title: Folate deficiency, hyperhomocysteinemia, low urinary creatinine, and hypomethylation of leukocyte DNA are risk factors for arsenic-induced skin lesions.
abstract: BACKGROUND
  Arsenic methylation relies on folate-dependent one-carbon metabolism and facilitates urinary As elimination. Clinical manifestations of As toxicity vary considerably among individuals and populations, and poor methylation capacity is thought to confer greater susceptibility.
  
  
  OBJECTIVE
  After determining that folate deficiency, hyperhomocysteinemia, and low urinary creatinine are associated with reduced As methylation, and that As exposure is associated with increased genomic methylation of leukocyte DNA, we asked whether these factors are associated with As-induced skin lesion risk among Bangladeshi adults.
  
  
  METHODS
  We conducted a nested case-control study of 274 cases who developed lesions 2 years after recruitment, and 274 controls matched to cases for sex, age, and water As.
  
  
  RESULTS
  The odds ratios and 95% confidence intervals (CIs) for development of skin lesions for participants who had low folate (< 9 nmol/L), hyperhomocysteinemia (men, > 11.4 micromol/L; women, > 10.4 micromol/L), or hypomethylated leukocyte DNA at recruitment (< median) were 1.8 (95% CI, 1.1-2.9), 1.7 (95% CI, 1.1-2.6), and 1.8 (95% CI, 1.2-2.8), respectively. Compared with the subjects in the first quartile, those in the third and fourth quartiles for urinary creatinine had a 0.4-fold decrease in the odds of skin lesions (p < 0.01).
  
  
  CONCLUSIONS
  These results suggest that folate deficiency, hyperhomocysteinemia, and low urinary creatinine, each associated with decreased As methylation, are risk factors for As-induced skin lesions. The increased DNA methylation associated with As exposure previously observed, and confirmed among controls in this study, may be an adaptive change because hypomethylation of leukocyte DNA is associated with increased risk for skin lesions.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Ave., B1, New York, NY 10032 USA.
authors.forename: J Richard
authors.initials: JR
authors.lastname: Pilsner
authors.forename: Xinhua
authors.initials: X
authors.lastname: Liu
authors.forename: Habibul
authors.initials: H
authors.lastname: Ahsan
authors.forename: Vesna
authors.initials: V
authors.lastname: Ilievski
authors.forename: Vesna
authors.initials: V
authors.lastname: Slavkovich
authors.forename: Diane
authors.initials: D
authors.lastname: Levy
authors.forename: Pam
authors.initials: P
authors.lastname: Factor-Litvak
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Graziano
authors.forename: Mary V
authors.initials: MV
authors.lastname: Gamble
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001151:Arsenic / Q000633:toxicity*; D003404:Creatinine / Q000652:urine*; D019175:DNA Methylation / Q000502:physiology; D005260:Female; D005494:Folic Acid Deficiency / Q000503:physiopathology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000503:physiopathology*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012871:Skin Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult
chemical_list: D003404:Creatinine; D001151:Arsenic