Decreased urinary beta-defensin-1 expression as a biomarker of response to arsenic.
Ingestion of arsenic (As) through contaminated drinking water results in increased risks of skin, lung, kidney, and bladder cancers. Due to its association with kidney and bladder cancers, we hypothesized that analysis of the urinary proteome could provide insight into the mechanisms of As toxicity. Urine from participants in a cross-sectional As biomarker study conducted in Nevada, classified as having either high (>or= 100 microg total urinary As/l) or low exposure (< 100 microg total urinary As/l) was analyzed by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Two polypeptides, 2.21 and 4.37 kDa, were significantly decreased in the high exposure group (p < 0.05) and were limited to men when stratified by sex. To replicate these findings, urine from participants in a second As study in Chile was analyzed and results confirmed the decrease of the 4.37 kDa polypeptide as well as a 4.76 kDa polypeptide among highly exposed men. These peaks were identified and confirmed as human beta-defensin-1 (HBD-1) peptides. In a separate in vitro experiment, gene expression analysis of As-treated cell lines demonstrated reduced HBD1 mRNA confirming that the observed decrease in HBD-1 resulted from As exposure. HBD-1 is an antimicrobial peptide constitutively expressed in multiple tissues including epithelial cells of the respiratory and urogenital systems. Recent studies support its role as a tumor suppressor gene for urological cancers suggesting that decreased HBD-1 levels may play a role in the development of cancers associated with As exposure. Further studies are warranted to investigate the role of HBD-1 in As-related toxicity.
School of Public Health, University of California, Berkeley, California 94720-7356, USA.
Christine M
CM
Hegedus
Christine F
CF
Skibola
Marcella
M
Warner
Danica R
DR
Skibola
David
D
Alexander
Sophia
S
Lim
Nygerma L
NL
Dangleben
Luoping
L
Zhang
Michael
M
Clark
Ruth M
RM
Pfeiffer
Craig
C
Steinmaus
Allan H
AH
Smith
Martyn T
MT
Smith
Lee E
LE
Moore
D000328:Adult; D001151:Arsenic / Q000009:adverse effects* / Q000633:toxicity; D018053:Arsenites / Q000633:toxicity; D015415:Biomarkers / Q000652:urine; D002677:Chile; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004784:Environmental Monitoring; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced; D009505:Nevada; D040081:Protein Array Analysis; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D017670:Sodium Compounds / Q000633:toxicity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D001743:Urinary Bladder / Q000187:drug effects* / Q000473:pathology; D014874:Water Pollutants, Chemical / Q000009:adverse effects* / Q000633:toxicity; D055815:Young Adult; D023083:beta-Defensins / Q000235:genetics / Q000652:urine*
D018053:Arsenites; D015415:Biomarkers; C406407:DEFB1 protein, human; D012333:RNA, Messenger; D017670:Sodium Compounds; D014874:Water Pollutants, Chemical; D023083:beta-Defensins; C017947:sodium arsenite; D001151:Arsenic