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ToxSci Advance Access published online on October 7, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp213
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

The Role of Hypoxia in 2-Butoxyethanol-induced Hemangiosarcoma

Daphna Laifenfeld*, Annalyn Gilchrist*, David Drubin*, Milena Jorge*, Sean F. Eddy*, Brian P. Frushour*, Bill Ladd*, Leslie A. Obert§, Mark M. Gosink§, Jon C. Cook§, Kay Criswell§, Christopher J. Somps§, Petra Koza-Taylor§, Keith O Elliston* and Michael P. Lawton§,¶

* Genstruct Inc., Cambridge, MA 02140 § Pfizer Global Research and Development, Groton, CT 06340

To whom correspondence should be addressed: Dr. Michael P. Lawton, Pfizer Global Research and Development, Eastern Point Road, MS8274-1234, Groton, CT 06340, 860-441-1568 (phone), 860-715-7455 (fax), michael.lawton{at}pfizer.com (email)

Received July 6, 2009; revision received August 27, 2009; accepted September 4, 2009


  Abstract

To understand the molecular mechanisms underlying compound-induced hemangiosarcomas in mice, and therefore their human relevance, a systems biology approach was undertaken using transcriptomics and Causal NetworkTM Modeling from mice treated with 2-butoxyethanol (2-BE). 2-BE is a hemolytic agent that induces hemangiosarcomas in mice. We hypothesized that the hemolysis induced by 2-BE would result in local tissue hypoxia, a well-documented trigger for endothelial cell proliferation leading to hemangiosarcoma. Gene expression data from bone marrow, liver, and spleen of mice exposed to a single dose (4h) or 7 daily doses of 2-BE were used to develop a mechanistic model of hemangiosarcoma. The resulting mechanistic model confirms previous work proposing that 2-BE induces macrophage activation and inflammation in the liver. In addition, the model supports local tissue hypoxia in the liver and spleen, coupled with increased Epo signaling and erythropoiesis in the spleen and bone marrow, and suppression of mechanisms that contribute to genomic stability, events that could be contributing factors to hemangiosarcoma formation. Finally, an immunohistochemistry method (HypoxyprobeTM) demonstrated that tissue hypoxia was present in the spleen and bone marrow. Together, the results of this study identify molecular mechanisms that initiate hemangiosarcoma, a key step in understanding safety concerns that can impact drug decision processes, and identified hypoxia as a possible contributing factor for 2-BE-induced hemangiosarcoma in mice.

Key Words: Hemangiosarcoma; hypoxia; angiogenesis; endothelial cells; endothelial precursor cells; mechanism of action; human relevance; 2-butoxyethanol.


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