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Title: A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2‐microglobulin

Abstract

Objectives: Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. Methods: In a cross-sectional study N = 512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd = 2.67 μg/L], moderately [U-Cd = 4.23 μg/L] and highly [U-Cd = 9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA. Results: Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend = 0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p = 0.001) and UB2M concentrations (p = 0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations betweenmore » Cd in blood and natural log-transformed UB2M (β = 1.2, 95% CI 0.72–1.6) compared to GG carriers (β = 0.30, 95% CI 0.15–0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β = 0.55, 95% CI 0.27–0.84) compared to GG carriers (β = 0.018, 95% CI − 0.79–0.11). Conclusions: MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels. -- Highlights: ► Cadmium is toxic to the kidney but the susceptibility differs between individuals. ► The toxic effect of cadmium is scavenged by metallothioneins. ► A common variant of metallothionein 1A was genotyped in 512 cadmium exposed humans. ► Variant carriers of this polymorphism showed more kidney damage from cadmium. ► The frequency of these variants needs to be taken into account in risk assessment.« less

Authors:
 [1];  [1];  [2];  [1]; ;  [3];  [1];  [2]
  1. Department of Occupational Health, School of Public Health, Fudan University, Shanghai (China)
  2. Department of Occupational and Environmental Medicine, Lund University, SE-22185, Lund (Sweden)
  3. Department of Bone Metabolism, Institute of Radiation Medicine, Fudan University, Shanghai (China)
Publication Date:
OSTI Identifier:
22216009
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 3; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABSORPTION SPECTROSCOPY; BLOOD; CADMIUM; CONCENTRATION RATIO; ENZYME IMMUNOASSAY; ENZYMES; EXCRETION; KIDNEYS; METALLOTHIONEIN; NUCLEOTIDES; POLYMERASE CHAIN REACTION; SMELTERS; TOXICITY

Citation Formats

Lei, Lijian, Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi, Chang, Xiuli, Rentschler, Gerda, Tian, Liting, Zhu, Guoying, Chen, Xiao, Jin, Taiyi, and Broberg, Karin. A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2‐microglobulin. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.006.
Lei, Lijian, Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi, Chang, Xiuli, Rentschler, Gerda, Tian, Liting, Zhu, Guoying, Chen, Xiao, Jin, Taiyi, & Broberg, Karin. A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2‐microglobulin. United States. https://doi.org/10.1016/J.TAAP.2012.09.006
Lei, Lijian, Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi, Chang, Xiuli, Rentschler, Gerda, Tian, Liting, Zhu, Guoying, Chen, Xiao, Jin, Taiyi, and Broberg, Karin. 2012. "A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2‐microglobulin". United States. https://doi.org/10.1016/J.TAAP.2012.09.006.
@article{osti_22216009,
title = {A polymorphism in metallothionein 1A (MT1A) is associated with cadmium-related excretion of urinary beta 2‐microglobulin},
author = {Lei, Lijian and Department of Epidemiology, School of Public Health, Shanxi Medical University, Shanxi and Chang, Xiuli and Rentschler, Gerda and Tian, Liting and Zhu, Guoying and Chen, Xiao and Jin, Taiyi and Broberg, Karin},
abstractNote = {Objectives: Cadmium (Cd) toxicity of the kidney varies between individuals despite similar exposure levels. In humans Cd is mainly bound to metallothioneins (MT), which scavenge its toxic effects. Here we analyzed whether polymorphisms in MT genes MT1A and MT2A influence Cd-related kidney damage. Methods: In a cross-sectional study N = 512 volunteers were selected from three areas in South-Eastern China, which to varying degree were Cd-polluted from a smelter (control area [median Cd in urine U-Cd = 2.67 μg/L], moderately [U-Cd = 4.23 μg/L] and highly [U-Cd = 9.13 μg/L] polluted areas). U-Cd and blood Cd (B-Cd) concentrations were measured by graphite-furnace atomic absorption spectrometry. MT1A rs11076161 (G/A), MT2A rs10636 (G/C) and MT2A rs28366003 (A/G) were determined by Taqman assays; urinary N-Acetyl-beta-(D)-Glucosaminidase (UNAG) by spectrometry, and urinary β2-microglobulin (UB2M) by ELISA. Results: Higher B-Cd (natural log-transformed) with increasing number of MT1A rs11076161 A-alleles was found in the highly polluted group (p-value trend = 0.033; all p-values adjusted for age, sex, and smoking). In a linear model a significant interaction between rs11076161 genotype and B-Cd was found for UNAG (p = 0.001) and UB2M concentrations (p = 0.001). Carriers of the rs11076161 AA genotype showed steeper slopes for the associations between Cd in blood and natural log-transformed UB2M (β = 1.2, 95% CI 0.72–1.6) compared to GG carriers (β = 0.30, 95% CI 0.15–0.45). Also for UNAG (natural log-transformed) carriers of the AA genotype had steeper slopes (β = 0.55, 95% CI 0.27–0.84) compared to GG carriers (β = 0.018, 95% CI − 0.79–0.11). Conclusions: MT1A rs11076161 was associated with B-Cd concentrations and Cd-induced kidney toxicity at high exposure levels. -- Highlights: ► Cadmium is toxic to the kidney but the susceptibility differs between individuals. ► The toxic effect of cadmium is scavenged by metallothioneins. ► A common variant of metallothionein 1A was genotyped in 512 cadmium exposed humans. ► Variant carriers of this polymorphism showed more kidney damage from cadmium. ► The frequency of these variants needs to be taken into account in risk assessment.},
doi = {10.1016/J.TAAP.2012.09.006},
url = {https://www.osti.gov/biblio/22216009}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 265,
place = {United States},
year = {Sat Dec 15 00:00:00 EST 2012},
month = {Sat Dec 15 00:00:00 EST 2012}
}