In a group of 465 patients diagnosed as having chronic mercury toxicity (CMT), 32.3% had severe fatigue, 88.8% had memory loss, and 27.5% had depression. A significant correlation was found between CMT and the Apo-lipoprotein E4 genotype (p=0.001). An investigation into an additional 864 consecutively seen general practice patients, resulted in 30.3% having evidence consistent with CMT, and once again a significant correlation was found with the APO-E4 genotype (p=0.001). Removal of amalgam mercury fillings when combined with appropriate treatment resulted in a significant symptom reduction (p<0.001) to levels reported by healthy subjects.

Mercury has been measured in Danish medieval bones interred at several cemeteries. Bone diagenesis is estimated to play an insignificant role based on measurements of soil samples taken vertically and horizontally away from the thighbone at three graves. Our study shows that mercury-containing medicine has been administered in 79% of the leprosy cases and 40% of the syphilis cases. A substantial number of the monks interred in the cloister walk of the Cistercian Abbey at Øm show heavily increased mercury levels, whereas none of the friars interred in the Franciscan Friary of Svendborg show elevated mercury concentrations. This is interpreted as originating either from exposure to mercury-containing red ink in the scriptorium of the Abbey, or perhaps slightly more likely, from preparing or administering mercury-containing medicine in the hospital of the Abbey.

Exposure to mercury has been linked to elevations in blood pressure (BP), though few data are available. We examined the cross-sectional relationship between blood mercury concentration and BP in a representative US sample of 1240 women, aged 16–49 years, from the National Health and Nutrition Examination Survey 1999–2000. We found no association overall between mercury and BP in multivariate models. We stratified our data by dietary fish intake (presumably reflecting the consumption of long-chain n-3 fatty acids that may reduce BP) resulting in 759 fish consumers and 481 non-fish consumers. We found that for each 1.3 μg/L (interquartile distance) increase in mercury, systolic BP significantly increased by 1.83 mm Hg (95% CI: 0.36, 3.30) among non-fish consumers. A similar pattern was seen for diastolic BP, although it was non-significant. While an adverse effect of mercury exposure at background levels on BP was not present overall, an adverse association was present among non-fish-consuming young and middle-aged women.

Background Data on mercury exposure of the Austrian population were inadequate. This study was performed to determine the causal factors underlying mercury exposure and selenium concentrations, and to estimate the gender-related health impacts.

Methodology Venous blood samples of 78 women and 81 men were drawn at the Austrian Red Cross, Vienna. Mercury contents in acid-digested whole blood samples were measured after amalgam enrichment by CV-AAS, and selenium by AAS (heated quartz-cell) after hydrid formation.

Results The average total mercury blood content of Austrians was low (2.38 ± 1.55 μgL− 1; N = 152). Mercury and selenium concentrations were not different between the genders (P > 0.05) but we observed discrepancies regarding the causal factors. Mercury levels in men were influenced not only by fish consumption but also by age, education level, and amalgam fillings, whereas in women, only the diet (fish/seafood, red wine consumption) determined blood mercury (P < 0.05). Moreover, only the males indicated a depressive effect of dental amalgam on hematocrit (P < 0.05). Regarding selenium, age and alcohol consumption led to lower concentrations in men, whereas a high-level education had the opposite effect; no determinant was found for women. For the whole study group, a significant effect of chronic disease on selenium levels could be detected (P < 0.05). 18% of women and 13% of men showed marginal selenium deficiency (blood selenium < 65 μgL− 1). Selenium and mercury concentrations were not correlated.

Conclusions Our results indicate the need to evaluate and integrate gender-related findings in metal toxicology and trace element research, because different causal factors require different preventive measures to reduce mercury exposure and the risk of low selenium concentrations. Future research is needed on the gender- and age-related differences in fish/seafood consumption habits, the modifications of mercury toxicokinetics through sex hormones, the selenium supply in Austria, and the clinical relevance of a low selenium status.

The association between environmentally released mercury, special education and autism rates in Texas was investigated using data from the Texas Education Department and the United States Environmental Protection Agency. A Poisson regression analysis adjusted for school district population size, economic and demographic factors was used. There was a significant increase in the rates of special education students and autism rates associated with increases in environmentally released mercury. On average, for each 1000 lb of environmentally released mercury, there was a 43% increase in the rate of special education services and a 61% increase in the rate of autism. The association between environmentally released mercury and special education rates were fully mediated by increased autism rates. This ecological study suggests the need for further research regarding the association between environmentally released mercury and developmental disorders such as autism. These results have implications for policy planning and cost analysis.

Introduction. Asians, Pacific Islanders, and Native Americans are a potentially high-risk group for dietary exposure to methylmercury through fish consumption. However, blood mercury levels in this group have not been identified in recent reports of the National Health and Nutrition Examination Survey (NHANES) for the years 1999–2002.

Methods. We used NHANES data from 1999–2002 to obtain population estimates of blood mercury levels among women of childbearing age classified as belonging to the “other” racial/ethnic group (Asian, Pacific Islander, Native American, and multiracial; n = 140). Blood mercury levels in this group were compared with those among all other women participants, classified as Mexican American, non-Hispanic black, non-Hispanic white, and “other” Hispanic.

Results. An estimated 16.59 ± 4.0% (mean ± SE) of adult female participants who self-identified as Asian, Pacific Islander, Native American, or multiracial (n = 140) had blood mercury levels ≥5.8 μg/L, and 27.26 ± 4.22% had levels ≥3.5 μg/L. Among remaining survey participants (n = 3,497), 5.08 ± 0.90% had blood mercury levels ≥5.8 μg/L, and 10.86 ± 1.45% had levels ≥3.5 μg/L.

Conclusions. Study subjects in NHANES who self-identified as Asian, Pacific Islander, Native American, or multiracial had a higher prevalence of elevated blood mercury than all other racial/ethnic participants in the survey. Future studies should address reasons for the high mercury levels in this group and explore possible interventions for lowering risk of methylmercury exposure in this population.

A 14-year-old boy was seen because of irritability, insomnia, lethargy, and profusesweating, together with hypertension (blood pressure: 160/120 mm Hg), tachycardia, and a diffuse erythematous rash with desquamation of the palms and soles. Initial biochemical investigation suggested a diagnosis of pheochromocytoma, but subsequently a history of exposure to mercury vapor was obtained. This case emphasizes the clinical and blochemical similarities between mercury poisoning (acrodynia) and pheochromocytoma.

Fish is an important item in the diet of Amazonians, and per se is their best single source of essential nutrients. Rapid urbanization and migration are bringing changes in dietary habits of Amazonians. Exposure to fish-Hg during pregnancy and lactation were studied in 100 women and newborns from Porto Velho. Tissue-Hg concentrations and neurodevelopment (Gesell Developmental Schedules) were assessed at birth and at 6 months in exclusively breastfed infants. Maternal mean frequency of fish consumption was low (<2 meals/week; range 0–>7 meals/week) compared to Amazonian standards. Women consuming <2 fish meals/week showed less median hair-Hg (3.5 μg g−1) than women that consumed 2 fish meals/week (5.7 μg g).

Median total Hg in maternal hair (5.4 μg g−1) was higher than in newborns (1.6 μg g−1). Significant correlation was observed between maternal hair-Hg and infant hair-Hg at birth (r=0.353; p<0.01) and at six months (r=0.510; p<0.01). Placenta-Hg was also significantly correlated to maternal hair-Hg (r=0.321; p<0.01), newborn hair-Hg (r=0.219; p<0.05), maternal blood-Hg (r=0.250; p<0.01) and to umbilical cord-Hg (r=0.857; p<0.01). Most infants (74%) had normal Gesell Schedules but among the 26% showing neuro-motor development delays only six (7%) had multiple (motor, language, and adaptative) delays. The infants with multiple delays were born from mothers with range of hair-Hg comparable to mothers of normally developed infants. Coincidentally, mothers of infants with multiple delays also showed the lowest range of income and level of education. Fish consumption, income, and level of education varied greatly among these breastfeeding urban mothers. It seems that development delays of exclusively breastfed infants are a component of the health inequalities that accompanies socioeconomic disadvantages.

Methylmercury (MeHg) is one of the most risky substances to affect humans through fish consumption, and the fetus is known to be in the most susceptible group. Our objective in this study is to examine the relationships of total mercury (THg) and MeHg concentrations between umbilical cord tissue and other tissues as biomarkers of fetal exposure to MeHg in the Japanese population. In total, 116 paired samples were collected in three Japanese districts, the Tsushima Islands, Fukuoka City, and Katsushika ward of metropolitan Tokyo. THg was measured for hair and THg and MeHg were measured in cord tissues, maternal blood, and cord blood. The relationships among tissues in Hg concentrations were similar among districts. Therefore, we analyzed the relationships using all the samples. More than 90% of Hg in cord tissue, cord blood, and maternal blood was MeHg. THg and MeHg in cord blood was about two times higher than in maternal blood. A strong correlation was found between THg and MeHg in cord tissue. The cord tissue THg and MeHg showed a strong correlation with cord blood Hg, which is recognized as the best biomarker for fetal exposure to MeHg. The findings of this study indicate the significance of cord tissue THg and MeHg as biomarkers for fetal exposure to MeHg at parturition.

Methyl mercury is a developmental neurotoxicant. Exposure results principally from consumption by pregnant women of seafood contaminated by mercury from anthropogenic (70%) and natural (30%) sources. Throughout the 1990s, the U.S. Environmental Protection Agency (EPA) made steady progress in reducing mercury emissions from anthropogenic sources, especially from power plants, which account for 41% of anthropogenic emissions. However, the U.S. EPA recently proposed to slow this progress, citing high costs of pollution abatement. To put into perspective the costs of controlling emissions from American power plants, we have estimated the economic costs of methyl mercury toxicity attributable to mercury from these plants. We used an environmentally attributable fraction model and limited our analysis to the neurodevelopmental impacts—specifically loss of intelligence. Using national blood mercury prevalence data from the Centers for Disease Control and Prevention, we found that between 316,588 and 637,233 children each year have cord blood mercury levels > 5.8 μg/L, a level associated with loss of IQ. The resulting loss of intelligence causes diminished economic productivity that persists over the entire lifetime of these children. This lost productivity is the major cost of methyl mercury toxicity, and it amounts to $8.7 billion annually (range, $2.2–43.8 billion; all costs are in 2000 US$). Of this total, $1.3 billion (range, $0.1–6.5 billion) each year is attributable to mercury emissions from American power plants. This significant toll threatens the economic health and security of the United States and should be considered in the debate on mercury pollution controls.

Research on the pathogenesis of nonischemic dilated cardiomyopathy (DCM) has largely been focused on the role of viral pathogens and altered immunity. Trace elements have only rarely been considered; however, clinical observations that trace elements influence cardiovascular disease have been made in populations with extreme dietary deficiency or occupational exposure. Recently, animal models of DCM have been used to explore interactions among trace elements, viral pathogens, and the immune system. Discovery of interactions of trace elements with causes for DCM has heightened awareness of potential contributions of environmental variables to DCM pathogenesis. This article reviews the present knowledge regarding trace elements, in particular selenium and mercury, in the pathogenesis of viral and immune-mediated DCM. Based on recent studies, the authors propose a novel paradigm for the pathogenesis of viral DCM that incorporates trace element imbalance and its interactions with the cellular physiology of viral-induced cardiomyocyte dysfunction.

To investigate the relations among total mercury levels in hair, toenail, and urine, together with potential effects of methylmercury intake on renal tubular function, we determined their levels, and urinary N-acetyl-β-d-glucosaminidase activity (NAG) and α1-microglobulin (AMG) in 59 women free from occupational exposures, and estimated daily mercury intakes from fish and other seafood using a food frequency questionnaire. Mercury levels (mean±SD) in the women were in hair, in toenail, and creatinine in urine; and, there were positive correlations among them (P<0.001). The daily mercury intake of was significantly correlated with total mercury levels in hair, toenail, and urine (r=0.551, 0.537, and 0.604, P<0.001). Among the women, the NAG and AMG were positively correlated with both the daily mercury intake and mercury levels in hair, toenail, and urine (P<0.01); and, these relations were almost similar when using multiple regression analysis to adjust for possible confounders such as urinary cadmium ( creatinine) and smoking status. In conclusion, mercury resulting from fish consumption can explain total mercury levels in hair, toenail, and urine to some degree (about 30%), partly through the degradation into the inorganic form, and it may confound the renal tubular effect of other nephrotoxic agents. Also, the following equation may be applicable to the population neither with dental amalgam fillings nor with occupational exposures: [hair mercury (μg/g)]=2.44×[toenail mercury (μg/g)].

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 µg/kg, subsequent dose 0.07 µg·kg–1·day–1 im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 ± 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 100 µM).

Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with L-NAME, the L-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2– production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

We evaluated the color vision of mercury-contaminated patients and investigated possible retinal origins of losses using electroretinography. Participants were retired workers from a fluorescent lamp industry diagnosed with mercury contamination (n = 43) and age-matched controls (n = 21). Color discrimination was assessed with the Cambridge Colour Test (CCT). Retinal function was evaluated by using the ISCEV protocol for full-field electroretinography (full-field ERG), as well as by means of multifocal electroretinography (mfERG). Color-vision losses assessed by the CCT consisted of higher color-discrimination thresholds along the protan, deutan, and tritan axes and significantly larger discrimination ellipses in mercury-exposed patients compared to controls. Full-field ERG amplitudes from patients were smaller than those of the controls for the scotopic response b-wave, maximum response, sum of oscillatory potentials (OPs), 30-Hz flicker response, and light-adapted cone response. OP amplitudes measured in patients were smaller than those of controls for O2 and O3. Multifocal ERGs recorded from ten randomly selected patients showed smaller N1–P1 amplitudes and longer latencies throughout the 25-deg central field. Full-field ERGs showed that scotopic, photopic, peripheral, and midperipheral retinal functions were affected, and the mfERGs indicated that central retinal function was also significantly depressed. To our knowledge, this is the first demonstration of retinal involvement in visual losses caused by mercury toxicity.

BACKGROUND AND OBJECTIVES: To study the mortality from cardiovascular diseases after long-term exposure to inorganic mercury.

POPULATION AND METHOD: 3,998 workers exposed to mercury in Minas de Almadén y Arrayanes S.A. were studied. The follow-up period was a century, since 1895 to 1994. The study was completed assessing the vital status and the basic cause of death, in case of fatalities. Standardized mortality ratios (SMR) by age, sex and calendar period were calculated. Expected deaths were obtained from age, sex and calendar period specific from rates for the Spanish and regional populations.

RESULTS: A significant increase in mortality due to circulatory diseases was found (SMR 1.11, 95% confidence interval [CI], 1.02-1.20), especially for hypertension (SMR 2.78, 95% CI, 1.89-3.95), cerebrovascular diseases (SMR 1.17, 95% CI, 1.01-1.35), and other diseases of the heart (SMR 1.51, 95% CI, 1.29-1.76). Ischemic heart disease showed a significant decrease in these workers, with an SMR 0.69, and a CI between 0.57 and 0.84. Cerebrovascular diseases showed a trend over the time since first exposure, duration of exposure and with the accumulated expected exposure, while none of the exposure variables was linearly associated with mortality due to ischemic heart diseases. There was also a trend over the time since first exposure for mortality due to hypertension and other heart diseases.

CONCLUSIONS: This study suggests an association between long-term exposure to inorganic mercury in workers of mercury mines and an increased risk of circulatory mortality, especially mortality due to hypertension and cerebrovascular diseases.

Amalgam, which has been in use in dentistry for 150 years, consists of 50% elemental mercury and a mixture of silver, tin, copper and zinc. Minute amounts of mercury vapour are released continuously from amalgam. Amalgam contributes substantially to human mercury load. Mercury accumulates in some organs, particulary in the brain, where it can bind to protein more tightly than other heavy metals (e.g. lead, cadmium). Therefore, the elimination half time is assumed to be up to 1 -18 years in the brain and bones. Mercury is assumed to be one of the most toxic non-radioactive elements. There are pointers to show that mercury vapour is more neurotoxic than methyl-mercury in fish. Review of recent literature suggests that mercury from dental amalgam may lead to nephrotoxicity, neurobehavioural changes, autoimmunity, oxidative stress, autism, skin and mucosa alterations or non-specific symptoms and complaints. The development of Alzheimer's disease or multiple sclerosis has also been linked to low-dose mercury exposure. There may be individual genetical or acquired susceptilities for negative effects from dental amalgam. Mercury levels in the blood, urine or other biomarkers do not reflect the mercury load in critical organs. Some studies regarding dental amalgam reveal substantial methodical flaws. Removal of dental amalgam leads to permanent improvement of various chronic complaints in a relevant number ofpatients in various trials. Summing up, available data suggests that dental amalgam is an unsuitable material for medical, occupational and ecological reasons.

The first well-documented outbreak of acute methyl mercury (MeHg) poisoning by consumption of contaminated fish occurred in Minamata, Japan, in 1953. The clinical picture was officially recognized and called Minamata disease (MD) in 1956. However, 50 years later there are still arguments about the definition of MD in terms of clinical symptoms and extent of lesions. We provide a historical review of this epidemic and an update of the problem of MeHg toxicity. Since MeHg dispersed from Minamata to the Shiranui Sea, residents living around the sea were exposed to low-dose MeHg through fish consumption for about 20 years (at least from 1950 to 1968). These patients with chronic MeHg poisoning continue to complain of distal paresthesias of the extremities and the lips even 30 years after cessation of exposure to MeHg. Based on findings in these patients the symptoms and lesions in MeHg poisoning are reappraised. The persisting somatosensory disorders after discontinuation of exposure to MeHg were induced by diffuse damage to the somatosensory cortex, but not by damage to the peripheral nervous system, as previously believed.

Higher mercury concentrations were found in brain regions and blood of some patients with Alzheimer's disease (AD). Low levels of inorganic mercury were able to cause AD- typical nerve cell deteriorations in vitro and in animal experiments. Other metals like zinc, aluminum, copper, cadmium, manganese, iron, and chrome are not able to elicit all of these deteriorations in low levels, yet they aggravate the toxic effects of mercury (Hg). Main human sources for mercury are fish consumption (Methyl-Hg) and dental amalgam (Hg vapour). Regular fish consumption reduces the risk of development of AD. Amalgam consists of approx. 50 % of elementary mercury which is constantly being vaporized and absorbed by the organism. Mercury levels in brain tissues are 2 - 10 fold higher in individuals with dental amalgam. Persons showing a genetically determined subgroup of transportation protein for fats (apolipoprotein E4) have an increased AD risk.

Apoliprotein E (APO E) is found in high concentrations in the central nervous system. The increased AD risk through APO E4 might be caused by its reduced ability to bind heavy metals. Latest therapeutic approaches to the treatment of Alzheimer disease embrace pharmaceuticals which remove or bind metals from the brain. Preliminary success has been documented with chelation of synergistic toxic metals (Fe, Al, Zn, Cu) and therefore also Hg. The available data does not answer the question, whether mercury is a relevant risk factor in AD distinctively. In sum, the findings from epidemiological and demographical studies, the frequency of amalgam application in industrialized countries, clinical studies, experimental studies and the dental state of Alzheimer patients in comparison to controls suggest a decisive role for inorganic mercury in the etiology of Alzheimer's disease. Other factors currently discussed as causes (e. g. other metals, inflammations, dietetic factors, vitamin deficiency, oxidative distress, and metabolic impairments) may act as co-factors.

The incidence of neurodegenerative disease like Parkinson's disease and Alzheimer's disease (AD) increases dramatically with age; only a small percentage is directly related to familial forms. The etiology of the most abundant, sporadic forms is complex and multifactorial, involving both genetic and environmental factors. Several environmental pollutants have been associated with neurodegenerative disorders. The present article focuses on results obtained in experimental neurotoxicology studies that indicate a potential pathogenic role of lead and mercury in the development of neurodegenerative diseases. Both heavy metals have been shown to interfere with a multitude of intracellular targets, thereby contributing to several pathogenic processes typical of neurodegenerative disorders, including mitochondrial dysfunction, oxidative stress, deregulation of protein turnover, and brain inflammation.

Exposure to heavy metals early in development can precondition the brain for developing a neurodegenerative disease later in life. Alternatively, heavy metals can exert their adverse effects through acute neurotoxicity or through slow accumulation during prolonged periods of life. The pro-oxidant effects of heavy metals can exacerbate the age-related increase in oxidative stress that is related to the decline of the antioxidant defense systems. Brain inflammatory reactions also generate oxidative stress. Chronic inflammation can contribute to the formation of the senile plaques that are typical for AD. In accord with this view, nonsteroidal anti-inflammatory drugs and antioxidants suppress early pathogenic processes leading to Alzheimer's disease, thus decreasing the risk of developing the disease. The effects of lead and mercury were also tested in aggregating brain-cell cultures of fetal rat telencephalon, a three-dimensional brain-cell culture system.

The continuous application for 10 to 50 days of non-cytotoxic concentrations of heavy metals resulted in their accumulation in brain cells and the occurrence of delayed toxic effects. When applied at non-toxic concentrations, methylmercury, the most common environmental form of mercury, becomes neurotoxic under pro-oxidant conditions. Furthermore, lead and mercury induce glial cell reactivity, a hallmark of brain inflammation. Both mercury and lead increase the expression of the amyloid precursor protein; mercury also stimulates the formation of insoluble beta-amyloid, which plays a crucial role in the pathogenesis of AD and causes oxidative stress and neurotoxicity in vitro. Taken together, a considerable body of evidence suggests that the heavy metals lead and mercury contribute to the etiology of neurodegenerative diseases and emphasizes the importance of taking preventive measures in this regard.

The relationship between prenatal exposure to methyl mercury and neurologic and developmental abnormalities was ascertained among 234 Cree Indian children aged 12 to 30 months from four northern Quebec communities. A pedlatrlc neurologist, "blinded" to the children's level of exposure, assessed neurologic, physical, mental, and psychosoclal development Methyl mercury exposure was estimated from maternal hair segments representing the period of pregnancy. Abnormality of the tendon reflexes, observed in 13 boys (11 per cent) and in 14 girls (12 per cent), was positively associated with methyl mercury exposure only in boys and there was no consistent dose-response relationship. Other neurologic disorders were less prevalent and none was positively associated with exposure; indeed, incoordinatlon was negatively associated with exposure in girls. The mild, isolated neurologic abnormalities found after prenatal exposure to methyl mercury in northern Quebec were different from the effects of prenatal exposure described in other areas, and their clinical importance can be determined only by continued medical surveillance.

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 microg/kg, subsequent dose 0.07 microg.kg(-1).day(-1) im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 +/- 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 100 microM).

Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with l-NAME, the l-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2(-) production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.

There is a risk of severe neurological disease, nephropathy and cutaneous complications during mercury poisoning. We report a case of acute generalized exanthematous pustulosis, associated with histologically confirmed acute cytolytic hepatitis without liver failure, after application of a topical home-made ointment containing mercury. The patient was previously sensitized with mercurothiolate. A high level of mercury was found in the blood (68mug/L, normal <5mug/L). Clinical and biological features disappeared after the ointment was discontinued. Biological acute hepatitis was probably from type IV sensitization, like that seen in acute generalized exanthematous pustulosis, with no evidence of direct mercury poisoning and after lithiasis, viral, immune and drug side effects were excluded. Liver injury during acute generalized exanthematous pustulosis is uncommon and usually mild, but should be searched for.

OBJECTIVES: Thimerosal is a mercurial preservative that was widely used in multidose vaccine vials in the United States and Europe until 2001 and continues to be used in many countries throughout the world. We conducted a pharmacokinetic study to assess blood levels and elimination of ethyl mercury after vaccination of infants with thimerosal-containing vaccines.

METHODS: Blood, stool, and urine samples were obtained before vaccination and 12 hours to 30 days after vaccination from 216 healthy children: 72 newborns (group 1), 72 infants aged 2 months (group 2), and 72 infants aged 6 months (group 3). Total mercury levels were measured by atomic absorption. Blood mercury pharmacokinetics were calculated by pooling the data on the group and were based on a 1-compartment first-order pharmacokinetics model.

RESULTS: For groups 1, 2, and 3, respectively, (1) mean +/- SD weights were 3.4 +/- 0.4, 5.1 +/- 0.6, and 7.7 +/- 1.1 kg; (2) maximal mean +/- SD blood mercury levels were 5.0 +/- 1.3, 3.6 +/- 1.5, and 2.8 +/- 0.9 ng/mL occurring at 0.5 to 1 day after vaccination; (3) maximal mean +/- SD stool mercury levels were 19.1 +/- 11.8, 37.0 +/- 27.4, and 44.3 +/- 23.9 ng/g occurring on day 5 after vaccination for all groups; and (4) urine mercury levels were mostly nondetectable. The blood mercury half-life was calculated to be 3.7 days and returned to prevaccination levels by day 30.

CONCLUSIONS: The blood half-life of intramuscular ethyl mercury from thimerosal in vaccines in infants is substantially shorter than that of oral methyl mercury in adults. Increased mercury levels were detected in stools after vaccination, suggesting that the gastrointestinal tract is involved in ethyl mercury elimination. Because of the differing pharmacokinetics of ethyl and methyl mercury, exposure guidelines based on oral methyl mercury in adults may not be accurate for risk assessments in children who receive thimerosal-containing vaccines.

Background A high dietary intake of mercury from consumption of fish has been hypothesized to increase the risk of coronary heart disease.

Methods Using a nested case–control design, we investigated the association between mercury levels in toenails and the risk of coronary heart disease among male health professionals with no previous history of cardiovascular disease or cancer who were 40 to 75 years of age in 1986. Toenail clippings were collected in 1987 from 33,737 cohort members, and during five years of follow-up, we documented 470 cases of coronary heart disease (coronary-artery surgery, nonfatal myocardial infarction, and fatal coronary heart disease). Each patient was matched according to age and smoking status with a randomly selected control subject.

Results The mercury level was significantly correlated with fish consumption (Spearman r=0.42, P<0.001), and the mean mercury level was higher in dentists than in nondentists (mean, 0.91 and 0.45 µg per gram, respectively; P<0.001). After age, smoking, and other risk factors for coronary heart disease had been controlled for, the mercury level was not significantly associated with the risk of coronary heart disease. When the highest and lowest quintiles of mercury level were compared, the relative risk of coronary heart disease was 0.97 in the highest level (95 percent confidence interval, 0.63 to 1.50; P value for trend=0.78). Adjustment for intake of n–3 fatty acids from fish did not appreciably change these results.

Conclusions Our findings do not support an association between total mercury exposure and the risk of coronary heart disease, but a weak relation cannot be ruled out.

Background A high dietary intake of mercury from consumption of fish has been hypothesized to increase the risk of coronary heart disease.

Methods Using a nested case–control design, we investigated the association between mercury levels in toenails and the risk of coronary heart disease among male health professionals with no previous history of cardiovascular disease or cancer who were 40 to 75 years of age in 1986. Toenail clippings were collected in 1987 from 33,737 cohort members, and during five years of follow-up, we documented 470 cases of coronary heart disease (coronary-artery surgery, nonfatal myocardial infarction, and fatal coronary heart disease). Each patient was matched according to age and smoking status with a randomly selected control subject.

Results The mercury level was significantly correlated with fish consumption (Spearman r=0.42, P<0.001), and the mean mercury level was higher in dentists than in nondentists (mean, 0.91 and 0.45 µg per gram, respectively; P<0.001). After age, smoking, and other risk factors for coronary heart disease had been controlled for, the mercury level was not significantly associated with the risk of coronary heart disease. When the highest and lowest quintiles of mercury level were compared, the relative risk of coronary heart disease was 0.97 in the highest level (95 percent confidence interval, 0.63 to 1.50; P value for trend=0.78). Adjustment for intake of n–3 fatty acids from fish did not appreciably change these results.

Conclusions Our findings do not support an association between total mercury exposure and the risk of coronary heart disease, but a weak relation cannot be ruled out.

Parkinson's disease (PD) is associated with loss of total glutathione (GSH) which may contribute to progressive cell death. Peripheral GSH administration has been used clinically with reported benefits. Despite this, there is little specific information to characterize its cellular uptake or clearance, brain elevation with peripheral delivery or neuroprotective efficacy in PD models. The current study was carried out to provide this information using in vitro and in vivo approaches. In rat mesencephalic culture, the monoethyl ester of GSH (GEE), but not GSH (1–10 mM, 24 h) produced a dose-dependent elevation in GSH. The half-life for clearance was 10.14 h and was not different in cells depleted of GSH prior to loading.

Elevation of GSH with GEE protected neurons from oxidative stress with H2O2 or metabolic stress with the complex I and II inhibitors MPP+ and malonate, respectively. To determine if peripheral administration of GEE could elevate brain GSH levels, rats were administered 0.1–50 mg/kg/day GEE via osmotic minipump either subcutaneously (sc) or via a cannula placed into the left cerebral ventricle (icv) for 28 days. Only central delivery of GEE resulted in significant elevations of brain GSH. Elevation of brain GSH by icv infusion of GEE was examined for its neuroprotective effects against chronic central delivery of MPP+. Infusion of 0.142 mg/kg/day MPP+ for 28 days caused a selective ipsilateral loss of striatal dopamine. Co-infusion of MPP+ with 10 mg/kg/day GEE significantly protected against striatal dopamine loss. These findings show that the ethyl ester of GSH but not GSH per se can elevate intracellular GSH, that brain elevation of GSH requires central delivery of the ethyl ester and that this elevation provides neuroprotection against oxidative stress or chronic mitochondrial impairment.

Background Brain glutathione levels are decreased in schizophrenia, a disorder that often is chronic and refractory to treatment. N-acetyl cysteine (NAC) increases brain glutathione in rodents. This study was conducted to evaluate the safety and effectiveness of oral NAC (1 g orally twice daily [b.i.d.]) as an add-on to maintenance medication for the treatment of chronic schizophrenia over a 24-week period.

Methods A randomized, multicenter, double-blind, placebo-controlled study. The primary readout was change from baseline on the Positive and Negative Symptoms Scale (PANSS) and its components. Secondary readouts included the Clinical Global Impression (CGI) Severity and Improvement scales, as well as general functioning and extrapyramidal rating scales. Changes following a 4-week treatment discontinuation were evaluated. One hundred forty people with chronic schizophrenia on maintenance antipsychotic medication were randomized; 84 completed treatment.

Results Intent-to-treat analysis revealed that subjects treated with NAC improved more than placebo-treated subjects over the study period in PANSS total [−5.97 (−10.44, −1.51), p = .009], PANSS negative [mean difference −1.83 (95% confidence interval: −3.33, −.32), p = .018], and PANSS general [−2.79 (−5.38, −.20), p = .035], CGI-Severity (CGI-S) [−.26 (−.44, −.08), p = .004], and CGI-Improvement (CGI-I) [−.22 (−.41, −.03), p = .025] scores. No significant change on the PANSS positive subscale was seen. N-acetyl cysteine treatment also was associated with an improvement in akathisia (p = .022). Effect sizes at end point were consistent with moderate benefits.

 

Objective. This systematic review evaluates the evidence on the association between lead exposure and cardiovascular end points in human populations.

Methods. We reviewed all observational studies from database searches and citations regarding lead and cardiovascular end points.

Results. A positive association of lead exposure with blood pressure has been identified in numerous studies in different settings, including prospective studies and in relatively homogeneous socioeconomic status groups. Several studies have identified a dose–response relationship. Although the magnitude of this association is modest, it may be underestimated by measurement error. The hypertensive effects of lead have been confirmed in experimental models. Beyond hypertension, studies in general populations have identified a positive association of lead exposure with clinical cardiovascular outcomes (cardiovascular, coronary heart disease, and stroke mortality; and peripheral arterial disease), but the number of studies is small. In some studies these associations were observed at blood lead levels < 5 μg/dL.

Conclusions. We conclude that the evidence is sufficient to infer a causal relationship of lead exposure with hypertension. We conclude that the evidence is suggestive but not sufficient to infer a causal relationship of lead exposure with clinical cardiovascular outcomes. There is also suggestive but insufficient evidence to infer a causal relationship of lead exposure with heart rate variability.

Public Health Implications. These findings have immediate public health implications. Current occupational safety standards for blood lead must be lowered and a criterion for screening elevated lead exposure needs to be established in adults. Risk assessment and economic analyses of lead exposure impact must include the cardiovascular effects of lead. Finally, regulatory and public health interventions must be developed and implemented to further prevent and reduce lead exposure.

Few studies have compared associations of blood lead and tibia lead with blood pressure and hypertension, and associations have differed in samples with occupational exposure compared with those with mainly environmental lead exposure. African Americans have been underrepresented in prior studies. The authors performed a cross-sectional analysis of 2001–2002 data from a community-based cohort in Baltimore, Maryland, of 964 men and women aged 50–70 years (40% African American, 55% White, 5% other race/ethnicity) to evaluate associations of blood lead and tibia lead with systolic and diastolic blood pressure and hypertension while adjusting for a large set of potential confounding variables. Blood lead was a strong and consistent predictor of both systolic and diastolic blood pressure in models adjusted and not adjusted for race/ethnicity and socioeconomic status. Tibia lead was associated with hypertension status before adjustment for race/ethnicity and socioeconomic status (p = 0.01); after such adjustment, the association was borderline significant (p = 0.09). Propensity score analysis suggested that standard regression analysis may have exaggerated the attenuation. These findings are discussed in the context of complex causal pathways. The data suggest that lead has an acute effect on blood pressure via recent dose and a chronic effect on hypertension risk via cumulative dose.

Background. Lead exposure has been associated with higher blood pressure, hypertension, electrocardiogram abnormalities, and increased mortality from circulatory causes.

Objective. We assessed the association between bone lead—a more accurate biomarker of chronic lead exposure than blood lead—and risk for future ischemic heart disease (IHD).

Methods. In a prospective cohort study (VA Normative Aging Study), 837 men who underwent blood or bone lead measurements at baseline were followed-up for an ischemic heart disease event between 1 September 1991 and 31 December 2001. IHD was defined as either a diagnosis of myocardial infarction or angina pectoris that was confirmed by a cardiologist. Events of fatal myocardial infarction were assessed from death certificates.

Results. An IHD event occurred in 83 cases (70 nonfatal and 13 fatal). The mean blood, tibia, and patella lead levels were higher in IHD cases than in noncases. In multivariate Cox-proportional hazards models, one standard deviation increase in blood lead level was associated with a 1.27 (95% confidence interval, 1.01–1.59) fold greater risk for ischemic heart disease. Similarly, a one standard deviation increase in patella and tibia lead levels was associated with greater risk for IHD (hazard ratio for patella lead = 1.29; 95% confidence interval, 1.02–1.62).

Conclusions. Men with increased blood and bone lead levels were at increased risk for future IHD. Although the pathogenesis of IHD is multifactorial, lead exposure may be one of the risk factors.

Mercury is a heavy metal that exists naturally in the environment. Major sources include the burning of fossil fuels (especially coal) and municipal waste incineration. Mercury can exist in several forms, with the most hazardous being organic methylmercury. In waterways (lakes, rivers, reservoirs, etc.), mercury is converted to methylmercury, which then accumulates in fish, especially in large predatory fish. Fish and fish products are the major—if not the only—source of methylmercury in humans. Mercury has long been recognized as a neurotoxin for humans, but in the last 10 years, its potentially harmful effects on cardiovascular diseases (CVD) have raised a cause for concern, mostly due to the proposed role of mercury in oxidative stress propagation. Some epidemiological studies have indeed found an association between increased levels of mercury in the body and risk of CVD. There are several plausible mechanisms to explain the association; these are discussed in this review. We also review the epidemiological studies that have investigated the association between mercury and CVD.

Background Even though previous studies have suggested an association between high fish intake and reduced coronary heart disease (CHD) mortality, men in Eastern Finland, who have a high fish intake, have an exceptionally high CHD mortality. We hypothesized that this paradox could be in part explained by high mercury content in fish.

Methods and Results We studied the relation of the dietary intake of fish and mercury, as well as hair content and urinary excretion of mercury, to the risk of acute myocardial infarction (AMI) and death from CHD, cardiovascular disease (CVD), and any cause in 1833 men aged 42 to 60 years who were free of clinical CHD, stroke, claudication, and cancer. Of these, 73 experienced an AMI in 2 to 7 years. Of the 78 deceased men, 18 died of CHD and 24 died of CVD. Men who had consumed local nonfatty fish species had elevated hair mercury contents. In Cox models with the major cardiovascular risk factors as covariates, dietary intakes of fish and mercury were associated with significantly increased risk of AMI and death from CHD, CVD, and any death. Men in the highest tertile (2.0 µg/g) of hair mercury content had a 2.0-fold (95% confidence interval, 1.2 to 3.1; P=.005) age- and CHD-adjusted risk of AMI and a 2.9-fold (95% CI, 1.2 to 6.6; P=.014) adjusted risk of cardiovascular death compared with those with a lower hair mercury content. In a nested case-control subsample, the 24-hour urinary mercury excretion had a significant (P=.042) independent association with the risk of AMI. Both the hair and urinary mercury associated significantly with titers of immune complexes containing oxidized LDL.

Conclusions These data suggest that a high intake of mercury from nonfatty freshwater fish and the consequent accumulation of mercury in the body are associated with an excess risk of AMI as well as death from CHD, CVD, and any cause in Eastern Finnish men and this increased risk may be due to the promotion of lipid peroxidation by mercury.

 

Cadmium is a well-known human carcinogen and a potent nephrotoxin. Lipid peroxidation is involved in cadmium-related toxicity. Vitamin E and β-carotene are effective antioxidants and free radical scavengers. Therefore, the present study was carried out to investigate the potential protective effects of vitamin E and β-carotene alone or in combination against cadmium (Cd) toxicity. Cadmium chloride (CdCl2, 5 mg/kg BW, 1/15 LD50), vitamin E (100 mg/kg BW), β-carotene (10 mg/kg BW), and vitamin E with β-carotene (100 + 10 mg/kg BW, respectively) were orally administered by gavage alone or in combination. The tested doses were given to rats every other day (15 times). Results obtained showed that CdCl2 significantly (P<0.05) induced free radicals in plasma, liver and brain.

The activities of glutathione S-transferase (GST) (plasma and liver), alkaline phosphatase (AlP) (plasma and liver), aspartate aminotransferase (AST), alanine aminotransferase (ALT) (liver) and acetylcholinesterase (AChE) (plasma and brain) were significantly (P<0.05) decreased due to CdCl2 administration, whereas, the activities of AST and ALT were increased in plasma. Treatment with CdCl2 caused a significant (P<0.05) increase in glucose, urea, creatinine and bilirubin in plasma. On the other hand, results showed that CdCl2 significantly (P<0.05) decreased plasma total protein (TP), albumin (A), blood hemoglobin (Hb), total erythrocytic count (TEC) and packed cell volume (PCV), while total leukocyte count (TLC) increased. Treatment with CdCl2 caused a significant (P<0.05) decrease in sperm concentration, motility (%), weight of testes and epididymis, and increase in dead and abnormal sperm. Results demonstrated the beneficial influences of vitamin E, β-carotene alone and/or in combination in reducing the harmful effects of CdCl2.

Homocysteine levels are associated with peripheral arterial disease (PAD) in observational studies. Lead and cadmium are risk factors for PAD that affect thiol metabolism, and they may partly explain the association of homocysteine with PAD. To evaluate the roles of lead and cadmium exposure in confounding the association between homocysteine and PAD, the authors performed a cross-sectional study among 4,447 persons aged 40 years who participated in the 1999–2002 National Health and Nutrition Examination Survey (NHANES). PAD was defined as an ankle-brachial blood pressure index less than 0.90 in at least one leg. After adjustment for sociodemographic variables, the odds ratio for PAD in the highest quintile of homocysteine compared with the lowest was 1.92 (ptrend = 0.004). Adjusting for blood lead and cadmium levels reduced this odds ratio to 1.37 (ptrend = 0.13), and further adjusting for estimated glomerular filtration rate and smoking reduced it to 0.89 (ptrend = 0.87). Adjustment for other risk factors did not affect this association. In the general population, the association of homocysteine level with PAD can be completely explained by confounding due to smoking, increased blood lead and cadmium levels, and impaired renal function. The association of lead and cadmium with PAD risk deserves further investigation.

Lead and homocysteine are both associated with cardiovascular disease and cognitive dysfunction. We evaluated the relations among blood lead, tibia lead, and homocysteine levels by cross-sectional analysis of data among subjects in the Baltimore Memory Study, a longitudinal study of 1,140 randomly selected residents in Baltimore, Maryland, who were 50–70 years of age. Tibia lead was measured by 109Cd K-shell X-ray fluorescence. The subject population had a mean ± SD age of 59.3 ± 5.9 years and was 66.0% female, 53.9% white, and 41.4% black or African American. Mean ± SD blood lead, tibia lead, and homocysteine levels were 3.5 ± 2.4 μg/dL, 18.9 ± 12.5 μg/g, and 10.0 ± 4.1 μmol/L, respectively. In unadjusted analysis, blood lead and homocysteine were moderately correlated (Pearson’s r = 0.27, p < 0.01). After adjustment for age, sex, race/ethnicity, educational level, tobacco and alcohol consumption, and body mass index using multiple linear regression, results revealed that homocysteine levels increased 0.35 μmol/L per 1.0 μg/dL increase in blood lead (p < 0.01). The relations of blood lead with homocysteine levels did not differ in subgroups distinguished by age, sex, or race/ethnicity. Tibia lead was modestly correlated with blood lead (Pearson’s r = 0.12, p < 0.01) but was not associated with homocysteine levels. To our knowledge, these are the first data to reveal an association between blood lead and homocysteine. These results suggest that homocysteine could be a mechanism that underlies the effects of lead on the cardiovascular and central nervous systems, possibly offering new targets for intervention to prevent the long-term consequences of lead exposure.

Context: Myocardial infarction (MI) and strokes are leading causes of death in the US. Surgical and medical treatments can be helpful, but carry risks of morbidity and mortality.

Objective: To evaluate whether cardiac events were reduced for patients with known vascular disease who were treated with intravenous ethylene diamine tetra-acetic acid (EDTA) chelation therapy.

Design: Retrospective study with a 3-year follow-up, compared with similar patient groups by use of meta-analysis.

Population and setting: A total of 220 consecutive patients with known vascular disease were treated with chelation therapy during 1992-2001. Eight outpatient centres were included: five from the US and one each from Denmark, the Netherlands and Brazil. Average patient age was 64 years, 72.3% were males and 18.2% were smokers. Average number of treatments was 58.

Main outcome measures: MI, stroke and death from any cause were primary outcome measures. Secondary measures were resolution of symptoms and need for coronary artery bypass surgery (CABG) and percutaneous transluminal coronary angioplasty.

Results: According to the meta-analysis, expected outcomes in a 3-year follow-up period for 220 patients with coronary artery disease treated only with conventional therapies would be 15 MIs and six deaths. There were no deaths and no MIs in this group of patients who received chelation therapy. Four patients had strokes but recovered well. There were two angioplasties and six CABG procedures. Compared with similar patient populations treated with conventional therapies, patients who also were chelated had a 93.6% lesser need for angioplasty and a 62.5% reduced need for CABG. Of the patients that initiated treatment with symptoms, 68.7% had complete resolution of symptoms.

 

Post Minamata incident there has been awareness about mercury toxicity even among the general public. Previous researches contributed a vast amount of data regarding acute mercury exposure, but gradually information about the low dose [Ninomiya, T., Ohmori, H., Hashimoto, K., Tsuruta, K., Ekino, S., 1995. Expansion of methylmercury poisoning outside minamata: an epidemiological study on chronic methylmercury poisoninig outside of Minamata. Environ. Res. 70 (1) 47–50; Lebel, J., Mergler, D., Lucotte, M., Amorim, M., Dolbec, J., Miranda, D., Arantes, G., Rheault, I., Pichet, P., 1996. Evidence of early nervous system dysfunction in Amazonian populations exposed to low-levels of methylmercury. Neurotoxicology 17 (1) 157–167] of mercury toxicity has been trickling in. With mercury contaminating rain-, ground- and sea-water no one is safe. Polluted water leads to mercury laced fish, meat and vegetable. In aquatic environments, inorganic mercury is microbiologically transformed into lipophilic organic compound ‘methylmercury’. This transformation makes mercury more prone to biomagnification in food chains.

Consequently, populations with traditionally high dietary intake of food originating from fresh or marine environment have highest dietary exposure to mercury. Extensive research done on locals across the globe have already established this, persons who routinely consume fish or a particular species of fish are at an increased risk of methylmercury poisoning. The easy access of the toxicant to man through multiple pathways air, water, food, cosmetic products and even vaccines increase the exposure. Foetus and children are more susceptible towards mercury toxicity. Mothers consuming diet containing mercury pass the toxicant to foetus and to infants through breast milk. Decreased performance in areas of motor function and memory has been reported among children exposed to presumably safe mercury levels. Similarly, disruption of attention, fine motor function and verbal memory was also found in adults on exposure to low mercury levels. It is an occupational hazard for dental staff, chloralkali factory workers and goldminers, etc. Mercury has been found to be a causative agent of various sorts of disorders, including neurological, nephrological, immunological, cardiac, motor, reproductive and even genetic. Recently heavy metal mediated toxicity has been linked to diseases like Alzeihemer's, Parkinson's, Autism, Lupus, Amyotrophic lateral sclerosis, etc. Besides this, it poses danger to wildlife. Therefore, it becomes imperative to spread the information regarding the threat of mercury exposure amongst the scientists and masses.

Background This is a community comparison study that examines persons living in a subdivision exposed to petroleum products and mercury.

Methods We compared their health status and questionnaire responses to those living in another community with no known exposures of this type.

Results Pristane house dust among the exposed homes was higher than in the comparison communities. The exposed subdivision has higher ambient air mercury levels compared to the control community. The prevalence of rheumatic diseases (OR = 10.78; CI = 4.14, 28.12) and lupus (OR = 19.33; CI = 1.96, 190.72) was greater in the exposed population compared to the unexposed. A higher prevalence of neurological symptoms, respiratory symptoms and several cardiovascular problems including stroke (OR = 15.41; CI = 0.78, 304.68) and angina (OR = 5.72; CI = 1.68, 19.43) was seen.

Conclusion There were statistically significant differences in B cells, Natural Killer Cells, gamma glutamyl transferase, globulin and serum calcium levels between control and exposed subjects.

Chemical exposure can trigger or accelerate the development of autoimmune manifestations. Although heavy metals are elementary chemical structures, they can have profound and complex effects on the immune system. In genetically susceptible mice or rats, administration of subtoxic doses of mercury induces both the production of highly specific autoantibodies and a polyclonal activation of the immune system. We review in this article some of the mechanisms by which heavy metal exposure can lead to autoimmunity.

Based on in vitro studies and short-term in vivo studies, all mercurials were for a long time considered as prototypic immunosuppressive substances. Recent studies have confirmed that organic mercurials such as methyl mercury (MeHg) and ethyl mercury (EtHg) are much more potent immunosuppressors than inorganic mercury (Hg). However, Hg interacts with the immune system in the presence of a susceptible genotype to cause immunostimulation, antinucleolar antibodies targeting fibrillarin, and systemic immune-complex (IC) deposits, a syndrome called Hg-induced autoimmunity (HgIA). Recent studies in mice with a susceptible genotype has revealed that the immunosuppressive effect of MeHg and EtHg will within 1–3 weeks be superseded by immunostimulation causing an HgIA-like syndrome. At equimolar doses of Hg, MeHg has the weakest immunostimulating, autoimmunogen, and IC-inducing effect, while the effect of thimerosal is similar to that of inorganic mercury. The immunosuppression is caused by the organic mercurials per se. Since they undergo rapid transformation to inorganic Hg, studies are being undertaken to delineate the importance of the organic substances per se and the newly formed inorganic Hg for induction of autoimmunity.

Mercury (Hg) has long been recognized as a neurotoxicant; however, recent work in animal models has implicated Hg as an immunotoxicant. In particular, Hg has been shown to induce autoimmune disease in susceptible animals with effects including overproduction of specific autoantibodies and pathophysiologic signs of lupus-like disease. However, these effects are only observed at high doses of Hg that are above the levels to which humans would be exposed through contaminated fish consumption. While there is presently no evidence to suggest that Hg induces frank autoimmune disease in humans, a recent epidemiological study has demonstrated a link between occupational Hg exposure and lupus.

In our studies, we have tested the hypothesis that Hg does not cause autoimmune disease directly, but rather that it may interact with triggering events, such as genetic predisposition, exposure to antigens, or infection, to exacerbate disease. Treatment of mice that are not susceptible to Hg-induced autoimmune disease with very low doses and short term exposures of inorganic Hg (20–200 μg/kg) exacerbates disease and accelerates mortality in the graft versus host disease model of chronic lupus in C57Bl/6 × DBA/2 mice. Furthermore, low dose Hg exposure increases the severity and prevalence of experimental autoimmune myocarditis (induced by immunization with cardiac myosin peptide in adjuvant) in A/J mice. To test our hypothesis further, we examined sera from Amazonian populations exposed to Hg through small-scale gold mining, with and without current or past malaria infection. We found significantly increased prevalence of antinuclear and antinucleolar antibodies and a positive interaction between Hg and malaria. These results suggest a new model for Hg immunotoxicity, as a co-factor in autoimmune disease, increasing the risks and severity of clinical disease in the presence of other triggering events, either genetic or acquired.

In certain strains of mice, subtoxic doses of HgCl2 (mercuric chloride; mercury) induce a complex autoimmune condition characterized by the production of antinucleolar IgG Abs, lymphoproliferation, increased serum levels of IgG1/IgE Abs, and deposition of renal immune complexes. 4-1BB is an important T cell costimulatory molecule that has been implicated in T cell proliferation and cytokine production, especially production of IFN-. To elucidate T cell control mediated by the 4-1BB signaling pathway in this syndrome, we assessed the effect of administering agonistic anti-4-1BB mAb on mercury-induced autoimmunity. Groups of A.SW mice (H-2s) received mercury/control Ig or mercury/anti-4-1BB or PBS alone. Anti-4-1BB mAb treatment resulted in a dramatic reduction of mercury-induced antinucleolar Ab titers, serum IgG1/IgE induction, and renal Ig deposition. These effects may be related to the present finding that anti-4-1BB mAb decreases B cell numbers and function. The anti-4-1BB mAb-treated mercury group also showed a marked reduction in Th2-type cytokines but an increase in Th1-type cytokines and chemokines. Increased IFN- production due to anti-4-1BB mAb treatment appears to be responsible for the observed B cell defects because neutralization of IFN- in vivo substantially restored B cell numbers and partly restored IgG1/IgE. Collectively, our results indicate that 4-1BB mAb can down-regulate mercury-induced autoimmunity by affecting B cell function in an IFN--dependent manner and thus, preventing the development of autoantibody production and tissue Ig deposition.

Dental amalgam is a mercury-based filling containing approximately 50% of metallic mercury (Hg0). Human placenta does not represent a real barrier to the transport of Hg0; hence, fetal exposure occurs as a result of maternal exposure to Hg, with possible subsequent neurodevelopmental disabilities in infants. This study represents a substudy of the international NIH-funded project "Early Childhood Development and polychlorinated biphenyls Exposure in Slovakia". The main aim of this analysis was to assess the relationship between maternal dental amalgam fillings and exposure of the developing fetus to Hg. The study subjects were mother–child pairs (N=99). Questionnaires were administered after delivery, and chemical analyses of Hg were performed in the samples of maternal and cord blood using atomic absorption spectrometry with amalgamation technique. The median values of Hg concentrations were 0.63 g/l (range 0.14–2.9 g/l) and 0.80 g/l (range 0.15–2.54 g/l) for maternal and cord blood, respectively. None of the cord blood Hg concentrations reached the level considered to be hazardous for neurodevelopmental effects in children exposed to Hg in utero (EPA reference dose for Hg of 5.8 g/l in cord blood). A strong positive correlation between maternal and cord blood Hg levels was found (=0.79; P<0.001). Levels of Hg in the cord blood were significantly associated with the number of maternal amalgam fillings (=0.46, P<0.001) and with the number of years since the last filling (=- 0.37, P<0.001); these associations remained significant after adjustment for maternal age and education. Dental amalgam fillings in girls and women of reproductive age should be used with caution, to avoid increased prenatal Hg exposure.

BACKGROUND: Methyl mercury (MeHg) and metallic Hg are well known as neurotoxic agents. Dental amalgam contributes significantly to elemental Hg vapour exposure in the general population. There is little information about Hg concentration in human amniotic fluid (AF) of pregnant women and its potential toxic effect on the fetuses.

OBJECTIVE: Primary to assess the relationship between the presence of detectable mercury (Hg) concentration in human AF, number and surface areas of amalgam fillings of pregnant women; secondary to analyse their obstetric history and perinatal complications.

METHODS: Seventy-two pregnant women took part in this prospective study. One dentist recorded the dental status, presence, number and surface areas of amalgam fillings. Total Hg concentration in AF was determined in digested samples using automatic cold vapour atomic absorption equipment. The detection limit of Hg in AF, determined from blank readings, was 0.08 ng/ml. To estimate the dependence of the explanatory variables (such as number and surface areas of amalgam fillings, fish consumption, presence of liver or neurological diseases and smoking habits) on mercury concentration several linear regression models were built up. Stepwise logistic regression procedures were running on total sample and on patients with at least one amalgam filling (Positive Filling group = PF). Principal component analysis (PCA) provided two factors, which explained for more the 60% of the variance among the variables.

RESULTS: The overall mean Hg concentration in AF among all patients was 0.37+/-0.49 ng/ml. Nineteen (26.4%) women had a Hg concentration <0.08 ng/ml (Hg negative group). In 53 (73.6%) patients, with a concentration > or = 0.08 ng/ml (Hg positive group), the mean value of Hg was 0.49+/-0.52 ng/ml. The average number of amalgam fillings was 2.26 +/- 3.19 in the Hg negative group and 5.32+/-3.03 in the Hg positive group (ANOVA one-way p=0.04). A dependence of mercury concentration on number of amalgam fillings (p=0.03), surface area of the amalgam fillings (p=0.04) and fish consumption (p=0.04) was observed but not at a significant level. In stepwise logistic procedure the number of amalgam fillings gave a contribution to the model (p=0.04), although null value was included in the confidence intervals. We observed no statistically significant differences (chi2 test) among the patients with a Hg concentration <0.08 ng/ml (n=19) and those with a concentration > or = 0.08 (n=53) with regard to obstetric history and perinatal complications.

CONCLUSIONS: Number and surface areas of amalgam fillings influenced positively Hg concentration in AF but not at a significant level. Moreover Hg levels detected in AF were low and no adverse outcomes were observed through pregnancies and in the newborns.

Total mercury concentrations (mean plus or minus standard deviation) in breast milk, blood, and hair samples collected 6 wk after delivery from 30 women who lived in the north of Sweden were 0.6 plus or minus 0.4 ng/g (3.0 plus or minus 2.0 nmol/kg), 2.3 plus or minus 1.0 ng/g (11.5 plus or minus 5.0 nmol/kg), and 0.28 plus or minus 0.16 mu g/g (1.40 plus or minus 0.80 mu mol/kg), respectively. In milk, an average of 51% of total mercury was in the form of inorganic mercury, whereas in blood an average of only 26% was present in the inorganic form. Total and inorganic mercury levels in blood (r = .55, p = .003; and r = .46, p = .016; respectively) and milk (r = .47, p = .01; and r = .45, p = .018; respectively) were correlated with the number of amalgam fillings.

The concentrations of total mercury and organic mercury (calculated by subtraction of inorganic mercury from total mercury) in blood (r = .59, p = .0006; and r = .56, p = .001; respectively) and total mercury in hair (r = .52, p = .006) were correlated with the estimated recent exposure to methylmercury via intake of fish. There was no significant between the milk levels of mercury in any chemical form and the estimated methylmercury intake. A significant correlation was found between levels of total mercury in blood and in milk (r = .66, p = .0001), with milk levels being an average of 27% of the blood levels. There was an association between inorganic mercury in blood and milk (r = .96, p < .0001); the average level of inorganic mercury in milk was 55% of the level of inorganic mercury in blood. No significant correlations were found between the levels of any form of mercury in milk and the levels of organic mercury in blood.

The results indicated that there was an efficient transfer of inorganic mercury from blood to milk and that, in this population, mercury from amalgam fillings was the main source of mercury in milk. Exposure of the infant to mercury from breast milk was calculated to range up to 0.3 mu g/kg - d, of which approximately one-half was inorganic mercury. This exposure, however, corresponds to approximately one-half the tolerable daily intake for adults recommended by the World Health Organization. We concluded that efforts should be made to decrease mercury burden in fertile women.

ABSTRACT: In a retrospective study we report results of EDTA chelation in 470 patients, using a number of parameters, most of them objective. Although the patients acted as their own control, we observed improvement of 80 to 91%, depending upon the measurement used. Of 92 patients referred for surgical intervention, only 10 required ultimate surgery after or during their chelation therapy, thus saving an estimated 3 million dollars of insurance money. Our experience covers a period of 6 years and we saw no severe effects or casualties arising from the treatment. We conclude that EDTA chelation therapy is safe, effective and cost-saving.

ABSTRACT: Mortality from cancer was reduced 90% during an 18-year follow-up of 59 patients treated with Calcium-EDTA. Only one of 59 treated patients (1.7%) died of cancer while 30 of 172 non treated control subjects (17.6%) died of cancer (P=0.002). Death from artherosclerosis was also reduced. Treated patients had no evidence of cancer at the time of entry into this study. Observations relate only to long-term prevention of death from malignant disease, if chelation therapy is begun before clinical evidence of cancer occurs. Control and treated patients lived in the same neighborhood, adjacent to a heavily traveled highway in a small Swiss city. Both groups were exposed to the same amount of lead from automobile exhaust, industrial pollution and other carcinogens. Exposure to carcinogens was no greater for the studied population than exists in most other metropolitan areas throughout the world. Statistical analysis showed EDTA chelation therapy to be the only significant difference between controls and treated patients to explain the marked reduction in cancer mortality.

Edta is well recognized as a therapy for lead toxicity. EDTA also removes other toxic heavy metals and nutritional elements such as iron which promote cancer by catalyzing free radical pathology.

Lead from automobile exhausts, petrochemicals form wear of automobile tires, cadmium, and other carcinogens are present in higher concentrations adjacent to heavily traveled automobile highways. These substances cause cancer and potentate other carcinogens.

It was reported in an earlier paper that cancer mortality among 231 adults living along a heavily traveled highway was higher than among persons living in a traffic-free section of the same city1 Nervous disorders, headaches, fatigue, gastrointestinal disorders, depression, and substance abuse was also observed with higher frequency.2 It was postulated that lead exposure from automobile exhausts might be one cause of this difference.

Beginning in 1961, a group of 59 patients with such symptoms was treated with parenteral doses of Calcium EDTA. Symptoms improved and urinary delta-amino levulinic acid diminished.3

Subsequent to the EDTA chelation therapy, a decrease in cancer mortality was observed. When compared with a control group of untreated patients who did not receive EDTA, many fewer cancer deaths were recorded.4,5 The control group was similar to the treated group in all ways except to the EDTA chelation therapy.

The purpose of this present study is to determine more precisely and to statistically analyze the long-term change in cancer mortality after treatment with EDTA.

 

PURPOSE. To understand the mechanisms mediating retinal ganglion cell loss in glaucoma, the gene expression patterns were compared for transferrin, ceruloplasmin, and ferritin between normal and glaucomatous retina in monkey and human eyes.

METHODS. Laser photocoagulation was used to produce unilateral experimental glaucoma in monkeys. Gene expression was assessed by in situ hybridization and quantitative reverse transcription polymerase chain reaction (PCR). Immunohistochemistry was used to examine the retinal expression of iron-related proteins in the retina in experimental monkey glaucoma and human glaucoma.

RESULTS. Comparison of glaucomatous with control monkey retinas demonstrated increased mRNA expression of transferrin, ceruloplasmin, and ferritin heavy and light chains. In situ hybridization localized retinal gene expression of transferrin mainly to the inner nuclear layer and ferritin to both the inner and outer nuclear layers. Immunohistochemical examination of monkey and human glaucoma for these iron-related proteins demonstrated increases at the protein level.

CONCLUSIONS. Increased mRNA and protein levels of the iron-regulating proteins transferrin, ceruloplasmin, and ferritin are present in glaucoma. Together, these results suggest the involvement of iron and copper metabolism and associated antioxidant systems in the pathogenesis of glaucoma.

 

Heavy metal pollution of soils resulting from sewage and wastewater irrigation is causing major concern due to the potential risk involved. In the present study Musi River and its environs were assessed for heavy metal contamination. The study area was assessed for Zn, Cr, Cu, Ni, Co and Pb in soils, forage grass, milk from cattle, leafy and non-leafy vegetables. Partitioning pattern of soil revealed high levels of Zn, Cr, and Cu associated with labile fractions, making them more mobile and plant available. The associated risk was assessed using hazard quotient (HQ). Human risk was assessed in people known to consume these contaminated foods by analyzing metals concentrations in venous blood and urine. Results showed high amounts of Pb, Zn, Cr, and Ni compared to permissible limits. HQ was found to be high for Zn followed by Cr and Pb with special reference to leafy vegetables particularly spinach and amaranthus.

Background  Organic farming is a production technique that imposes major restrictions on the use of fertilizers, pesticides, feed additives and veterinary drugs and for this reason consumers perceive organic foods to be healthier. The content of health-promoting molecules such as ascorbic acid, β-carotene, lycopene and salicylic acid are important aspects of the nutritional quality of organic foods.

Aim  To evaluate health promoting substances and the heavy metal content of tomato berries grown using conventional, integrated pest management (IPM) and organic farming techniques.
Methods  Moisture was determined by drying, crude protein by the Kjeldhal method, and ashes by incineration at 550°C. Ergosterol, ascorbic acid, β-carotene, lycopene and salicylic acid were determined by HPLC. The levels of heavy metals were measured by atomic absorption spectroscopy.

Results  Compared to crops grown using conventional and IPM methods, organic tomatoes contained more salicylic acid but less vitamin C and lycopene. Organic tomatoes had higher Cd and Pb levels but a lower Cu content. Organic fruits had a slightly higher protein content than conventionally cultivated fruits, but the difference was minimal and consequently the nutritive significance was poor.

Conclusions  Farming techniques may have an impact on the quality of tomatoes. Their higher salicylate content supports the notion that organic foodstuffs are more wholesome. However, the lower lycopene and ascorbic acid levels of organic tomatoes are not to be regarded as positive. No residues of pesticides and ergosterol were detected.

Antioxidant activity of a molecule is attributed to various mechanisms such as prevention of chain initiation, binding of transition metal ion catalysts and decomposition of peroxides. This study was aimed at evaluating the metal chelating and hydrogen peroxide (H2O2) scavenging activity of melatonin. The metal chelating and H2O2 scavenging activity increased with increasing concentrations of melatonin (20–60 μg/mL). α-Tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) were used as standards. Sixty micrograms per milliliter concentration of melatonin exhibited 95% chelating effect on ferrous ions and scavenged 83% of H2O2. On the other hand, the same concentration of α-tocopherol, BHA, and BHT exhibited 58, 61, and 72% inhibition, respectively, of the formation of the Fe2+–ferrozine complex and scavenged 48, 20, and 23%, respectively, of H2O2. Based on these results, it is concluded that melatonin is an effective metal chelating agent and scavenger of H2O2. These properties may be major reasons for the melatonin's ability to inhibit lipid peroxidation.

The present study was designed to examine the antioxidative effect of curcumin, resveratrol and melatonin pre-treatment on cadmium-induced oxidative damage and cadmium distribution in an experimental model in mice. Male CD mice were treated once daily for 3 days with curcumin (50 mg/kg b.w., p.o.), resveratrol (20 mg/kg b.w., p.o.) or melatonin (12 mg/kg, p.o.), dispersed in 0.5% methylcellulose. One hour after the last dose of antioxidants cadmium chloride was administered (7 mg/kg b.w., s.c.) to pre-treated animals and control animals receiving methylcellulose. At 24th h after Cd administration the lipid peroxidation (LP – expressed as malondialdehyde production), reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx) were estimated in liver homogenates. Cadmium concentration was measured in the liver, kidneys, testes and brain by AAS.

Cadmium chloride administration to mice induced hepatic lipid peroxidation (to 133%, p < 0.001), decreased GSH content (to 65%, p < 0.001) and inhibited catalase (to 68%, p < 0.001) and GPx activity (to 60%, p < 0.001) in the liver. Curcumin, resveratrol and melatonin oral pre-treatment completely prevented the Cd-induced lipid peroxidation and Cd-induced inhibition of GPx hepatic activity. Resveratrol was effective against Cd-induced inhibition of catalase activity (p < 0.001). The decrease in hepatic GSH level was not prevented by curcumin, resveratrol or melatonin pre-treatment. In mice treated with antioxidants alone the level of LP, GSH, GPx or CAT was not different from control levels. The pre-treatment with antioxidants did not affect cadmium distribution in the tissues of Cd-intoxicated mice. The results demonstrate that curcumin, resveratrol and melatonin pre-treatment effectively protect against cadmium-induced lipid peroxidation and ameliorate the adverse effect of cadmium on antioxidant status without any reduction in tissue Cd burden.

 

Cadmium (Cd) is a heavy metal affecting human health both through environmental and occupational exposure. There is evidence that Cd accumulates in several organs and is carcinogenic to humans. In vivo, Cd mimics the effect of estrogens in the uterus and mammary gland. In estrogen-responsive breast cancer cell lines, Cd stimulates proliferation and can also activate the estrogen receptor independent of estradiol. The ability of this metalloestrogen to increase gene expression in MCF7 cells is blocked by anti-estrogens suggesting that the activity of these compounds is mediated by ERα. The aims of this work were to test whether melatonin inhibits Cd-induced proliferation in MCF7 cells, and also to study whether melatonin specifically inhibits Cd-induced ERα transactivation.

We show that melatonin prevents the Cd-induced growth of synchronized MCF7 breast cancer cells. In transient transfection experiments, we prove that both ERα- and ERβ-mediated transcription are stimulated by Cd. Melatonin is a specific inhibitor of Cd-induced ERα-mediated transcription in both estrogen response elements (ERE)- and AP1-containing promoters, whereas ERβ-mediated transcription is not inhibited by the pineal indole. Moreover, the mutant ERα-(K302G, K303G), unable to bind calmodulin, is activated by Cd but becomes insensitive to melatonin treatment. These results proved that melatonin inhibits MCF7 cell growth induced by Cd and abolishes the stimulatory effect of the heavy metal in cells expressing ERα at both ERE-luc and AP1-luc sites. We can infer from these experiments that melatonin regulates Cd-induced transcription in both ERE- and AP1 pathways. These results also reinforce the hypothesis of the anti-estrogenic properties of melatonin as a valuable tool in breast cancer therapies.

The incidence of serious infections caused by multidrug-resistant gram-positive and gram-negative bacteria has been increasing rapidly worldwide despite advances in antibacterial therapy in the last two decades. Among multidrug-resistant gram-positive and gram-negative bacteria, methicillin-resistant Staphylococcus aureus, carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii are of great importance, because they have emerged as primary nosocomial pathogens in hospital outbreaks. In this study, we investigated whether melatonin has antibacterial effects against these microorganisms in vitro. The minimum inhibitory concentration of melatonin was determined using a standard microdilution method at 24 and 48 hr. Melatonin inhibited microbial growth at both 24 and 48 hr; but results showed that melatonin had antibacterial effects against these microorganisms after 48 hr of incubation in lower doses [concentrations between 31.25 to 125 [mu]g/mL (0.13-0.53 mM)]. Also, it was determined that melatonin has a more potent antimicrobial effect on gram-negative microorganism. Among possible mechanisms, it is concluded that melatonin showed antibacterial effects by reducing intracellular substrates.

Cadmium (Cd) is a human carcinogen present in tobacco smoke and contaminated industrial soils. Metallothioneins (MTs) are intracellular proteins involved in protecting against Cd. The toxic effects of Cd can be modified by compounds able to modulate MTs synthesis. Melatonin has oncostatic properties and has also been shown to counteract the toxic effects of Cd. In this study we examine the possible role of melatonin in Cd-induced expression of several MT isoforms (MT-2A, MT-1X, MT-1F and MT-1E) in three human tumor cell lines (MCF-7, MDA-MB-231 and HeLa). We found that, in all cell types, melatonin increases Cd-induced expression of MT-2A, which is considered to protect against Cd toxicity. As regards MT-1 subtypes, which have been related with cell invasiveness and high histological grade tumors, melatonin caused Cd-induced expression in both breast cancer cell lines to decrease. These effects point towards melatonin's possible role as a preventive agent for carcinogenesis dependent on Cd contamination.

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-[alpha] has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-[alpha]-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.

The presence of melatonin in wine and different liquors was investigated and the intake of wine by human volunteers and possible increase of their serum melatonin levels was examined. Red and white wines, in addition to different liquors, were used to measure their melatonin content. Additionally, twenty volunteers aged from 25 to 49 drank 100 mL red or white wine, and serum melatonin levels were measured before and 1 h after wine intake. Melatonin was mostly present in red wine and lower levels were found in white wine and other liquors. Consequently, when human volunteers drank wine, the level of melatonin in serum was significantly higher 1 h after red wine intake than before. Thus, the presence of melatonin in relatively high concentrations in red wine and its contribution to increasing serum melatonin levels after its intake by human volunteers is demonstrated.

Glycemic control and prevention of secondary complications are the most important goals of using pharmacologic treatment of diabetes mellitus (DM). The inadequate responses to oral hypoglycemic agents may be attributed to inadequate postreceptor events even when insulin levels are quite sufficient, and associated with oxidative stress induced by long-term hyperglycemia. The administration of antioxidants such as melatonin and zinc may improve tissue responses to insulin and increase the efficacy of drugs, e.g. metformin, which act through this pathway. This project was designed to evaluate the effects of melatonin and zinc on the lipid profile and renal function in type 2 DM patients poorly controlled with metformin. A placebo-controlled, double-blind clinical trial was performed in which 46 type 2 diabetic patients were selected and allocated into three groups.

These groups were treated with single daily oral doses of both 10 mg of melatonin and 50 mg of zinc acetate alone: 10 mg of melatonin and 50 mg of zinc acetate in addition to the regularly used metformin or placebo, given at bedtime for 90 days. Fasting lipid profiles and microalbuminuria (MAU) were measured before initiating the treatments (zero time) and after 30 and 90 days of treatment. Daily administration of melatonin and zinc improved the impaired lipid profile and decreased the level of MAU; the addition of this treatment regimen in combination with metformin improved the tissue responses to this oral hypoglycemic agent. In conclusion, the combination of melatonin and zinc acetate, when used alone or in combination with metformin, improves DM-related complications such as the impaired lipid profile and MAU in type 2 DM patients.

melatonin is a potent scavenger of a variety of free radicals. The aim of this study was to investigate the radioprotective effect of melatonin against oxidative stress and tissue injury induced by gamma radiation. Rats were subjected to two doses of 2 and 4 Gy from cesium-137 source. Four days prior to irradiation, animals received melatonin daily (10 mg/kg body weight i.p.). In the irradiated animals, the oxidative stress markers malondialdehyde (MDA) and protein carbonyl were significantly increased in the liver, while a marked decrease in hepatic contents of DNA, RNA, and glutathione (GSH) as well as activity of glutathione-S-transferase (GST) was demonstrated. In addition, catalase (CAT) activity was increased in the liver 5 days after irradiation.

The levels of total lipids, cholesterol, triglyceride (TG), low-density lipoprotein (LDL), urea, and creatinine, as well as activities of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT), were significantly increased in sera of the irradiated rats. This is coupled with decreased serum levels of high-density lipoprotein (HDL), total protein and albumin, and total globulins by irradiation. The administration of melatonin alone daily for 4 days caused significant decreases in MDA and protein carbonyl content and produced significant elevations of GSH content and GST activity in the liver. Moreover, significant decreases in total lipids, cholesterol, and TG without change in LDL or HDL levels in serum were demonstrated.

Treatment with melatonin for 4 days before acute irradiation significantly abolished radiation-induced elevations in MDA and protein carbonyl levels in the liver and significantly maintained hepatic GSH content, GST, and CAT activities close to the control values. Preirradiation treatment with melatonin showed significantly higher hepatic DNA and RNA contents than irradiated rats. The levels of total lipids, cholesterol, TG, HDL, LDL, total proteins, albumin, total globulins, creatinine, and urea, as well as the activities of AST, ALT, and GGT in serum were significantly ameliorated when melatonin was injected before irradiation. In conclusion, the increase in oxidative stress markers and the concomitant change in antioxidant levels indicate the role of oxidative stress in radiation-induced tissue damage. Moreover, melatonin shows a radioprotective impact against ionizing-radiation-induced oxidative stress and organ injury.

Metabolic syndrome (MS) as a group of risk factors is strongly associated with diabetes type 2 and cardiovascular disease. Insulin resistance plays a key role in the pathogenesis of MS. Recent studies have shown that melatonin may influence insulin secretion and glucose homeostasis. Therefore, the present study analyzed the relationships between the melatonin and the insulin in patients with MS and controls. The melatonin rhythm, insulin and lipid levels were studied in 40 subjects (21 patients and 19 controls) in reproductive age. The night melatonin–insulin ratio was correlated negatively with low-density lipoprotein cholesterol (r = −0.370, p = 0.024) and total cholesterol (r = −0.348, p = 0.030), and positively with high-density lipoprotein cholesterol levels (r = +0.414, p = 0.010).

Night-time melatonin levels were related to night-time insulin concentrations (r = +0.313, p = 0.049). The correlation was pronounced in patients with MS (r = +0.640, p = 0.002), but did not reach statistical significance in controls (P > 0.05). In the patients with MS unlike the controls the night–day melatonin difference (%) correlated negatively with the fasting glucose (r = −0.494, p = 0.023) and positively to daily insulin (r = +0.536, p = 0.012). Our results show that melatonin–insulin interactions may exist in patients with MS, as well as relationships between melatonin–insulin ratio and the lipid profile. Pineal disturbances could influence the pathogenesis and the phenotype variations of the MS. Larger studies are needed to confirm or reject this hypothesis and to clarify the role of the melatonin in the metabolic disturbances.