Genetic variability and cadmium metabolism and toxicity

Abstract: Cadmium (Cd) is ubiquitous in the environment. Human exposure in non-smokers occurs mainly via intake of healthy food like vegetables, cereals, and shellfish. Adverse health effects on kidney and bone at low-level environmental Cd exposure are well-documented in adults. There is considerable inter-individual variation in both metabolism (toxicokinetics) and toxicity (toxicodynamics) of Cd. This may be due to genetic factors. The aim of this thesis was to identify genetic factors that are associated with Cd metabolism and toxicity. As Cd is a foreign element, there is no endogenous metabolism of uptake. However, there is evidence that the transporters of other elements such as iron and zinc are not sufficiently specific to prevent uptake of Cd. Further, the zinc-binding protein metallothionein (MT) protects against toxicity of Cd in the kidney. Thus, the first study examined the association of single nucleotide polymorphisms (SNPs) in iron homeostasis genes with Cd concentrations in two groups of women, one from the Argentinean Andes and the other from rural Bangladesh. The second study examined the association of SNPs in two zinc homeostasis genes, SLC39A8 and SLC39A14 with Cd concentrations in the same groups of women as in the first study. The third study analysed whether polymorphisms in the metallothionein genes MT1A and MT2A influence Cd-related kidney damage in volunteers from three areas in southern China with various degrees of Cd pollution. All study designs were cross-sectional. We found (1) that one SNP in the iron-related transferrin receptor gene TFRC (rs3804141) was associated with Cd concentrations in urine in both women from Argentina and Bangladesh: carriers of AA had 56-58% and carriers of GA had 22% higher urinary Cd concentrations than GG. The consistency of the results in two different populations hints at a causal relation. Further, we found (2) that SNPs in the zinc-related genes SLC39A14 and SLC39A8 were associated with blood Cd concentrations, for SLC39A14 this may occur via differential gene expression. Finally, we found (3) that AA carriers of rs11076161 MT1A had higher Cd concentrations in blood among individuals in the highest Cd exposure group. Also, with increasing Cd exposure, carriers of this genotype experienced more Cd-related kidney toxicity. The present data are of significance for the theoretic understanding of the metabolism and toxicology of Cd, and, at the same time they are valuable in risk assessment, an issue of great importance, in light of the non-existing range between present exposure to Cd and toxicity in many parts of the world, including Sweden