Glutathione enzyme and selenoprotein polymorphisms associate with mercury biomarker levels in Michigan dental professionals.
ABSTRACT: Mercury is a potent toxicant of concern to both the general public and occupationally exposed workers (e.g., dentists). Recent studies suggest that several genes mediating the toxicokinetics of mercury are polymorphic in humans and may influence inter-individual variability in mercury accumulation. This work hypothesizes that polymorphisms in key glutathione synthesizing enzyme, glutathione S-transferase, and selenoprotein genes underlie inter-individual differences in mercury body burden as assessed by analytical mercury measurement in urine and hair, biomarkers of elemental mercury and methylmercury, respectively. Urine and hair samples were collected from a population of dental professionals (n=515), and total mercury content was measured. Average urine (1.06±1.24 microg/L) and hair mercury levels (0.49±0.63 microg/g) were similar to national U.S. population averages. Taqman assays were used to genotype DNA from buccal swab samples at 15 polymorphic sites in genes implicated in mercury metabolism. Linear regression modeling assessed the ability of polymorphisms to modify the relationship between mercury biomarker levels and exposure sources (e.g., amalgams, fish consumption). Five polymorphisms were significantly associated with urine mercury levels (GSTT1 deletion), hair mercury levels (GSTP1-105, GSTP1-114, GSS 5'), or both (SEPP1 3'UTR). Overall, this study suggests that polymorphisms in selenoproteins and glutathione-related genes may influence elimination of mercury in the urine and hair or mercury retention following exposures to elemental mercury (via dental amalgams) and methylmercury (via fish consumption).
Project description:Mercury (Hg) exposure, a worldwide public health concern, predominantly takes two forms--methylmercury from fish consumption and elemental Hg from dental amalgam restorations. We recruited 630 dental professionals from an American Dental Association meeting to assess Hg body burden and primary sources of exposure in a dually exposed population. Participants described occupational practices and fish consumption patterns via questionnaire. Hg levels in biomarkers of elemental Hg (urine) and methylmercury (hair and blood) were measured with a Direct Mercury Analyzer-80 and were higher than the general US population. Geometric means (95% CI) were 1.28 (1.19-1.37) ?g/l in urine, 0.60 (0.54-0.67) ?g/g in hair and 3.67 (3.38-3.98) ?g/l in blood. In multivariable linear regression, personal amalgams predicted urine Hg levels along with total years in dentistry, amalgams handled, working hours and sex. Fish consumption patterns predicted hair and blood Hg levels, which were higher among Asians compared with Caucasians. Five species contributed the majority of the estimated Hg intake from fish--swordfish, fresh tuna, white canned tuna, whitefish and king mackerel. When studying populations with occupational exposure to Hg, it is important to assess environmental exposures to both elemental Hg and methylmercury as these constitute a large proportion of total exposure.
Project description:Modification of the epigenome may be a mechanism underlying toxicity and disease following chemical exposure. Animal and human data suggest that mercury (Hg) impacts DNA methylation. We hypothesize that methylmercury and inorganic Hg exposures from fish consumption and dental amalgams, respectively, may be associated with altered DNA methylation at global repetitive elements (long interspersed elements, LINE-1) and candidate genes related to epigenetic processes (DNMT1) and protection against Hg toxicity (SEPW1, SEPP1). Dental professionals were recruited at Michigan Dental Association (MDA) meetings in 2009 and 2010. Subjects (n=131) provided survey data (e.g. exposure sources, demographics) and biological samples for Hg measurement and epigenetic analysis. Total Hg was quantified via atomic absorption spectrophotometry in hair and urine, indicative of methylmercury and inorganic Hg exposures, respectively. Global repetitive and candidate gene methylation was quantified via pyrosequencing of bisulfite converted DNA isolated from buccal mucosa. Hair Hg (geometric mean (95% CI): 0.37 (0.31-0.44) µg/g) and urine Hg (0.70 (0.60-0.83) µg/L) were associated with sources of exposure (fish consumption and dental amalgams, respectively). Multivariable linear regression revealed a trend of SEPP1 hypomethylation with increasing hair Hg levels, and this was significant (P<0.05) among males. The trend remained when excluding non-dentists. No significant relationships between urine Hg and DNA methylation were observed. Thus, in a limited cohort, we identified an association between methylmercury exposure and hypomethylation of a potentially labile region of the genome (SEPP1 promoter), and this relationship was gender specific.
Project description:<h4>Background</h4>Some clinical studies have suggested that ingestion of n-3 polyunsaturated fatty acids (PUFA) has neuroprotective effects on peripheral nerve function. However, few epidemiological studies have examined the effect of dietary n-3 PUFA intake from fish consumption on peripheral nerve function, and none have controlled for co-occurrence of methylmercury exposure from fish consumption.<h4>Objectives</h4>We evaluated the effect of estimated dietary n-3 PUFA intake on peripheral nerve function after adjusting for biomarkers of methylmercury and elemental mercury in a convenience sample of 515 dental professionals.<h4>Methods</h4>We measured sensory nerve conduction (peak latency and amplitude) of the median, ulnar and sural nerves and total mercury concentrations in hair and urine samples. We estimated daily intake (mg/day) of the total n-3 PUFA, n-3 docosahexaenoic acid (DHA), and n-3 eicosapentaenoic acid (EPA) based on a self-administrated fish consumption frequency questionnaire. We also collected information on mercury exposure, demographics and other covariates.<h4>Results</h4>The estimated median intakes of total n-3 PUFA, n-3 EPA, and n-3 DHA were 447, 105, and 179 mg/day, respectively. The mean mercury concentrations in urine (1.05 ?g/L) and hair (0.49 ?g/g) were not significantly different from the US general population. We found no consistent association between n-3 PUFA intake and sensory nerve conduction after adjusting for mercury concentrations in hair and urine although some positive associations were observed with the sural nerve.<h4>Conclusions</h4>In a convenience sample of dental professionals, we found little evidence suggesting that dietary intake of n-3 PUFAs from fish has any impact on peripheral nerve function after adjustment for methylmercury exposure from fish and elemental mercury exposure from dental amalgam.
Project description:Nonsynonymous single nucleotide polymorphisms in glutathione s-transferase pi 1 (GSTP1; Ile/Val 105, Ala/Val 114) have been associated with altered toxicant metabolism in epidemiological cohorts. We explored the impact of GSTP1 genotype on enzyme kinetics and heavy metal inhibition in vitro. Four GSTP1 allozymes (105/114: Ile/Ala, Val/Ala, Ile/Val, Val/Val) were expressed in and purified from Escherichia coli. Enzyme activity assays quantifying the rate of glutathione conjugation with 1-chloro-2,4-dinitrobenzene (CDNB) revealed significant differences in kinetic parameters depending on genotype (p<0.01). Allozymes with Ile105 had better catalytic efficiency and greater affinity for CDNB (mean ± SEM: Ile105 Ala114 K(m)=0.33 ± 0.07 mM vs. Val105 Ala114 K(m)=1.15 ± 0.07 mM). Inhibition of GSTP1 activity by heavy metals was assessed following treatment with mercury (inorganic-HgCl(2), methylmercury-MeHg), selenium, cadmium, lead, arsenic, and manganese. All allozymes were inhibited by HgCl(2) (IC(50) range: 24.1-172 ?M), MeHg (93.9-480 ?M), and selenium (43.7-62.8 ?M). Genotype significantly influenced the potency of mercury with GSTP1 Ile105 Val114 the least sensitive and Val105 Ala114 the most sensitive to inhibition by HgCl(2) and MeHg. Overall, genotype of two nonsynonymous polymorphisms in GSTP1 influenced enzyme kinetics pertaining to an electrophilic substrate and inhibition by two mercury species.
Project description:BACKGROUND: The n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, which are present in fish, are protective against myocardial infarction. However, fish also contains methylmercury, which influences the risk of myocardial infarction, possibly by generating oxidative stress. Methylmercury is metabolized by conjugation to glutathione, which facilitates elimination. Glutathione is also an antioxidant. Individuals with certain polymorphisms in glutathione-related genes may tolerate higher exposures to methylmercury, due to faster metabolism and elimination and/or better glutathione-associated antioxidative capacity. They would thus benefit more from the protective agents in fish, such as eicosapentaenoic+docosahexaenoic acid and selenium. The objective for this study was to elucidate whether genetic polymorphisms in glutathione-related genes modify the association between eicosapentaenoic+docosahexaenoic acid or methylmercury and risk of first ever myocardial infarction. METHODS: Polymorphisms in glutathione-synthesizing (glutamyl-cysteine ligase catalytic subunit, GCLC and glutamyl-cysteine ligase modifier subunit, GCLM) or glutathione-conjugating (glutathione S-transferase P, GSTP1) genes were genotyped in 1027 individuals from northern Sweden (458 cases of first-ever myocardial infarction and 569 matched controls). The impact of these polymorphisms on the association between erythrocyte-mercury (proxy for methylmercury) and risk of myocardial infarction, as well as between plasma eicosapentaenoic+docosahexaenoic acid and risk of myocardial infarction, was evaluated by conditional logistic regression. The effect of erythrocyte-selenium on risk of myocardial infarction was also taken into consideration. RESULTS: There were no strong genetic modifying effects on the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction risk. When eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury were divided into tertiles, individuals with GCLM-588 TT genotype displayed a lower risk relative to the CC genotype in all but one tertile; in most tertiles the odds ratio was around 0.5 for TT. However, there were few TT carriers and the results were not statistically significant. The results were similar when taking plasma eicosapentaenoic+docosahexaenoic acid, erythrocyte-selenium and erythrocyte-mercury into account simultaneously. CONCLUSIONS: No statistically significant genetic modifying effects were seen for the association between plasma eicosapentaenoic+docosahexaenoic acid or erythrocyte-mercury and risk of myocardial infarction. Still, our results indicate that the relatively rare GCLM-588 TT genotype may have an impact, but a larger study is necessary for confirmation.
Project description:Previous research has found that women and children living in rural, interior communities in Suriname have high concentrations of mercury in hair. Freshwater fish from these areas also have high concentrations of mercury. Artisanal and small-scale gold mining operations in parts of the country use elemental mercury to extract gold from soils and sediments. Total mercury and methylmercury concentrations have been determined in hair and blood from pregnant women across the country. Pregnant women from interior communities have significantly higher concentrations of both total and methylmercury in hair (median total mercury in hair 3.64?µg/g) compared with pregnant women from two urban coastal cities, Paramaribo (0.63?µg/g) and Nickerie (0.74?µg/g). Total and methylmercury concentrations in blood and hair are highly correlated (r?=?0.986, r?=?0.974) with methylmercury making up 86% of the total in blood and 97% of the total in hair. Most women in the interior regions rely heavily on local fish as part of their regular diet, and many live outsides of areas with active ASGM operations. This study demonstrates that diet and fish consumption largely govern mercury exposures in pregnant women in Suriname.
Project description:Mercury (Hg) is a potent neurotoxicant. We hypothesized that single nucleotide polymorphisms (SNPs) in genes coding glutathione-related proteins, selenoproteins and metallothioneins may modify the relationship of mercury biomarkers with changes in peripheral nerve function. Dental professionals (n=515) were recruited in 2009 and 2010. Sensory nerve function (onset latency, peak latency and amplitude) of the median, ulnar and sural nerves was recorded. Samples of urine, hair and DNA were collected. Covariates related to demographics, nerve function and elemental and methyl-mercury exposure were also collected. Subjects included 244 dentists (47.4%) and 269 non-dentists (52.2%; mostly dental hygienists and dental assistants). The mean mercury levels in urine (1.06 ?g/L) and hair (0.51 ?g/g) were not significantly different from the US general population (0.95 ?g/L and 0.47 ?g/g, respectively). In multivariate linear models predicting nerve function adjusting for covariates, only 3 out of a total of 504 models showed stable and statistically significant interaction of SNPs with mercury biomarkers. Overall, given the possibility of false positives, the results suggested little evidence of effect modification of the SNPs on the relationship between mercury biomarkers with peripheral nerve function at exposure levels that are relevant to the general US population.
Project description:Immune dysregulation associated with mercury has been suggested, although data in the general population are lacking. Chronic exposure to low levels of methylmercury (organic) and inorganic mercury is common, such as through fish consumption and dental amalgams.We examined associations between mercury biomarkers and antinuclear antibody (ANA) positivity and titer strength.Among females 16-49 years of age (n = 1,352) from the National Health and Nutrition Examination Survey (NHANES) 1999-2004, we examined cross-sectional associations between mercury and ANAs (indirect immunofluorescence; cutoff ? 1:80). Three biomarkers of mercury exposure were used: hair (available 1999-2000) and total blood (1999-2004) predominantly represented methylmercury, and urine (1999-2002) represented inorganic mercury. Survey statistics were used. Multivariable modeling adjusted for several covariates, including age and omega-3 fatty acids.Sixteen percent of females were ANA positive; 96% of ANA positives had a nuclear speckled staining pattern. Geometric mean (geometric SD) mercury concentrations were 0.22 (0.03) ppm in hair, 0.92 (0.05) ?g/L blood, and 0.62 (0.04) ?g/L urine. Hair and blood, but not urinary, mercury were associated with ANA positivity (sample sizes 452, 1,352, and 804, respectively), after adjusting for confounders: for hair, odds ratio (OR) = 4.10 (95% CI: 1.66, 10.13); for blood, OR = 2.32 (95% CI: 1.07, 5.03) comparing highest versus lowest quantiles. Magnitudes of association were strongest for high-titer (? 1:1,280) ANA: hair, OR = 11.41 (95% CI: 1.60, 81.23); blood, OR = 5.93 (95% CI: 1.57, 22.47).Methylmercury, at low levels generally considered safe, was associated with subclinical autoimmunity among reproductive-age females. Autoantibodies may predate clinical disease by years; thus, methylmercury exposure may be relevant to future autoimmune disease risk.
Project description:Recent studies have suggested that several genes that mediate mercury metabolism are polymorphic in humans.We hypothesized that single-nucleotide polymorphisms (SNPs) in metallothionein (MT) genes may underlie interindividual differences in mercury biomarker levels. We studied the potential modifying effects of MT SNPs on mercury exposure-biomarker relationships.We measured total mercury in urine and hair samples of 515 dental professionals. We also surveyed occupational and personal exposures to dental amalgam and dietary fish consumption, from which daily methylmercury (MeHg) intake was estimated. Log-transformed urine and hair levels were modeled in multivariable linear regression separately against respective exposure surrogates, and the effect modification of 13 MT SNPs on exposure was investigated.The mean mercury levels in urine (1.06 ?g/L) and hair (0.51 ?g/g) were not significantly different from the U.S. general population (0.95 ?g/L and 0.47 ?g/g, respectively). The mean estimated daily MeHg intake was 0.084 ?g/kg/day (range, 0-0.98 ?g/kg/day), with 25% of study population intakes exceeding the current U.S. Environmental Protection Agency reference dose of 0.1 ?g/kg/day. Multivariate regression analysis showed that subjects with the MT1M (rs2270837) [corrected] AA genotype (n = 10) or the MT2A (rs10636) CC genotype (n = 42) had lower urinary mercury levels than did those with the MT1M or MT2A GG genotype (n = 329 and 251, respectively) after controlling for exposure and potential confounders. After controlling for MeHg intake, subjects with MT1A (rs8052394) GA and GG genotypes (n = 24) or the MT1M (rs9936741) TT genotype (n = 459) had lower hair mercury levels than did subjects with MT1A AA (n = 113) or MT1M TC and CC genotypes (n = 15), respectively.Our findings suggest that some MT genetic polymorphisms may influence mercury biomarker concentrations at levels of exposure relevant to the general population.
Project description:INTRODUCTION:Glutathione (GSH) pathways play a key role the metabolism and elimination of the neurotoxicant methylmercury (MeHg). We hypothesized that maternal genetic variation linked to GSH pathways could influence MeHg concentrations in pregnant mothers and children and thereby also affect early life development. METHODS:The GCLM (rs41303970, C/T), GCLC (rs761142, T/G) and GSTP1 (rs1695, A/G) polymorphisms were genotyped in 1449 mothers in a prospective study of the Seychellois population with a diet rich in fish. Genotypes were analyzed in association with maternal hair and blood Hg, fetal blood Hg (cord blood Hg), as well as children's mental (MDI) and motor development (PDI; MDI and PDI assessed by Bayley Scales of Infant Development at 20?months). We also examined whether genotypes modified the association between Hg exposure and developmental outcomes. RESULTS:GCLC rs761142 TT homozygotes showed statistically higher mean maternal hair Hg (4.12?ppm) than G carriers (AG 3.73 and GG 3.52?ppm) (p?=?0.037). For the combination of GCLC rs761142 and GCLM rs41303970, double homozygotes TT?+?CC showed higher hair Hg (4.40?ppm) than G?+?T carriers (3.44?ppm; p?=?0.018). No associations were observed between GSTP1 rs1695 and maternal hair Hg or between any genotypes and maternal blood Hg or cord blood Hg. The maternal GSTP1 rs1695 rare allele (G) was associated with a lower MDI among children (??=?-1.48, p?=?0.048). We also observed some interactions: increasing Hg in maternal and cord blood was associated with lower PDI among GCLC rs761142 TT carriers; and increasing Hg in hair was associated with lower MDI among GSTP1 rs1695 GG carriers. CONCLUSIONS:Maternal genetic variation in genes involved in GSH synthesis is statistically associated with Hg concentrations in maternal hair, but not in maternal or fetal blood. We observed interactions that suggest maternal GSH genetics may modify associations between MeHg exposure and neurodevelopmental outcomes.