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ToxSci Advance Access published online on May 4, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl007
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received December 16, 2005
Accepted April 19, 2006

Carcinogenicity

Mechanisms of 2-Butoxyethanol-Induced Hemangiosarcomas

Stacy M. Corthals 1, Lisa M. Kamendulis 1, and James E. Klaunig 1 *

1 Division of Toxicology, Department of Pharmacology and Toxicology Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202 USA

* To whom correspondence should be addressed.
James E. Klaunig, E-mail: jklauni{at}iupui.edu


  Abstract

Chronic exposure to 2-butoxyethanol increased liver hemangiosarcomas in male mice. The mechanism for the selective induction of hemangiosarcomas by 2-butoxyethanol is unknown but has been suggested to occur through non DNA reactive mechanisms. The occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to red blood cell hemolysis and iron deposition and activation of macrophages (Kupffer cells) in the liver, events which exhibit a threshold in both animals and humans. 2-Butoxyethanol is metabolized to 2-butoxyacetaldehyde and 2-butoxyacetic acid, and although the aldehyde metabolite is short lived, the potential exists for this metabolite to cause DNA damage. The present studies examined whether 2-butoxyethanol and metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid damaged mouse endothelial cell DNA using the Comet assay. No increase in DNA damage was observed following 2- butoxyethanol (1-10 mM), 2-butoxyacetaldehyde (0.1-1.0mM), or 2-butoxyacetic acid (1-10mM) in endothelial cells after 2, 4, or 24 hrs of exposure. Additional studies examined the involvement of hemolysis and macrophage activation in 2-butoxyethanol carcinogenesis. DNA damage was produced by hemolyzed RBCs (10 x 106, 4 hrs), ferrous sulfate (0.1-1.0µM; 2-24 hrs) and hydrogen peroxide (50-100µM; 1-4 hrs) in endothelial cells. Hemolyzed RBCs also activated macrophages, as evidenced by increased TNF{alpha}, while neither 2-butoxyethanol nor butoxyacetic acid increased TNF{alpha} from macrophages. The effect of activated macrophages on endothelial cell DNA damage and DNA synthesis was also studied. Co-culture of endothelial cells with activated macrophages increased endothelial cell DNA damage after 4 or 24 hrs, and increased endothelial cell DNA synthesis after 24 hrs. These data demonstrate that 2-butoxyethanol and related metabolites do not directly cause DNA damage. Supportive evidence also demonstrated that damaged RBCs, iron and/or products from macrophage activation (possibly reactive oxygen species), produce DNA damage in endothelial cells, and that activated macrophages stimulate endothelial cell proliferation. These events coupled together provide the events necessary for the induction of hemangiosarcomas by 2-butoxyethanol.


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