Polymorphisms in glutathione-related genes affect methylmercury retention

Methylmercury is eliminated from the human body as glutathione (GSH) conjugates. GSH production is mediated by glutamyl-cysteine ligase (GCL) and conjugation by glutathione S-transferases (GST). In this study, the authors tested whether polymorphisms in GCL and GST genes modify methylmercury retention. Erythrocyte mercury concentration (EryHg), plasma polyunsaturated fatty acids (PPUFA), and genotype for GCLC, GCLM, GSTA1, GSTM1, GSTP1, and GSTT1 were determined in 365 individuals. A general linear model was developed for analyzing whether genotype modified the regression of EryHg on PPUFA. The presence of one variant allele for either GCLC-129 or GSTP1-114 was associated with higher EryHg and steeper regression slope. No similar trends were shown for GCLM, GSTA1, GSTM1, or GSTT1. These findings indicate that GCLC polymorphisms that affect GSH production also affect methylmercury retention, and that GSTP1 may play a role in conjugating methylmercury with GSH.     

Genetic influences on the retention of inorganic mercury

Mercury is eliminated as glutathione (GSH) conjugates. GSH production is mediated by glutamyl-cysteine ligase (GCL), and conjugation by glutathione S-transferases (GST). This study tested if polymorphisms in GCL and GST genes modify mercury retention in humans exposed to elemental mercury vapor. Total mercury concentrations in whole blood, plasma and urine, and genotypes for GCLC, GCLM, GSTA1, GSTM1, GSTP1, and GSTT1 were determined in 309 gold miners, gold buyers and controls. The presence of the GCLM-588T allele was associated with increased blood, plasma and urine mercury levels. These results indicate that genotypes with decreased GSH availability for mercury conjugation affect the metabolism of inorganic mercury.     

Polymorphisms in Glutathione-Related Genes Affect Methylmercury Retention

Methylmercury is eliminated from the human body as glutathione (GSH) conjugates. GSH production is mediated by glutamyl-cysteine ligase (GCL) and conjugation by glutathione S-transferases (GST). In this study, the authors tested whether polymorphisms in GCL and GST genes modify methylmercury retention. Erythrocyte mercury concentration (EryHg), plasma polyunsaturated fatty acids (PPUFA), and genotype for GCLC, GCLM, GSTA1, GSTM1, GSTP1 and GSTT1 were determined in 365 individuals. A general linear model was developed for analyzing whether genotype modified the regression of EryHg on PPUFA. The presence of one variant allele for either GCLC-129 or GSTP1-114 was associated with higher EryHg and steeper regression slope. No similar trends were shown for GCLM, GSTA1, GSTM1 or GSTT1. These findings indicate that GCLC polymorphisms that affect GSH production also affect methylmercury retention, and that GSTP1 may play a role in conjugating methylmercury with GSH.     

Chronic beryllium disease and glutathione biosynthesis genes

OBJECTIVE: Because glutathione (GSH) has been reported to be increased in chronic beryllium disease (CBD) and is associated with immune modulation, associations between CBD and gene polymorphisms of the rate-limiting enzyme in GSH synthesis, glutamate cysteine ligase (GCL), were investigated. Glutamate cysteine ligase consists of a catalytic subunit (GCLC) and modifier subunit (GCLM). METHODS: Patients with CBD, beryllium-sensitized subjects (BeS), and beryllium-exposed subjects without CBD were genotyped for the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR), the GCLC-129 single nucleotide polymorphism (SNP), and the GCLM-588 SNP. RESULTS: Results indicate that GCLC TNR genotype 7/7 is negatively associated with CBD (odds ratio [OR] = 0.28, 95% confidence interval [CI] = 0.08-0.95) and the GCLM-588 C/C SNP genotype is associated with CBD susceptibility (OR = 3.07, 95% CI = 1.00-9.37). No differences were noted in the BeS group. CONCLUSIONS: This study suggests that GSH modulation may play a role in CBD pathogenesis, but not in sensitization to beryllium.     

The Matthew effect in environmental science publication: A bibliometric analysis of chemical substances in journal articles

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.     

Markers of high fish intake are associated with decreased risk of a first myocardial infarction

High intake of fish has been associated with reduced risk of CHD. The high content of n-3 polyunsaturated fatty acids (PUFA) in fish has been suggested to be a protective factor. In addition, fish is the entirely dominating source of methylmercury for the general population, and the concentration of Hg in erythrocytes (Ery-Hg) is often used as an index of fish consumption. Our aim was to study the relationships between a first-ever myocardial infarction, Ery-Hg, activity of gluthathione peroxidase in erythrocytes (Ery-GSH-Px) and plasma concentration of the n-3 PUFA eicosapentaenoic and docosahexaenoic acids (P-PUFA). In a population-based prospective nested case-control study within Northern Sweden seventy-eight cases of a first-ever myocardial infarction were compared with 156 controls with respect to Ery-Hg, P-PUFA and Ery-GSH-Px. Both Ery-Hg and P-PUFA, but not Ery-GSH-Px, were significantly higher in subjects reporting high fish intake (at least one meal per week) than in those with lower intake. This finding suggests that Ery-Hg and P-PUFA reflect previous long-term fish intake. Low risk of myocardial infarction was associated with high Ery-Hg or high P-PUFA. In a multivariate model the risk of myocardial infarction was further reduced in subjects with both high Ery-Hg and high P-PUFA (odds ratio 0.16, 95 % CI 0.04, 0.65). In conclusion, there is a strong inverse association between the risk of a first myocardial infarction and the biomarkers of fish intake, Ery-Hg and P-PUFA, and this association is independent of traditional risk factors.     

Influence of glutathione-related genes on symptoms and immunologic markers among vulcanization workers in the southern Sweden rubber industries

Objective The aim was to elucidate the role of genetic variants on symptoms of the eyes and airways, headache and nausea, as well as on immunologic markers, among vulcanization workers in the contemporary Swedish rubber industry. Polymorphisms in genes, which are involved in the defense against reactive oxygen species and metabolism of toxic substances present in the vulcanization fumes, were analyzed. Methods One hundred and forty-five exposed and 117 unexposed workers were included in the study. Medical and occupational histories were obtained in structured interviews. Symptoms were recorded and immunologic markers analyzed in blood. Polymorphisms in glutathione-related genes (glutamate cysteine ligase catalytic subunit (GCLC)-129, glutamate cysteine ligase modifier subunit (GCLM)-588, glutathione S-transferase alpha 1 (GSTA1)-52, GSTM1*O, GSTP1-105, GSTP1-114, and GSTT1*O) were analyzed by Taqman-based allelic discrimination and ordinary PCR. Results A protective effect of GSTA1-52 (G/A + A/A) genotype on symptoms and immunologic cells, in particular among exposed workers, was suggested. Exposed workers with GSTT1*O had increased risk of nosebleed compared to exposed workers with GSTT1*1. Exposed workers with GSTP1-105 (ile/val + val/val) had decreased levels of total immunoglobulin E (IgE) compared to exposed workers with GSTP1-105 ile/ile. GCLC-129 variant genotype demonstrated increased levels of immunologic cells among exposed workers, although statistical significance was not reached. Conclusion Our data indicate that hereditary factors influence the susceptibility to symptoms and the immunologic response of workers in the rubber industry.     

The influence of genetic polymorphisms of GSTP1 on the development of asbestosis

OBJECTIVE: Genetic factors play an important role in the development of asbestosis. The aim of this study was to investigate whether genetic polymorphisms of glutathione S-transferase (GST) P1 represent a risk factor for this disease. METHODS: The study population included 262 workers with asbestosis and 265 matched controls. Information on cumulative asbestos exposure was available. A real-time PCR based on the 5' nuclease assay was designed for the analysis of GSTP1 Ile105Val and Ala114Val polymorphisms. RESULTS: Asbestosis was associated with GSTP1 genotype coding for an enzyme with high conjugation capacity versus genotypes resulting in intermediate and low enzyme activity (odds ratio = 1.49, confidence interval = 1.06-2.10). CONCLUSIONS: The key finding of the study was that GSTP1 genotype coding for an enzyme with high conjugation capacity significantly increases the risk of developing asbestosis.     

Influence of Glutathione S-Transferase Polymorphisms on Cognitive Functioning Effects Induced by p,p′-DDT among Preschoolers

Background

Early-life exposure to p,p′-DDT [2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] is associated with a decrease in cognitive skills among preschoolers at 4 years of age. We hypothesized that genetic variability in glutathione S-transferase (GST) genes (GSTP1, GSTM1, and GSTT1) could influence the effects of prenatal exposure to p,p′-DDT.

Methods

We used data from 326 children assessed in a prospective population-based birth cohort at the age of 4 years. In that study, the McCarthy Scales of Children’s Abilities were administrated by psychologists, organochlorine compounds were measured in cord serum, and genotyping was conducted for the coding variant Ile105Val from GSTP1 and for null alleles from GSTM1 and GSTT1. We used linear regression models to measure the association between organochlorines and neurodevelopmental scores by GST polymorphisms.

Results

p,p′-DDT cord serum concentration was inversely associated with general cognitive, memory, quantitative, and verbal skills, as well as executive function and working memory, in children who had any GSTP1 Val-105 allele. GSTP1 polymorphisms and prenatal p,p′-DDT exposure showed a statistically significant interaction for general cognitive skills (p = 0.05), quantitative skills (p = 0.02), executive function (p = 0.01), and working memory (p = 0.02). There were no significant associations between p,p′-DDT and cognitive functioning at 4 years of age according to GSTM1 and GSTT1 polymorphisms.

Conclusions

Results indicate that children with GSTP1 Val-105 allele were at higher risk of the adverse cognitive functioning effects of prenatal p,p′-DDT exposure.     

Genetic background of lead and mercury metabolism in a group of medical students in Austria

Background

Information on the impact of genetic predisposition on metal toxicokinetics in the human body is limited. There is increasing evidence that certain genetic polymorphisms modify lead and mercury toxicokinetics. This called for analysis of further candidate genes.

Objectives

Medical students (N=324) were examined in order to detect potential associations between lead exposure and polymorphisms in HFE, VDR, ALAD, and MT genes, as well as between mercury exposure and GSTT1, GSTM1, GSTA1, GSTP1, GCLC, and MT polymorphisms.

Methods

The levels of lead and mercury exposure of students were determined by blood, urine, and hair analyses (ICP-MS, CV-AAS). Genotyping of common polymorphisms was examined by MALDI-TOF MS and the TaqMan methodology. Associations between lead and mercury exposures and genetic background were examined by bivariate analysis, and by categorical regression analysis (CATREG) controlled by metal- and matrix-specific variables.

Results

Lead and mercury levels in urine, blood, and hair indicated low exposures. VDR polymorphism and joint presence of VDR/ALAD polymorphisms were significantly and independently associated with urine lead concentrations (CATREG P<0.05). Polymorphisms in GSTP1-114 and MT4 genes as well as dual gene combinations including GSTP1, GCLC, GSTT1, and GSTM1 polymorphisms were independent variables related to mercury body burdens (CATREG P<0.05). GSTP1-114/GSTT1 and GSTP1-105/GCLC combinations showed synergistic effects on hair mercury levels compared to single-gene variants.

Conclusions

We found evidence that certain genetic backgrounds were associated with lead and mercury metabolism, suggesting gene-environment and gene-gene-environment interactions. The modes of interaction remain to be evaluated.     

Genetic variants associated with arsenic susceptibility: study of purine nucleoside phosphorylase, arsenic (+3) methyltransferase, and glutathione S-transferase omega genes

BACKGROUND: Individual variability in arsenic metabolism may underlie individual susceptibility toward arsenic-induced skin lesions and skin cancer. Metabolism of arsenic proceeds through sequential reduction and oxidative methylation being mediated by the following genes: purine nucleoside phosphorylase (PNP), arsenic (+3) methyltransferase (As3MT), glutathione S-transferase omega 1 (GSTO1), and omega 2 (GSTO2). PNP functions as arsenate reductase; As3MT methylates inorganic arsenic and its metabolites; and both GSTO1 and GSTO2 reduce the metabolites. Alteration in functions of these gene products may lead to arsenic-specific disease manifestations. OBJECTIVES: To find any probable association between arsenicism and the exonic single nucleotide polymorphisms (SNPs) of the above-mentioned arsenic-metabolizing genes, we screened all the exons in those genes in an arsenic-exposed population. METHODS: Using polymerase chain reaction restriction fragment length polymorphism analysis, we screened the exons in 25 cases (individuals with arsenic-induced skin lesions) and 25 controls (individuals without arsenic-induced skin lesions), both groups drinking similar arsenic-contaminated water. The exonic SNPs identified were further genotyped in a total of 428 genetically unrelated individuals (229 cases and 199 controls) for association study. RESULTS: Among four candidate genes, PNP, As3MT, GSTO1, and GSTO2, we found that distribution of three exonic polymorphisms, His20His, Gly51Ser, and Pro57Pro of PNP, was associated with arsenicism. Genotypes having the minor alleles were significantly overrepresented in the case group: odds ratio (OR) = 1.69 [95% confidence interval (CI), 1.08-2.66] for His20His; OR = 1.66 [95% CI, 1.04-2.64] for Gly51Ser; and OR = 1.67 [95% CI, 1.05-2.66] for Pro57Pro. CONCLUSIONS: The results indicate that the three PNP variants render individuals susceptible toward developing arsenic-induced skin lesions.     

铀矿工GSTP1基因多态与MGMT基因和p16基因甲基化的关系

目的探讨氡职业暴露人群谷胱甘肽S-转移酶P1(GSTP1)基因多态与痰细胞6-氧-甲基嘌呤-DNA甲基转移酶(MGMT)和p16基因甲基化的关系。方法用聚合酶链反应-限制性片段长度多态性法(PCR-RFLP)确定70例氡职业暴露人群GSTP1的基因型;用聚合酶链反应-甲基化特异性法(MSP)确定痰细胞中MGMT和p16基因的甲基化与非甲基化状态。结果在70名铀矿工中,GSTP1基因A105G位点的纯合子(Ile/Ile)42例,杂合子(Ile/Val)25例和纯合子(Val/Val)3例。MGMT、p16基因甲基化率和总甲基化率分别为14.2%、8.6%和18.6%。与携带Ile/Ile人群相比,携带异常等位基因(Ile/Val与Val/Val)的人群MGMT基因甲基化和总甲基化率增加[P=0.037,OR=4.8,95%CI(1.1~21.0);P=0.016,OR=5.1,95%CI(1.4~19.6)];p16基因甲基化率差异无统计学意义[P=0.057,OR=4.6,95%CI(0.8~29.2)]。结论GSTP1(A105G)基因多态性与氡致MGMT基因甲基化和总甲基化的易感性有关。     

联合分析XRCC1、XPD和GSTP1基因单核苷酸多态性在铂类药物化疗敏感性中的预测作用

目的 联合分析X线修复交叉互补基因1（X-rayCOrSS—complementing1,XRCCl）第194和399位点,着色性干皮病基因D（XerodermapigmentosumgroupD,XPD）第312位点及谷胱甘肽-s-转移酶P1基因（GlutathioneS-Transferasepl,GSTPl）第105位点的单核苷酸多态性（singlenucleotidepolymorphisms,SNPs）在预测铂类药物化疗敏感性中的作用。方法采用基因测序法对50例恶性肿瘤患者的外周血进行XRCCl、XPD和GSTPl基因单核苷酸多态性（SNPs）检测,分析各基因型与铂类药物化疗敏感性的关系。结果有效率高的基因型为：XRCC1194位点的Arg／Trp和Trp／Trp,XRCC1399位点的Arg／Arg,XPD312位点的Asn／Asn,GSTPl105位点的Val／Val,它们的化疗有效率分别为57．1％、75．0％、60．9％、85．7％、87．5％。有两个以上和有1个或0个高效基因型患者的化疗有效率分别是78．9％、36．4％和0,有两个以上高效基因型的患者的敏感性明显高于有1个或0个高效基因型的患者,其差异有统计学意义（x2=25．79,P〈0．01）。结论对XRCC1、XPD和GSTP1基因的单核苷酸多态性进行联合检测,可能预测患者对铂类药物的敏感性。     

Bladder cancer, GSTs, NAT1, NAT2, SULT1A1, XRCC1, XRCC3, XPD genetic polymorphisms and coffee consumption: a case–control study

The aim of the study was to investigate NAT1, NAT2, GSTM1, GSTT1, GSTP1, SULT1A1, XRCC1, XRCC3 and XPD genetic polymorphisms, coffee consumption and risk of bladder cancer (BC) through a hospital-based case–control study. The study population included 197 incident BC cases and 211 controls. The association between genetic polymorphisms, coffee drinking and BC risk was assessed by logistic regression taking into account age, education, tobacco smoking and occupational exposures to polycyclic aromatic hydrocarbons and aromatic amines. No association was found between the genetic polymorphisms investigated and BC risk according to coffee consumption apart of a significant increased BC risk among GSTP1 105-114 Val carriers heavy coffee drinkers (>3 cups/day) (OR 3.18, 95%CI 1.06–9.55). In conclusion our findings suggest a very limited role, if any, of genetic polymorphisms investigated in modulating the BC risk in coffee drinkers.     

Hematological findings in neotropical fish Hoplias malabaricus exposed to subchronic and dietary doses of methylmercury, inorganic lead, and tributyltin chloride

Hematological indices are gaining general acceptance as valuable tools in monitoring various aspects the health of fish exposed to contaminants. In this work some effects of methyl mercury (MeHg), inorganic lead (Pb2+), and tributyltin (TBT) in a tropical fish species were evaluated by hematological methods after a trophic exposition at a subchronic level. Forty-two mature individuals of the freshwater top predator fish Hoplias malabaricus were exposed to trophic doses (each 5 days) of MeHg (0.075 microg g(-1)), Pb2+ (21 microg g(-1)), and TBT (0.3 microg g(-1)) using young fish Astyanax sp. as prey vehicle. After 14 successive doses over 70 days, blood was sampled from exposed and control groups to evaluate hematological effects of metals on erythrocytes, total leukocytes and differential leukocytes counts, hematocrit, hemoglobin concentration, and red blood cell indices mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Transmission electron microscopy and image analysis of erythrocytes were also used to investigate some morphometric parameters. Results show no significant effects in MCH and MCHC for all tested metals, but differences were found in erythrocytes, hemoglobin, hematocrit, MCV, and white blood cells counts. The number of leukocytes was increased in the presence of MeHg, suggesting effects on the immune system. Also the MCV increased in individuals exposed to MeHg. No ultrastructural damages were observed in red blood cells but the image analysis using light microscopy revealed differences in area, elongation, and roundness of erythrocytes from individuals exposed to Pb2+ and TBT but not in the group exposed to MeHg. The present work shows that changes in hematological and blood indices could highlight some barely detectable metal effects in fish after laboratory exposure to contaminated food, but their application in field biomonitoring using H. malabaricus will need more detailed studies and a careful consideration of environmental parameters.     

Effect of polymorphic metabolizing genes on micronucleus frequencies among benzene-exposed shoe workers in China

It is well-known that metabolism of benzene is required for the induction of toxicity and consequent health problems. Therefore, genetic variation in benzene (BZ) metabolism genes can influence health outcomes. However, large population studies are needed to provide more evidence for such relationship. We have conducted a large population investigation (385 BZ-exposed shoe workers and 197 matched healthy controls) on the association between inheritance of certain BZ metabolizing genes and the expression of micronuclei (MN). The latter was based on the cytokinesis-blocked MN assay. We analyzed the polymorphisms of GSTM1, GSTT1, GSTP1 (rs1695), CYP2E1 (rs3813867), CYP2E1 (rs2031920), CYP2E1 (rs6413432), mEH exon 3 (rs1051740), mEH exon 4 (rs2234922). Univariate Poisson regression analysis demonstrated that the BZ-exposed workers had significantly increased MN frequency compared with the controls (FR = 1.84, 95% CI: 1.56–2.18; P < 0.001), and showed a cumulative exposure dose–response relationship. The CYP2E1 rs3813867 mutant allele (CC + GC) (FR 1.15, 95% CI 1.02–1.29; P = 0.020) and rs2031920 variant allele (CT + TT) (FR = 1.23, 95% CI: 1.09–1.37, P < 0.01) was associated with higher MN frequency significantly compared with the wild genotype separately. Furthermore, the MN frequency in rs2031920 variant allele (CT + TT) (FR = 1.17, 95% CI: 1.04–1.31, P < 0.01) was also higher than the wild genotype when the age, gender and cumulative exposure dose was adjusted in Poisson regression. In addition, the CYP2E1, however, GSTM1null, GSTT1null, GSTP1 rs1695, rs6413432, rs1051740 and rs2234922 polymorphisms showed no association with MN frequency. Our results indicate that two promoter polymorphisms in the CYP2E1 gene, especially the rs2031920 variant allele, were involved with the BZ-induction of MN and may contribute to risk of cancer among exposed workers.     

Polymorphisms in Iron Homeostasis Genes and Urinary Cadmium Concentrations among Nonsmoking Women in Argentina and Bangladesh

Background: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cd is absorbed via iron transporters.Objectives: We evaluated the impact of iron homeostasis genes [divalent metal transporter 1 (SLC11A2), transferrin (TF), transferrin receptors (TFR2 and TFRC), and ferroportin (SLC40A1)] on Cd accumulation.Methods: Subjects were nonsmoking women living in the Argentinean Andes [n = 172; median urinary Cd (U-Cd) = 0.24 µg/L] and Bangladesh (n = 359; U-Cd = 0.54 µg/L) with Cd exposure mainly from food. Concentrations of U-Cd and Cd in whole blood or in erythrocytes (Ery-Cd) were measured by inductively coupled plasma mass spectrometry. Fifty polymorphisms were genotyped by Sequenom. Gene expression was measured in whole blood (n = 72) with Illumina DirectHyb HumanHT-12 v4.0.Results: TFRC rs3804141 was consistently associated with U-Cd. In the Andean women, mean U-Cd concentrations were 22% (95% CI: –2, 51%), and they were 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In the Bangladeshi women, mean U-Cd concentrations were 22% (95% CI: 1, 48%), and they were 58% (95% CI: –3, 157%) higher in women with GA and AA versus GG genotype, respectively [adjusted for age and plasma ferritin in both groups; p_trend = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin (r_S = –0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 µg/L only, r_S = 0.40, p = 0.046). Rs3804141 did not modify these associations or predict TFRC expression. Cd was not consistently associated with any of the other polymorphisms evaluated.Conclusions: One TFRC polymorphism was associated with urine Cd concentration, a marker of Cd accumulation in the kidney, in two very different populations. The consistency of the findings supports the possibility of a causal association.     

Influence of polymorphic metabolic enzymes on biotransformation and effects of diphenylmethane diisocyanate

Objectives To identify effect modification produced by genetic traits found in metabolic enzymes, to investigate how these affect the levels of different biomarkers of sprayed and thermo-degraded polyurethane (PUR) based on 4,4′-diphenylmethane diisocyanate (MDI) and to determine how associated respiratory disorders are affected. Methods Two partly overlapping groups of 141 and 158 factory employees exposed to sprayed or heated MDI-PUR glue were examined in years 0 and 2, respectively, for occurrence of polymorphisms in five genes (N-acetyltransferase NAT2 and the glutathione S-transferases GSTM1, GSTM3, GSTP1 [codon 105 and 114] and GSTT1) on the basis of the polymerase chain reaction, exposure biomarkers in plasma and urine (P- and U-MDX), by means of gas chromatography-mass spectrometry, specific serum IgG antibodies against MDI (S-IgG-MDI) by means of ELISA, total S-IgE, symptoms in the eyes, nose and lower airways as assessed by questionnaire and interview, and lung function as measured by spirometry. Results Both the GSTP1 ¹⁰⁵ isoleucine/isoleucine and GSTP1 ¹¹⁴ alanine/alanine genotypes showed higher levels of U-MDX than the other genotypes and the GSTP1 ¹¹⁴ genotype modified the P-MDX/U-MDX relationship. GSTP1 ¹⁰⁵ isoleucine/isoleucine was found to be associated with lower levels of S-IgG-MDI and fewer eye symptoms, but with an increased risk of symptoms in the airways, as well as with atopy. Presence of the GSTT1 gene resulted in somewhat lower lung function levels than did the null genotype. A slow NAT2 acetylating capacity was associated with lower P- and U-MDX and S-IgG-MDI levels, and better lung function, but a higher risk of eye and airway symptoms. Analysing the effects of combinations of the different genes provided no further information. Conclusions Although our study has clear limitations, it reveals various effect modifications produced by the GST and NAT2 genotypes. Gene-environment interactions are highly complex. Further research is needed to obtain a more comprehensive understanding of them.     

N-acetylcysteine as a potential antidote and biomonitoring agent of methylmercury exposure

BACKGROUND: Many people, by means of consumption of seafood or other anthropogenic sources, are exposed to levels of methylmercury (MeHg) that are generally considered to be quite low, but that may nevertheless produce irreversible brain damage, particularly in unborn babies. The only way to prevent or ameliorate MeHg toxicity is to enhance its elimination from the body. OBJECTIVES: Using N-acetylcysteine (NAC), we aimed to devise a monitoring protocol for early detection of acute exposure or relatively low MeHg levels in a rodent model, and to test whether NAC reduces MeHg levels in the developing embryo. RESULTS: NAC produced a transient, dose-dependent acceleration of urinary MeHg excretion in rats of both sexes. Approximately 5% of various MeHg doses was excreted in urine 2 hr after injection of 1 mmol/kg NAC. In pregnant rats, NAC markedly reduced the body burden of MeHg, particularly in target tissues such as brain, placenta, and fetus. In contrast, NAC had no significant effect on urinary MeHg excretion in preweanling rats. CONCLUSIONS: Because NAC causes a transient increase in urinary excretion of MeHg that is proportional to the body burden, it is promising as a biomonitoring agent for MeHg in adult animals. In view of this and because NAC is effective at enhancing MeHg excretion when given either orally or intravenously, can decrease brain and fetal levels of MeHg, has minimal side effects, and is widely available in clinical settings, NAC should be evaluated as a potential antidote and biomonitoring agent in humans.