Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

Abstract

Most people generally ingest cadmium in their food. Cadmium that has accumulated in tissues induces the synthesis of metallothioneins (MTs) which are metal-binding proteins that bind tightly to cadmium to inhibit its renal toxicity. Individuals whose ability to induce the synthesis of MTs is low seem likely to be particularly susceptible to the toxic effects of cadmium. In this study, we analyzed the polymorphism of the promoter region of the gene for MT-IIA, the major species of MT in humans, in 119 adult Japanese subjects. We found that about 18% of the subjects had an A --> G single-nucleotide polymorphism in the core region of the promoter near the TATA box. A reporter-gene assay using HEK293 cells showed that replacement of A by G at position -5 reduced the efficiency of the cadmium-induced transcription of the gene for MT-IIA. This single-nucleotide polymorphism inhibited the binding of nuclear proteins to the core promoter region of the gene for MT-IIA. When the promoter region upstream of the TATA box was replaced by a sequence that contained three dioxin-responsive elements, the reporter-gene assay demonstrated that the A --> G single-nucleotide polymorphism resulted in a marked reduction in the rate of dioxin-induced transcription. These results suggest that the A --> G single-nucleotide polymorphism reduces the efficiency of those aspects of the transcription of the gene for MT-IIA that are controlled by general transcription factors.

Individual Susceptibility to Cadmium Toxicity and Metallothionein Gene Polymorphisms: with References to Current Status of Occupational Cadmium Exposure

“…The genotypes of A/A, A/G, and G/G accounted for 98 (82.4%), 20 (16.8%), and 1 (0.8%) of them, respectively. We also confirmed that the A G SNP significantly reduced cadmium-induced transcription of the metallothionein-2A gene 72) , suggesting that although only one of our study participants had the G/G type, people with this genotype might be more sensitive to cadmium toxicity than those with the A/A type, because of a limited ability to induce metallothionein synthesis. Workers with the metallothionein-2A G/G genotype (perhaps also the A/G type) who work in industries that handle cadmium might be prone to developing various biological dysfunctions when exposed to cadmium, because cadmium affects various biological processes (see Discussion).…”

“…Since cadmium induces metallothionein synthesis at the transcriptional level, we analyzed genetic polymorphisms of the region around the transcriptional start site (a known promoter region) of the metallothionein-2A gene, the main isoform of human metallothionein genes 72) . We isolated DNA from blood samples provided by 119 Japanese individuals and used PCR to amplify a 222-base pair (bp) fragment located 202 bp upstream and 20 bp downstream of the transcription start site.…”

The effects of metallothionein 2A polymorphism on lead metabolism: are pregnant women with a heterozygote genotype for metallothionein 2A polymorphism and their newborns at risk of having higher blood lead levels?

“…It has been shown that the -5 A/G SNP in the MT2A reduces the eYciency of the induction of gene transcription by heavy metals (Kita et al 2006), whereupon lack of metallothionein gene expression makes the organism more sensitive to the toxic eVects of heavy metals (Nordberg 1998). In previous studies, it was found that the core promoter region polymorphism of metallothionein 2A increases the accumulation of Cd in human renal cortex , and the eVects of metallothionein 2A polymorphism on placental cadmium accumulation were shown (Tekin et al 2011).…”

Early biomarkers of cadmium exposure and nephrotoxicity

“…In a later study examining DNA isolated from leukocytes, a single-nucleotide polymorphism in the promoter region of the methallothionein-IIA gene was found in 18% of 119 Japanese subjects (Kita et al 2006). HEK293 cells expressing this single-nucleotide polymorphism had significantly decreased metallothionein expression in the presence of Cd (Kita et al 2006). Interestingly, Yoshida et al (1998) reported that there was no correlation between low metallothionein expression and renal-related cause of death or any signs of overt, renal pathology.…”

“…One explanation for this may be genetic differences in the promoter region of the methallothionein gene. In a later study examining DNA isolated from leukocytes, a single-nucleotide polymorphism in the promoter region of the methallothionein-IIA gene was found in 18% of 119 Japanese subjects (Kita et al 2006). HEK293 cells expressing this single-nucleotide polymorphism had significantly decreased metallothionein expression in the presence of Cd (Kita et al 2006).…”