title: Low-level environmental cadmium exposure is associated with DNA hypomethylation in Argentinean women.
abstract: BACKGROUND
  Cadmium, a common food pollutant, alters DNA methylation in vitro. Epigenetic effects might therefore partly explain cadmium's toxicity, including its carcinogenicity; however, human data on epigenetic effects are lacking.
  
  
  OBJECTIVE
  We evaluated the effects of dietary cadmium exposure on DNA methylation, considering other environmental exposures, genetic predisposition, and gene expression.
  
  
  METHODS
  Concentrations of cadmium, arsenic, selenium, and zinc in blood and urine of nonsmoking women (n = 202) from the northern Argentinean Andes were measured by inductively coupled mass spectrometry. Methylation in CpG islands of LINE-1 (long interspersed nuclear element-1; a proxy for global DNA methylation) and promoter regions of p16 [cyclin-dependent kinase inhibitor 2A (CDKN2A)] and MLH1 (mutL homolog 1) in peripheral blood were measured by bisulfite polymerase chain reaction pyrosequencing. Genotyping (n = 172) for the DNA (cytosine-5-)-methyltransferase 1 gene (DNMT1 rs10854076 and rs2228611) and DNA (cytosine-5-)-methyltransferase 3 beta gene (DNMT3B rs2424913 and rs2424932) was performed with Sequenom iPLEX GOLD SNP genotyping; and gene expression (n = 90), with DirectHyb HumanHT-12 (version 3.0).
  
  
  RESULTS
  Cadmium exposure was low: median concentrations in blood and urine were 0.36 and 0.23 µg/L, respectively. Urinary cadmium (natural log transformed) was inversely associated with LINE-1 methylation (β = -0.50, p = 0.0070; β = -0.44, p = 0.026, adjusted for age and coca chewing) but not with p16 or MLH1 methylation. Both DNMT1 rs10854076 and DNMT1 rs2228611 polymorphisms modified associations between urinary cadmium and LINE-1 (p-values for interaction in adjusted models were 0.045 and 0.064, respectively). The rare genotypes demonstrated stronger hypomethylation with increasing urinary cadmium concentrations. Cadmium was inversely associated with DNMT3B (r(S) = -0.28, p = 0.0086) but not with DNMT1 expression (r(S) = -0.075, p = 0.48).
  
  
  CONCLUSIONS
  Environmental cadmium exposure was associated with DNA hypomethylation in peripheral blood, and DNMT1 genotypes modified this association. The role of epigenetic modifications in cadmium-associated diseases needs clarification.
authors.affiliation: Department of Laboratory Medicine, Division of Occupational and Environmental Medicine, Lund University, Lund, Sweden.
authors.forename: Mohammad Bakhtiar
authors.initials: MB
authors.lastname: Hossain
authors.forename: Marie
authors.initials: M
authors.lastname: Vahter
authors.forename: Gabriela
authors.initials: G
authors.lastname: Concha
authors.forename: Karin
authors.initials: K
authors.lastname: Broberg
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001118:Argentina; D001151:Arsenic / Q000097:blood / Q000652:urine; D001483:Base Sequence; D002104:Cadmium / Q000097:blood / Q000633:toxicity* / Q000652:urine; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D005506:Food Contamination; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D012643:Selenium / Q000097:blood / Q000652:urine; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D015032:Zinc / Q000097:blood / Q000652:urine; D000097584:DNA Methyltransferase 3B
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001151:Arsenic; D002104:Cadmium; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins; D012643:Selenium; D015032:Zinc; D000097584:DNA Methyltransferase 3B; C501486:MLH1 protein, human; C000619380:DNMT1 protein, human