Folate deficiency, hyperhomocysteinemia, low urinary creatinine, and hypomethylation of leukocyte DNA are risk factors for arsenic-induced skin lesions.
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.
Pilsner
J Richard
JR
Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, 60 Haven Ave., B1, New York, NY 10032 USA.
Liu
Xinhua
X
Ahsan
Habibul
H
Ilievski
Vesna
V
Slavkovich
Vesna
V
Levy
Diane
D
Factor-Litvak
Pam
P
Graziano
Joseph H
JH
Gamble
Mary V
MV
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
D003404:Creatinine; D001151:Arsenic