title: The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma.
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 Network 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 (BM), liver, and spleen of mice exposed to a single dose (4 h) or seven 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 erythropoeitin signaling and erythropoiesis in the spleen and BM, and suppression of mechanisms that contribute to genomic stability, events that could be contributing factors to hemangiosarcoma formation. Finally, an immunohistochemistry method (Hypoxyprobe) demonstrated that tissue hypoxia was present in the spleen and BM. 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.
authors.affiliation: Genstruct, Inc., Cambridge, Massachusetts 02140, USA.
authors.forename: Daphna
authors.initials: D
authors.lastname: Laifenfeld
authors.forename: Annalyn
authors.initials: A
authors.lastname: Gilchrist
authors.forename: David
authors.initials: D
authors.lastname: Drubin
authors.forename: Milena
authors.initials: M
authors.lastname: Jorge
authors.forename: Sean F
authors.initials: SF
authors.lastname: Eddy
authors.forename: Brian P
authors.initials: BP
authors.lastname: Frushour
authors.forename: Bill
authors.initials: B
authors.lastname: Ladd
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Obert
authors.forename: Mark M
authors.initials: MM
authors.lastname: Gosink
authors.forename: Jon C
authors.initials: JC
authors.lastname: Cook
authors.forename: Kay
authors.initials: K
authors.lastname: Criswell
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Somps
authors.forename: Petra
authors.initials: P
authors.lastname: Koza-Taylor
authors.forename: Keith O
authors.initials: KO
authors.lastname: Elliston
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lawton
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D002454:Cell Differentiation; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D004920:Erythropoiesis; D004921:Erythropoietin / Q000378:metabolism; D005026:Ethylene Glycols; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006461:Hemolysis; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism* / Q000473:pathology; D049490:Systems Biology; D013997:Time Factors
chemical_list: D005026:Ethylene Glycols; D004921:Erythropoietin; C017096:n-butoxyethanol