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

Gerda Rentschler¹, Maria Kippler², Anna Axmon¹, Rubhana Raqib³, Eva-Charlotte Ekström⁴, Staffan Skerfving¹, Marie Vahter², Karin Broberg^1,2

¹Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden; ²Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; ³International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh; ⁴Department Women’s and Children’s Health, Uppsala University, Uppsala, Sweden

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Abstract

Background: Cadmium (Cd) is a human toxicant and carcinogen. Genetic variation might affect long-term accumulation. Cadmium is absorbed by iron transporters.

Objectives: To evaluate the impact of iron homeostasis genes (divalent metal transporter 1 SLC11A2; transferrin TF; transferrin receptors TFR2 and TFRC; ferroportin SLC40A1) on Cd accumulation.

Methods: Subjects were non-smoking women living in the Argentinean Andes [n=172; median urinary Cd (U-Cd)=0.24 μg/L] and Bangladesh (n=359; U-Cd=0.53 μg/L) with Cd exposure mainly from food. U-Cd and Cd in whole blood or erythrocytes (Ery-Cd) was measured by ICPMS. 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 Andeans, mean U-Cd concentrations were 22% (95% CI: -2, 51%) and 56% (95% CI: 10, 120%) higher in women with GA and AA genotypes, respectively, relative to women with the GG genotype. In Bangladesh, mean U-Cd concentrations were 22% (95% CI: 1, 48%) and 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 for 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 <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.

Citation: Rentschler G, Kippler M, Axmon A, Raqib R, Ekström EC, Skerfving S, Vahter M, Broberg K. Environ Health Perspect (): .doi:10.1289/ehp.1205672

Received: June 26, 2012; Accepted: February 14, 2013; Published: February 15, 2013

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