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.