The prospective role of abnormal methyl metabolism in cadmium toxicity.

Abstract

Several lines of evidence point to the probable role of abnormal methylation processes in the toxicology of metals and other xenobiotics. The spectrum of toxic effects exhibited by such metals as Ni, As, and Cd, as well as by Zn deficiency, often resemble those seen in animals chronically fed methyl-deficient diets. These metal-associated pathologies include cancer, atherosclerosis, birth defects, neurological disturbances, and pancreatic lesions. In addition, each of the above agents has been shown to alter normal methyl group metabolism in vivo or in vitro. In the present studies, we compared the effects on the enzyme DNA methyltransferase (MTase) of two metal ions: the essential metal Zn and the carcinogen Cd. MTase extracts were obtained from the hepatic nuclei of rats fed a methyl-deficient diet (lacking choline and folate) for 7 and 24 weeks. Control animals were fed the same diet supplemented with each of these vitamins. Zn and Cd both inhibited MTase in the nuclear extracts from both the control and the methyl-deficient rats. The inhibitory activity of Cd was greater than that of Zn regardless of whether the nuclear extracts were from the control or the deficient animals. In addition, the kinetics of Cd inhibition of MTase activity were different in the nuclear extracts from the control and methyl-deficient rats. The results provide evidence that the carcinogenic effects of Cd may be mediated in part through abnormal DNA methylation. Key words: Cd, Zn, carcinogenesis, DNA methyltransferase, methyl deficiency.

Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD

“…To determine whether developmental exposure to Pb interfered with DNA-methylation patterns, we examined the activity of DNA methyltransferase 1 (DNMT1) in the 23-year-old primate brain tissues. The activity of this methylating enzyme is selective for cytosine in a CpG dinucleotide, which is base-paired to a methylated CpG sequence on the complementary strand of DNA and is directly proportional to the abundance of methyl groups on CpG dinucleotides in the DNA (Poirier and Vlasova, 2002;Takiguchi et al, 2003). We found the activity of DNMT1 to be reduced by ϳ20% in brain tissue derived from developmentally Pb-exposed primates (Fig.…”

“…However, hypermethylation of the RELN gene has been shown to associate with schizophrenia (Abdolmaleky et al, 2005), indicating that latent pathogenic effects of epigenetic perturbations may work on more than one mechanism. Although our work specifically addressed latent effects of Pb, other metals may have a similar effect (Poirier and Vlasova, 2002;Takiguchi et al, 2003).…”

Epigenetic reprogramming and imprinting in origins of disease

“…Short-term exposure of rat liver cells to cadmium inhibited DNA methyltransferase activity, but prolonged exposure to this metal ion caused neoplastic transformation and attended increases in DNA methylation and DNA methyltransferase activity [66]. The pathologies of heavy metal (Ni, As, and Cd) toxicity in rodents resemble those seen in animals fed a methyl-deficient diet (lacking choline and folate) [67]. The metal ions, as well as the diet, significantly inhibited DNA methyltransferase activity, perhaps leading to hypomethylation of disease-causing genes.…”

Emerging Roles of Cadmium and Heme Oxygenase in Type-2 Diabetes and Cancer Susceptibility

“…Abnormal methylation or one-carbon metabolism has emerged as one of the potential mechanism that could underlie cadmium epigenetic effects. This was first observed in rats chronically fed with methyl-deficient diets (Poirier and Vlasova 2002) and later seen in studies of human urinary metabolite profiles (Ellis et al 2012). The new challenge now is to probe mechanisms of cadmium causation of epigenetic changes for which strategies for reversal of effects and prevention of effects can be developed.…”