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Toxicology

Toxicology

IF: 4.79
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Kupffer cells participate in 2-butoxyethanol-induced liver hemangiosarcomas

Published:11 April 2010 DOI: 10.1016/j.tox.2010.02.006 PMID: 20153399
Lisa M. Kamendulis, Stacy M. Corthals, James E. Klaunig

Abstract

2-Butoxyethanol increases hemangiosarcomas selectively in male mouse liver after chronic inhalation through mechanisms that have not fully been elucidated. Hemolysis, a primary toxic effect associated with 2-butoxyethanol exposure in rodents, increased hemosiderin (iron) deposition in Kupffer cells in the liver. These findings, along with the induction of hepatic neoplastic lesions, led to our hypothesis that the induction hemangiosarcomas by 2-butoxyethanol is due to the activation of Kupffer cells, subsequent to hemolysis, that results in the induction of DNA synthesis in target cells (endothelial cells); allowing for the selective proliferation of preneoplastic target cells and/or the promotion of new initiated cells. The present studies were conducted to determine whether Kupffer cells contributed to 2-butoxyethanol-induced endothelial DNA synthesis in the liver, thereby determining whether a linkage exists between these events. Male B6C3F1 mice were treated with 450 and 900?mg/kg 2-butoxyethanol (via daily gavage; 5×/week) for 7 days in the presence or absence of Kupffer cell depletion (via clodronate-encapsulated liposomes). 2-Butoxyethanol (450 and 900?mg/kg/day) increased the number of F4/80 stained cells (Kupffer cells) compared to controls (~1.3- and ~1.6-fold over control, respectively). Clodronate liposome treatment reduced the number of Kupffer cells by >90%, as assessed by F4/80 immunohistochemistry. Increased hemolysis, measured by increases in relative spleen weights and decreased hematocrit was confirmed in 2-butoxyethanol treated mice. The percentage of iron-stained endothelial cells increased by ~11-fold over control, and endothelial cell DNA synthesis increased ~1.7-fold over control in 2-butoxyethanol exposed mice. Importantly, Kupffer cell depletion reduced 2-butoxyethanol-induced iron staining and hepatic endothelial cell DNA synthesis. These studies provide evidence supporting the hypothesis that the Kupffer cell modulates 2-butoxyethanol-induced endothelial cell DNA synthesis, and therefore may contribute to hemangiosarcoma induction by 2-butoxyethanol.

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Related products
Procduct Name CAS Molecular Formula Supplier Price
2-Butoxyethanol 111-76-2 C6H14O2 817 suppliers $9.00-$400.00
Iron 7439-89-6 Fe 473 suppliers $10.00-$6520.00
F4/80 1 suppliers Inquiry
HEMOSIDERIN 9011-92-1 1 suppliers Inquiry
Pure Liposomes - Inquiry

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