Toxicology 221 (2006) 158–165
Molecular biomarkers of oxidative stress associated
with bromate carcinogenicity
Don Delker
a,∗
, Gary Hatch
b
, James Allen
a
, Bobby Crissman
c
, Michael George
a
,
David Geter
a
, Steve Kilburn
a
, Tanya Moore
a
, Gail Nelson
a
, Barbara Roop
a
,
Ralph Slade
b
, Adam Swank
a
, William Ward
a
, Anthony DeAngelo
a
a
Environmental Carcinogenesis Division, National Health and Environmental Effects Research Laboratory,
US Environmental Protection Agency, Research Triangle Park, NC 27711, United States
b
Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory,
US Environmental Protection Agency, Research Triangle Park, NC 27711, United States
c
NCBA/SEE Program, Washington, DC 20008, United States
Received 13 September 2005; received in revised form 1 December 2005; accepted 10 December 2005
Available online 27 January 2006
Abstract
Potassium bromate (KBrO
3
) is a chemical oxidizing agent found in drinking water as a disinfection byproduct of surface water
ozonation. Chronic exposures to KBrO
3
cause renal cell tumors in rats, hamsters and mice and thyroid and testicular mesothelial
tumors in rats. Experimental evidence indicates that bromate mediates toxicological effects via the induction of oxidative stress. To
investigate the contribution of oxidative stress in KBrO
3
-induced cancer, male F344 rats were administered KBrO
3
in their drinking
water at multiple concentrations for 2–100 weeks. Gene expression analyses were performed on kidney, thyroid and mesothelial cell
RNA. Families of mRNA transcripts differentially expressed with respect to bromate treatment included multiple cancer, cell death,
ion transport and oxidative stress genes. Multiple glutathione metabolism genes were up-regulated in kidney following carcinogenic
(400 mg/L) but not non-carcinogenic (20 mg/L) bromate exposures. 8-Oxodeoxyguanosine glycosylase (Ogg1) mRNA was up-
regulated in response to bromate treatment in kidney but not thyroid. A dramatic decrease in global gene expression changes was
observed following 1 mg/L compared to 20 mg/L bromate exposures. In a separate study oxygen-18 (
18
O) labeled KBrO
3
was
administered to male rats by oral gavage and tissues were analyzed for
18
O deposition. Tissue enrichment of
18
O was observed at
5 and 24 h post-KBr
18
O
3
exposure with the highest enrichment occurring in the liver followed by the kidney, thyroid and testes.
The kidney dose response observed was biphasic showing similar statistical increases in
18
O deposition between 0.25 and 50 mg/L
(equivalent dose) KBr
18
O
3
followed by a much greater increase above 50 mg/L. These results suggest that carcinogenic doses of
potassium bromate require attainment of a threshold at which oxidation of tissues occurs and that gene expression profiles may be
predictive of these physiological changes in renal homeostasis.
© 2005 Aww Research Foundation. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Potassium bromate; Oxidative stress; Gene expression; Tissue oxidation; Oxygen-18; Glutathione metabolism; Threshold; Risk assess-
ment; Molecular biomarkers
The research described in this article has been reviewed by the Health and Environmental Effects Research Laboratory, United States
Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the
Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.
∗
Corresponding author at: US Environmental Protection Agency, Environmental Carcinogenesis Division, 109 TW Alexander Drive (B143-06),
Durham, NC 27711, United States. Tel.: +1 919 541 7639; fax: +1 919 541 0694.
E-mail address: delker.don@epa.gov (D. Delker).
0300-483X/$ – see front matter © 2005 Aww Research Foundation. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.tox.2005.12.011