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Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers.

ABSTRACT: Recent research suggests that uric acid may be nephrotoxic at lower levels than previously recognized and that it may be one mechanism for lead-related nephrotoxicity. Therefore, in understanding mechanisms for lead-related nephrotoxicity, it would be of value to determine whether genetic polymorphisms that are associated with renal outcomes in lead workers and/or modify associations between lead dose and renal function are also associated with uric acid and/or modify associations between lead dose and uric acid. We analyzed data on three such genetic polymorphisms: delta-aminolevulinic acid dehydratase (ALAD), endothelial nitric oxide synthase (eNOS), and the vitamin D receptor (VDR). Mean (+/- SD) tibia, blood, and dimercaptosuccinic acid-chelatable lead levels were 37.2 +/- 40.4 microg/g bone mineral, 32.0+/- 15.0 g/dL, and 0.77+/- 0.86 microg/mg creatinine, respectively, in 798 current and former lead workers. Participants with the eNOSAsp allele had lower mean serum uric acid compared with those with the Glu/Glu genotype. Among older workers (age > or = median of 40.6 years), ALAD genotype modified associations between lead dose and uric acid levels. Higher lead dose was significantly associated with higher uric acid in workers with the ALAD1-1 genotype; associations were in the opposite direction in participants with the variant ALAD1-2 genotype. In contrast, higher tibia lead was associated with higher uric acid in those with the variant VDRB allele; however, modification was dependent on participants with the bb genotype and high tibia lead levels. We conclude that genetic polymorphisms may modify uric acid mediation of lead-related adverse renal effects.

SUBMITTER: Weaver VM

PROVIDER: S-EPMC1310911 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers.

Weaver Virginia M VM Schwartz Brian S BS Jaar Bernard G BG Ahn Kyu-Dong KD Todd Andrew C AC Lee Sung-Soo SS Kelsey Karl T KT Silbergeld Ellen K EK Lustberg Mark E ME Parsons Patrick J PJ Wen Jiayu J Lee Byung-Kook BK

Environmental health perspectives 20051101 11

Recent research suggests that uric acid may be nephrotoxic at lower levels than previously recognized and that it may be one mechanism for lead-related nephrotoxicity. Therefore, in understanding mechanisms for lead-related nephrotoxicity, it would be of value to determine whether genetic polymorphisms that are associated with renal outcomes in lead workers and/or modify associations between lead dose and renal function are also associated with uric acid and/or modify associations between lead d ...[more]

PMID: 16263504

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Project description:BackgroundExposure to lead (Pb) affects multiple health outcomes and physiological systems. In adults, even small increases in blood Pb levels have been associated with decreased glomerular filtration rate, increased risk of hypertension and increased incidence of essential tremor. To date, there have been few Pb-exposure assessments using the United States Occupational Health and Safety Administration (OSHA) regulations.ObjectiveThe aim of the present study was to assess Pb-exposure in terms of elevated blood lead levels (BLL) and urinary-δ-aminolevulinic acid (U-δ-ALA) levels of workers exposed to Pb in the lead acid battery industry in Tamil Nadu, India based on Pb exposure regulations set by the American Conference of Governmental Industrial Hygienists (ACGIH) and OSHA.Materials and methodsBLLs and U-δ-ALA were estimated in 449 male workers exposed to Pb across ten different job categories in a lead acid battery factory. Worker BLLs were estimated using atomic absorption spectrophotometry and U-δ-ALA was estimated using spectrophotometry.ResultsThe Biological Exposure Index of the American Conference of Governmental Industrial Hygienists (BEI-ACGIH) were used to assess Pb exposure. BLLs <30 μg/dL were found in 63.5% of workers, and 36.5% of workers had BLLs>30 μg/dL. The present study also assessed Pb exposure using OSHA regulations and found that 83.3% of workers had BLLs <40 μg/dL and 16.7% of workers had BLLs>40 μg/dL. Among these workers, 0.7% of workers had BLLs >60 μg/dL. An excessive excretion of U-δ-ALA (20-40 mg/L) was noted in pasting area workers (2.6%) followed by executives (2.2%) and assembly workers (0.9%).ConclusionsWorkers in the job categories of pasting and assembly, as well as executives, are at high risk of Pb exposure compared to other job categories. We recommend placing humidifiers on the roof and keeping a water bath closer the to plate cutting area to reduce fugitive Pb dust emissions. We recommended workers with BLLs >60 μg/dL be removed from jobs involving Pb exposure and return to work only when their BLLs are <40 μg/dL.Participant consentObtained.Ethics approvalThe study was approved by the ethics committee of the Regional Occupational Health Centre (Southern) Bengaluru, part of the National Institute of Occupational Health of India.Competing interestsThe authors declare no competing financial interests.

Project description:This study was undertaken to evaluate the effect of Zn and Cd pretreatment on the inhibition of delta-aminolaevulinic acid dehydratase (ALAD; porphobilinogen synthase, EC 4.2.1.24) by Pb. Male CD rats were pretreated with 200 mumol of Zn/kg s.c. (subcutaneously) or 18 mumol of Cd/kg s.c., 48 and 24 h before assay of ALAD. Pretreatment with Zn resulted in activation of hepatic and renal ALAD and attenuated the inhibition of this enzyme by Pb in vitro. Pretreatment with Cd increased hepatic ALAD activity, and the inhibitory effect of Pb on the hepatic enzyme was attenuated in this group. In contrast with the situation in liver, pretreatment with Cd did not affect the activity of renal ALAD and did not alter the inhibitory effect of Pb on the renal enzyme. The Pb IC50 (concentration causing half-maximal inhibition) values for hepatic and renal ALAD in Zn-pretreated rats and for hepatic ALAD in Cd-pretreated rats were increased above control, whereas the IC50 for renal ALAD in Cd-pretreated rats was unchanged. Cytosolic binding patterns for the three metals were assessed by gel-filtration chromatography and disclosed that 203Pb was co-eluted with Zn and Cd bound to liver and kidney Zn-thioneins and liver Cd,Zn-thionein, although minimal binding of 203Pb to kidney Cd,Zn-thionein was observed. Estimation of the molar ratio of metals bound revealed Cd/Zn ratios of 2 and 5 for Cd,Zn-thioneins from liver and kidney respectively. The inhibition of purified ALAD by Pb was also attenuated by addition of purified Zn-thioneins and Cd,Zn-thioneins from liver and kidney in the following order: liver Zn-thionein = kidney Zn-thionein greater than liver Cd,Zn-thionein much greater than kidney Cd,Zn-thionein. Thus liver and kidney Zn-thioneins and liver Cd,Zn-thionein with a low Cd/Zn ratio readily decrease the free pool of Pb available to interact with ALAD. These data also demonstrate that the capacity of metallothionein to alter the intracellular distribution of Pb and mediate the inhibition of ALAD by Pb is dependent on the tissue source and relative metal constitution of the metallothionein.

Project description:ObjectiveTo determine whether a polymorphism the in delta-aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults.MethodsThe authors studied men participating in the Department of Veterans Affairs' Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K-shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini-Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD-2, versus men without the allele.ResultsSixteen per cent of men carried the ALAD-2 allele. Median tibia and patella lead levels (first-third quartile) were 19 (13-28) and 27 (18-39) microg/g. Blood lead levels were consistent with non-occupational exposure: only 6% of men had levels > or =10 microg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD-2 carriers, among whom a 3 microg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI -0.54 to 0.01), compared with a 0.04 point lower score (95% CI -0.16 to 0.07) among non-carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (p(interaction) = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD-2 status.ConclusionsAlthough not statistically significant, these findings suggest that ALAD genotype may modify blood lead's adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.

Dataset Information

Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers.

Publications

Associations of uric acid with polymorphisms in the delta-aminolevulinic acid dehydratase, vitamin D receptor, and nitric oxide synthase genes in Korean lead workers.

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