Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

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 [mu]g/L] and Bangladesh (n = 359; U-Cd = 0.54 [mu]g/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.sub.trend] = 0.006 (Andes) and 0.009 (Bangladesh)]. TFRC expression in blood was negatively correlated with plasma ferritin ([r.sub.S] = -0.33, p = 0.006), and positively correlated with Ery-Cd (significant at ferritin concentrations of < 30 [mu]g/L only, [r.sub.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.

KEY WORDS: ferritin, SLC11A2, SLC40A1, TF, TFR2, transferrin. Environ Health Perspect 121:467-472 (2013). http://dx.doi.org/10.1289/ehp.1205672 [Online 15 February 2013]

Cadmium (Cd) is ubiquitous in the environment. Human exposure occurs via plant-derived foods and certain seafood, as well as from tobacco smoke (Olsson et al. 2002). Evidence of adverse health effects on kidney and bone has been reported in association with low-level environmental Cd exposure in adults (Akesson et al. 2005; Engstrom et al. 2012), and recent studies have reported associations with hormone-related cancers (Akesson et al. 2008; Julin et al. 2012).

In general, intestinal absorption of Cd is low: about 5% in adults (European Food Safety Authority 2009). However, because the half-time of Cd is very long (10-30 years), even small modifications in absorption rate can affect Cd accumulation and, in turn, its toxicity. Women are more prone than men to have low iron status, which is associated with a higher absorption of Cd in the intestines (Barany et al. 2005; Berglund et al. 1994; Gallagher et al. 2011; Kippler et al. 2007). As a consequence, women usually have higher Cd levels in blood (B-Cd) and urine (U-Cd) than men (Vahter et al. 2007). Twin studies have suggested genetic influences on Cd kinetics (Bjorkman et al. 2000; Whitfield et al. 2010), particularly in women (Bjorkman et al. 2000), but specific genetic mechanisms are uncertain. The rs28366003 G allele polymorphism of the MT2A metallothionein gene was associated with increased Cd in blood and reduced zinc (Zn) in serum in a Turkish study population (Kayaalti et al. 2011), and with higher Cd levels in kidney tissue collected at autopsy (Kayaalti et al. 2010), although the findings of the latter study need to be interpreted with caution because only one subject was homozygous for the G allele.

Uptake and transport of Cd is partly accomplished by proteins in the iron homeostasis system (Vesey 2010). …

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