on human lymphocytes exposed to MeHg in vitro, including observation of the kinetics of HL-60 cells (an acute myeloid leukemia lineage) treated with MeHg and PRL at different concentrations, with both treatments with the individual compounds and combined treatments. All treatments with MeHg produced a significant increase in the frequency of chromatid gaps, however, no significant difference was observed in the chromosomal breaks with any treatment. A dose-dependent increase in the mitotic index was observed for treatments with PRL, which also acts as a co-mitogenic factor, regulating proliferation by modulating the expression of genes that are essential for cell cycle progression and cytoskeleton organization. These properties contribute to the protective action of PRL against the cytotoxic and mutagenic effects of MeHg.
PMCID: PMC4199052  PMID: 25247425
methylmercury; prolactin; mutagenicity; mitotic index
10.  Are liver and renal lesions in East Greenland polar bears (Ursus maritimus) associated with high mercury levels? 
Environmental Health  2007;6:11.
In the Arctic, polar bears (Ursus maritimus) bio-accumulate mercury as they prey on polluted ringed seals (Phoca hispida) and bearded seals (Erignathus barbatus). Studies have shown that polar bears from East Greenland are among the most mercury polluted species in the Arctic. It is unknown whether these levels are toxic to liver and kidney tissue.
We investigated the histopathological impact from anthropogenic long-range transported mercury on East Greenland polar bear liver (n = 59) and kidney (n = 57) tissues.
Liver mercury levels ranged from 1.1–35.6 μg/g wet weight and renal levels ranged from 1–50 μg/g wet weight, of which 2 liver values and 9 kidney values were above known toxic threshold level of 30 μg/g wet weight in terrestrial mammals. Evaluated from age-correcting ANCOVA analyses, liver mercury levels were significantly higher in individuals with visible Ito cells (p < 0.02) and a similar trend was found for lipid granulomas (p = 0.07). Liver mercury levels were significantly lower in individuals with portal bile duct proliferation/fibrosis (p = 0.007) and a similar trend was found for proximal convoluted tubular hyalinisation in renal tissue (p = 0.07).
Based on these relationships and the nature of the chronic inflammation we conclude that the lesions were likely a result of recurrent infections and ageing but that long-term exposure to mercury could not be excluded as a co-factor. The information is important as it is likely that tropospheric mercury depletion events will continue to increase the concentrations of this toxic heavy metal in the Sub Arctic and Arctic marine food webs.
PMCID: PMC1855925  PMID: 17439647
11.  Low level methylmercury exposure affects neuropsychological function in adults 
The neurotoxic effects of methylmercury (MeHg) have been demonstrated in both human and animal studies. Both adult and fetal brains are susceptible to the effects of MeHg toxicity. However, the specific effects of adult exposures have been less well-documented than those of children with prenatal exposures. This is largely because few studies of MeHg exposures in adults have used sensitive neurological endpoints. The present study reports on the results of neuropsychological testing and hair mercury concentrations in adults (>17 yrs) living in fishing communities of Baixada Cuiabana (Mato Grosso) in the Pantanal region of Brazil.
A cross-sectional study was conducted in six villages on the Cuiaba River. Participants included 129 men and women older than 17 years of age. They were randomly selected in proportion to the age range and number of inhabitants in each village. Questionnaire information was collected on demographic variables, including education, occupation, and residence history. Mercury exposure was determined by analysis of hair using flameless atomic absorption spectrophotometry. The neurocognitive screening battery included tests from the Wechsler Memory Scale and the Wechsler Adult Intelligence Scale, Concentrated Attention Test of the Toulouse-Pierron Factorial Battery, the Manual Ability Subtests of the Tests of Mechanical Ability, and the Profile of Mood States.
Mercury exposures in this population were associated with fish consumption. The hair mercury concentration in the 129 subjects ranged from 0.56 to 13.6 μg/g; the mean concentration was 4.2 ± 2.4 micrograms/g and the median was 3.7 μg/g. Hair mercury levels were associated with detectable alterations in performance on tests of fine motor speed and dexterity, and concentration. Some aspects of verbal learning and memory were also disrupted by mercury exposure. The magnitude of the effects increased with hair mercury concentration, consistent with a dose-dependent effect.
This study suggests that adults exposed to MeHg may be at risk for deficits in neurocognitive function. The functions disrupted in adults, namely attention, fine-motor function and verbal memory, are similar to some of those previously reported in children with prenatal exposures.
PMCID: PMC165591  PMID: 12844364
12.  Analysis of Methylmercury Concentration in the Blood of Koreans by Using Cold Vapor Atomic Fluorescence Spectrophotometry 
Annals of Laboratory Medicine  2011;32(1):31-37.
Methylmercury is an organic form of mercury that is highly toxic to humans. Here, we present and establish a novel method to detect methylmercury concentrations in the blood of Koreans.
Methylmercury concentration was analyzed with an automated methylmercury analytic system (MERX, Brooks Rand Co., USA) using cold vapor atomic fluorescence spectrophotometry (CVAFS). A variety of biological materials were digested in methanolic potassium hydroxide solution. The analysis method was validated by examination of certified reference material (955c, National Institute of Standard and Technology, USA). We randomly selected 30 Korean adults (age 20 yr or older) to analyze total blood mercury and methylmercury concentrations.
The detection limit and methylmercury recovery rate using this method were 0.1 pg/L and, 99.19% (range: 89.33-104.89%), respectively. The mean blood concentration of methylmercury was 4.54±2.15 µg/L (N=30). The mean proportion of methylmercury to the total mercury concentration was 78.27% (range: 41.37-98.80%).
This study is the first report to analyze blood methylmercury concentration using CVAFS in Korea. We expect that this method will contribute to the evaluation of mercury exposure and the assessment of the toxicological impact of mercury in future studies.
PMCID: PMC3255500  PMID: 22259776
Methylmercury; Blood; Limit of detection
13.  Meeting Report: Methylmercury in Marine Ecosystems—From Sources to Seafood Consumers 
Environmental Health Perspectives  2008;116(12):1706-1712.
Mercury and other contaminants in coastal and open-ocean ecosystems are an issue of great concern globally and in the United States, where consumption of marine fish and shellfish is a major route of human exposure to methylmercury (MeHg). A recent National Institute of Environmental Health Sciences–Superfund Basic Research Program workshop titled “Fate and Bioavailability of Mercury in Aquatic Ecosystems and Effects on Human Exposure,” convened by the Dartmouth Toxic Metals Research Program on 15–16 November 2006 in Durham, New Hampshire, brought together human health experts, marine scientists, and ecotoxicologists to encourage cross-disciplinary discussion between ecosystem and human health scientists and to articulate research and monitoring priorities to better understand how marine food webs have become contaminated with MeHg. Although human health effects of Hg contamination were a major theme, the workshop also explored effects on marine biota. The workgroup focused on three major topics: a) the biogeochemical cycling of Hg in marine ecosystems, b) the trophic transfer and bioaccumulation of MeHg in marine food webs, and c) human exposure to Hg from marine fish and shellfish consumption. The group concluded that current understanding of Hg in marine ecosystems across a range of habitats, chemical conditions, and ocean basins is severely data limited. An integrated research and monitoring program is needed to link the processes and mechanisms of MeHg production, bioaccumulation, and transfer with MeHg exposure in humans.
PMCID: PMC2599767  PMID: 19079724
bioaccumulation; human health; mercury biomonitoring; mercury exposure; methylmercury
14.  The association between blood pressure and whole blood methylmercury in a cross-sectional study among Inuit in Greenland 
Environmental Health  2012;11:44.
The Inuit in Greenland have a high average consumption of marine species and are highly exposed to methylmercury, which in other studies has been related to hypertension. Data on the relation between methylmercury and hypertension is limited, especially in populations subjected to a high exposure of methylmercury. We examined the relation between whole blood mercury and blood pressure (BP) in Inuit in Greenland.
A cross-sectional population-based study among adult Inuit in Greenland was performed in 2005–2009. Information on socio-demography, lifestyle, BP, blood samples and clinical measurements was obtained – the latter after overnight fasting. BP was measured according to standardized guidelines. Whole blood mercury concentration was used as a marker of exposure. The analyses were restricted to Inuit aged 30–69 years with four Greenlandic grandparents (N = 1,861). Multivariate regression analyses with inclusion of confounders were done separately for men and women with the omission of participants receiving anti-hypertensive drugs, except for logistic regression analyses of the relation between mercury and presence of hypertension (yes/no).
The mean whole blood mercury level was 20.5 μg/L among men and 14.7 μg/L among women. In multivariate analyses adjusted for confounders, diastolic BP decreased with increasing mercury concentration. In men diastolic BP decreased significantly for each four-fold increase in mercury concentration (Beta = −0.04, standard error = 0.01, p = 0.001), while no relation between mercury and diastolic BP was found among women. For systolic BP, a similar non-statistically significant result was seen only for men (Beta = −0.02, standard error = 0.01, p = 0.06). A relation between mercury and hypertension was only found in men; the odds ratio for hypertension was 0.99 (95% CI: 0.98-0.99). No relation between quintiles of mercury and hypertension was found. The relationship between mercury and BP parameters may be non-linear: In analyses of quintiles of mercury the overall effect of mercury on BP parameters was only statistically significant for diastolic BP among men (Wald test, p = 0.01), however pairwise comparisons showed that some quintiles were not statistically different. This result is supported by LOESS modelling.
No adverse associations between whole blood mercury and blood pressure were found. With increasing whole blood mercury concentrations, diastolic BP and the risk of hypertension decreased among men in the study: this may be explained by confounding by exercise or unknown factors.
PMCID: PMC3403910  PMID: 22747793
Whole blood mercury; Blood pressure; Hypertension; Inuit; Greenland
15.  Does background postnatal methyl mercury exposure in toddlers affect cognition and behavior? 
Neurotoxicology  2009;31(1):1-9.
Because the toxicological effects of mercury (Hg) are more serious in the developing central nervous system of children than adults, there are growing concerns about prenatal and early childhood Hg exposure. This study examined postnatal methylmercury (MeHg) exposure and cognition and behavior in 780 children enrolled in the Treatment of Lead (Pb) - exposed Children clinical trial (TLC) with 396 children allocated to the succimer and 384 to the placebo groups. Mercury exposure was determined from analyses of blood drawn 1 week before randomization and 1 week after treatment began when succimer had its maximal effect on blood Pb (PbB). The baseline MeHg concentrations were 0.54 μg/L and 0.52 μg/L and post-treatment concentrations were 0.51 μg/L and 0.48 μg/L for placebo and succimer groups respectively. Because the baseline characteristics in the two groups were balanced and because succimer had little effect on MeHg concentration and no effect on the cognitive or behavioral test scores, the groups were combined in the analysis of MeHg and neurodevelopment. The children's IQ and neurobehavioral performance were tested at age 2, 5 and 7 years. We saw weak, non-significant but consistently positive associations between blood MeHg and IQ test scores in stratified, spline regression and generalized linear model data analyses. The behavioral problem scores were constant or decreased slightly with increasing MeHg concentration. Additional adjustment for PbB levels in multivariable models did not alter the conclusion for MeHg and IQ scores, but did confirm that concurrent PbB was strongly associated with IQ and behavior in TLC children. The effects of MeHg on neurodevelopmental indices did not substantially differ by PbB strata. We conclude that at the present background postnatal MeHg exposure levels of US children, adverse effects on children's IQ and behavior are not detectable.
PMCID: PMC3598585  PMID: 19969021
methylmercury; lead; children; neuropsychological tests; postnatal exposure
16.  Bioaccumulation syndrome: identifying factors that make some stream food webs prone to elevated mercury bioaccumulation 
Mercury is a ubiquitous contaminant in aquatic ecosystems, posing a significant health risk to humans and wildlife that eat fish. Mercury accumulates in aquatic food webs as methylmercury (MeHg), a particularly toxic and persistent organic mercury compound. While mercury in the environment originates largely from anthropogenic activities, MeHg accumulation in freshwater aquatic food webs is not a simple function of local or regional mercury pollution inputs. Studies show that even sites with similar mercury inputs can produce fish with mercury concentrations ranging over an order of magnitude. While much of the foundational work to identify the drivers of variation in mercury accumulation has focused on freshwater lakes, mercury contamination in stream ecosystems is emerging as an important research area. Here, we review recent research on mercury accumulation in stream-dwelling organisms. Taking a hierarchical approach, we identify a suite of characteristics of individual consumers, food webs, streams, watersheds, and regions that are consistently associated with elevated MeHg concentrations in stream fish. We delineate a conceptual, mechanistic basis for explaining the ecological processes that underlie this vulnerability to MeHg. Key factors, including suppressed individual growth of consumers, low rates of primary and secondary production, hydrologic connection to methylation sites (e.g. wetlands), heavily forested catchments, and acidification are frequently associated with increased MeHg concentrations in fish across both streams and lakes. Hence, we propose that these interacting factors define a syndrome of characteristics that drive high MeHg production and bioaccumulation rates across these freshwater aquatic ecosystems. Finally, based on an understanding of the ecological drivers of MeHg accumulation, we identify situations when anthropogenic effects and management practices could significantly exacerbate or ameliorate MeHg accumulation in stream fish.
PMCID: PMC2977981  PMID: 20536817
biomagnification; methylmercury; stream fish; trace elements; trophic transfer
17.  Effect of Marine Omega 3 Fatty Acids on Methylmercury-Induced Toxicity in Fish and Mammalian Cells In Vitro 
Methylmercury (MeHg) is a ubiquitous environmental contaminant which bioaccumulates in marine biota. Fish constitute an important part of a balanced human diet contributing with health beneficial nutrients but may also contain contaminants such as MeHg. Interactions between the marine n-3 fatty acids eicosapentaenoic acid (20:5n-3, EPA) and docosahexaenoic acid (22:6n-3, DHA) with MeHg-induced toxicity were investigated. Different toxic and metabolic responses were studied in Atlantic salmon kidney (ASK) cell line and the mammalian kidney-derived HEK293 cell line. Both cell lines were preincubated with DHA or EPA prior to MeHg-exposure, and cell toxicity was assessed differently in the cell lines by MeHg-uptake in cells (ASK and HEK293), proliferation (HEK293 and ASK), apoptosis (ASK), oxidation of the red-ox probe roGFP (HEK293), and regulation of selected toxicological and metabolic transcriptional markers (ASK). DHA was observed to decrease the uptake of MeHg in HEK293, but not in ASK cells. DHA also increased, while EPA decreased, MeHg-induced apoptosis in ASK. MeHg exposure induced changes in selected metabolic and known MeHg biomarkers in ASK cells. Both DHA and MeHg, but not EPA, oxidized roGFP in HEK293 cells. In conclusion, marine n-3 fatty acids may ameliorate MeHg toxicity, either by decreasing apoptosis (EPA) or by reducing MeHg uptake (DHA). However, DHA can also augment MeHg toxicity by increasing oxidative stress and apoptosis when combined with MeHg.
PMCID: PMC3359764  PMID: 22654480
18.  Methylmercury Exposure and Health Effects from Rice and Fish Consumption: A Review 
Methylmercury (MeHg) is highly toxic, and its principal target tissue in humans is the nervous system, which has made MeHg intoxication a public health concern for many decades. The general population is primarily exposed to MeHg through consumption of contaminated fish and marine mammals, but recent studies have reported high levels of MeHg in rice and confirmed that in China the main human exposure to MeHg is related to frequent rice consumption in mercury (Hg) polluted areas. This article reviews the progress in the research on MeHg accumulation in rice, human exposure and health effects, and nutrient and co-contaminant interactions. Compared with fish, rice is of poor nutritional quality and lacks specific micronutrients identified as having health benefits (e.g., n-3 long chain polyunsaturated fatty acid, selenium, essential amino acids). The effects of these nutrients on the toxicity of MeHg should be better addressed in future epidemiologic and clinical studies. More emphasis should be given to assessing the health effects of low level MeHg exposure in the long term, with appropriate recommendations, as needed, to reduce MeHg exposure in the rice-eating population.
PMCID: PMC2905572  PMID: 20644695
rice; fish; methylmercury exposure; nutrition; health effects
19.  Environmental Mercury and Its Toxic Effects 
Mercury exists naturally and as a man-made contaminant. The release of processed mercury can lead to a progressive increase in the amount of atmospheric mercury, which enters the atmospheric-soil-water distribution cycles where it can remain in circulation for years. Mercury poisoning is the result of exposure to mercury or mercury compounds resulting in various toxic effects depend on its chemical form and route of exposure. The major route of human exposure to methylmercury (MeHg) is largely through eating contaminated fish, seafood, and wildlife which have been exposed to mercury through ingestion of contaminated lower organisms. MeHg toxicity is associated with nervous system damage in adults and impaired neurological development in infants and children. Ingested mercury may undergo bioaccumulation leading to progressive increases in body burdens. This review addresses the systemic pathophysiology of individual organ systems associated with mercury poisoning. Mercury has profound cellular, cardiovascular, hematological, pulmonary, renal, immunological, neurological, endocrine, reproductive, and embryonic toxicological effects.
PMCID: PMC3988285  PMID: 24744824
Mercury; Toxicity; Environment
20.  Contaminant-related suppression of delayed-type hypersensitivity and antibody responses in harbor seals fed herring from the Baltic Sea. 
Environmental Health Perspectives  1995;103(2):162-167.
Recent mass mortalities among several marine mammal populations have led to speculation about increased susceptibility to viral infections as a result of contaminant-induced immunosuppression. In a 2.5-year study, we fed herring from either the relatively uncontaminated Atlantic Ocean or the contaminated Baltic Sea to two groups of captive harbor seals and monitored immune function in the seals. Seals fed the contaminated fish were less able to mount a specific immunological response to ovalbumin, as measured by in vivo delayed-type hypersensitivity (DTH) reactions and antibody responses. The skin reaction to this protein antigen was characterized by the appearance of mononuclear cells which peaked at 24 hr after intradermal administration, characteristic of DTH reactions in other animals studied. These DTH responses correlated well with in vitro tests of T-lymphocyte function, implicating this cell type in the reaction. Aryl-hydrocarbon (Ah) receptor-dependent toxic equivalent (TEQ) profiles in blubber biopsies taken from the seals implicated polychlorinated biphenyls rather than dioxins or furans in the observed immunosuppression. Marine mammal populations currently inhabiting polluted coastal environments in Europe and North America may therefore have an increased susceptibility to infections, and pollution may have played a role in recent virus-induced mass mortalities.
PMCID: PMC1519003  PMID: 7737064
21.  The Role of Canine Distemper Virus and Persistent Organic Pollutants in Mortality Patterns of Caspian Seals (Pusa caspica) 
PLoS ONE  2014;9(7):e99265.
Persistent organic pollutants are a concern for species occupying high trophic levels since they can cause immunosuppression and impair reproduction. Mass mortalities due to canine distemper virus (CDV) occurred in Caspian seals (Pusa caspica), in spring of 1997, 2000 and 2001, but the potential role of organochlorine exposure in these epizootics remains undetermined. Here we integrate Caspian seal mortality data spanning 1971–2008, with data on age, body condition, pathology and blubber organochlorine concentration for carcases stranded between 1997 and 2002. We test the hypothesis that summed PCB and DDT concentrations contributed to CDV associated mortality during epizootics. We show that age is the primary factor explaining variation in blubber organochlorine concentrations, and that organochlorine burden, age, sex, and body condition do not account for CDV infection status (positive/negative) of animals dying in epizootics. Most animals (57%, n = 67) had PCB concentrations below proposed thresholds for toxic effects in marine mammals (17 µg/g lipid weight), and only 3 of 67 animals had predicted TEQ values exceeding levels seen to be associated with immune suppression in harbour seals (200 pg/g lipid weight). Mean organonchlorine levels were higher in CDV-negative animals indicating that organochlorines did not contribute significantly to CDV mortality in epizootics. Mortality monitoring in Azerbaijan 1971–2008 revealed bi-annual stranding peaks in late spring, following the annual moult and during autumn migrations northwards. Mortality peaks comparable to epizootic years were also recorded in the 1970s–1980s, consistent with previous undocumented CDV outbreaks. Gompertz growth curves show that Caspian seals achieve an asymptotic standard body length of 126–129 cm (n = 111). Males may continue to grow slowly throughout life. Mortality during epizootics may exceed the potential biological removal level (PBR) for the population, but the low frequency of epizootics suggest they are of secondary importance compared to anthropogenic sources of mortality such as fishing by-catch.
PMCID: PMC4079250  PMID: 24987857
22.  Experimental and Natural Warming Elevates Mercury Concentrations in Estuarine Fish 
PLoS ONE  2013;8(3):e58401.
Marine food webs are the most important link between the global contaminant, methylmercury (MeHg), and human exposure through consumption of seafood. Warming temperatures may increase human exposure to MeHg, a potent neurotoxin, by increasing MeHg production as well as bioaccumulation and trophic transfer through marine food webs. Studies of the effects of temperature on MeHg bioaccumulation are rare and no study has specifically related temperature to MeHg fate by linking laboratory experiments with natural field manipulations in coastal ecosystems. We performed laboratory and field experiments on MeHg accumulation under varying temperature regimes using the killifish, Fundulus heteroclitus. Temperature treatments were established in salt pools on a coastal salt marsh using a natural temperature gradient where killifish fed on natural food sources. Temperatures were manipulated across a wider range in laboratory experiments with killifish exposed to MeHg enriched food. In both laboratory microcosms and field mesocosms, MeHg concentrations in killifish significantly increased at elevated temperatures. Moreover, in field experiments, other ancillary variables (salinity, MeHg in sediment, etc.) did not relate to MeHg bioaccumulation. Modeling of laboratory experimental results suggested increases in metabolic rate as a driving factor. The elevated temperatures we tested are consistent with predicted trends in climate warming, and indicate that in the absence of confounding factors, warmer sea surface temperatures could result in greater in bioaccumulation of MeHg in fish, and consequently, increased human exposure.
PMCID: PMC3595298  PMID: 23554891
23.  Evidence on the Human Health Effects of Low-Level Methylmercury Exposure 
Environmental Health Perspectives  2012;120(6):799-806.
Background: Methylmercury (MeHg) is a known neuro-toxicant. Emerging evidence indicates it may have adverse effects on the neuro-logic and other body systems at common low levels of exposure. Impacts of MeHg exposure could vary by individual susceptibility or be confounded by bene-ficial nutrients in fish containing MeHg. Despite its global relevance, synthesis of the available literature on low-level MeHg exposure has been limited.
Objectives: We undertook a synthesis of the current knowledge on the human health effects of low-level MeHg exposure to provide a basis for future research efforts, risk assessment, and exposure remediation policies worldwide.
Data sources and extraction: We reviewed the published literature for original human epidemio-logic research articles that reported a direct biomarker of mercury exposure. To focus on high-quality studies and those specifically on low mercury exposure, we excluded case series, as well as studies of populations with unusually high fish consumption (e.g., the Seychelles), marine mammal consumption (e.g., the Faroe Islands, circumpolar, and other indigenous populations), or consumption of highly contaminated fish (e.g., gold-mining regions in the Amazon).
Data synthesis: Recent evidence raises the possibility of effects of low-level MeHg exposure on fetal growth among susceptible subgroups and on infant growth in the first 2 years of life. Low-level effects of MeHg on neuro-logic outcomes may differ by age, sex, and timing of exposure. No clear pattern has been observed for cardio-vascular disease (CVD) risk across populations or for specific CVD end points. For the few studies evaluating immunologic effects associated with MeHg, results have been inconsistent.
Conclusions: Studies targeted at identifying potential mechanisms of low-level MeHg effects and characterizing individual susceptibility, sexual dimorphism, and non-linearity in dose response would help guide future prevention, policy, and regulatory efforts surrounding MeHg exposure.
PMCID: PMC3385440  PMID: 22275730
birth outcomes; cardio-vascular disease; epidemiology; health outcomes; low-level exposure; metals; methylmercury; neuro-logic outcomes
24.  Fetal and maternal immune responses to methylmercury exposure: a cross-sectional study 
Environmental research  2011;111(4):584-589.
Methylmercury (MeHg) is a ubiquitous environmental contaminant with known neurodevelopmental effects. In humans, prenatal exposures primarily occur through maternal consumption of contaminated fish. In this study, we evaluated the association between prenatal exposure to MeHg and titers of total immunoglobulins (Ig) and specific autoantibodies in both mothers and fetuses by analyzing maternal and cord blood serum samples. We examined multiple immunoglobulin isotypes to determine if these biomarkers could inform as to fetal or maternal responses since IgG but not IgM can cross the placenta. Finally, we evaluated serum cytokine levels to further characterize the immune response to mercury exposure.
The study was conducted using a subset of serum samples (N=61 pairs) collected from individuals enrolled in a population surveillance of MeHg exposures in the Brazilian Amazon during 2000/2001. Serum titers of antinuclear and antinucleolar autoantibodies were measured by indirect immunofluorescence. Serum immunoglobulins were measured by enzyme-linked immunosorbent assay (ELISA) and BioPlex multiplex assay. Serum cytokines were measured by BioPlex multiplex assay.
In this population, the geometric mean mercury level was within the 95th percentile for US populations of women of childbearing age but the upper level of the range was significantly higher. Fetal blood mercury levels were higher (1.35 times) than those in their mothers, but highly correlated (correlation coefficient [r]=0.71; 95% CI: 0.54, 0.89). Total IgG (r=0.40; 95% CI: 0.19, 0.62) and antinuclear autoantibody (odds ratio [OR]=1.05; 95% CI: 1.02, 1.08) levels in paired maternal and fetal samples were also associated; in contrast, other immunoglobulin (IgM, IgE, and IgA) levels were not associated between pairs. Total IgG levels were significantly correlated with both maternal (r=0.60; 95% CI: 0.25, 0.96) and cord blood mercury levels (r=0.61; 95% CI: 0.25, 0.97), but individual isotypes were not. Serum cytokines, interleukin-1β (r=0.37; 95% CI: 0.01, 0.73), interleukin-6 (r=0.34; 95% CI: 0.03, 0.65), and tumor necrosis factor-α (r=0.24; 95% CI: 0.015, 0.47), were positively correlated between maternal and fetal samples. Antinuclear and antinucleolar autoantibody titer and serum cytokine levels, in either maternal or cord blood, were not significantly associated with either maternal or cord blood mercury levels.
These data provide further evidence that there are likely IgG biomarkers of mercury-induced immunotoxicity in this population since IgG levels were elevated with increased, and associated with, mercury exposure. However, unlike previous data from adult males and non-pregnant females, we found no evidence that antinuclear and antinucleolar autoantibody titer is a reliable biomarker of mercury immunotoxicity in this population.
PMCID: PMC3081921  PMID: 21396635
Autoimmune; mercury; fetal; immunotoxicity
25.  Mercury-Selenium Relationships in Liver of Guiana Dolphin: The Possible Role of Kupffer Cells in the Detoxification Process by Tiemannite Formation 
PLoS ONE  2012;7(7):e42162.
Top marine predators present high mercury concentrations in their tissues as consequence of biomagnification of the most toxic form of this metal, methylmercury (MeHg). The present study concerns mercury accumulation by Guiana dolphins (Sotalia guianensis), highlighting the selenium-mediated methylmercury detoxification process. Liver samples from 19 dolphins incidentally captured within Guanabara Bay (Rio de Janeiro State, Brazil) from 1994 to 2006 were analyzed for total mercury (THg), methylmercury (MeHg), total organic mercury (TOrgHg) and selenium (Se). X-ray microanalyses were also performed. The specimens, including from fetuses to 30-year-old dolphins, comprising 8 females and 11 males, presented high THg (0.53–132 µg/g wet wt.) and Se concentrations (0.17–74.8 µg/g wet wt.). Correlations between THg, MeHg, TOrgHg and Se were verified with age (p<0.05), as well as a high and positive correlation was observed between molar concentrations of Hg and Se (p<0.05). Negative correlations were observed between THg and the percentage of MeHg contribution to THg (p<0.05), which represents a consequence of the selenium-mediated methylmercury detoxification process. Accumulation of Se-Hg amorphous crystals in Kupffer Cells was demonstrated through ultra-structural analysis, which shows that Guiana dolphin is capable of carrying out the demethylation process via mercury selenide formation.
PMCID: PMC3409158  PMID: 22860072

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