title: Age and dose sensitivities in the 2-butoxyethanol F344 rat model of hemolytic anemia and disseminated thrombosis.
abstract: In hemolytic disorders, such as sickle cell disease and beta-thalassemia, the mechanisms of thrombosis are poorly understood. Appropriate animal models would increase the understanding of the pathophysiology of thrombosis. We previously reported that rats exposed to 2-butoxyethanol (2-BE) developed hemolytic anemia and disseminated thrombosis resembling sickle cell disease and beta-thalassemia. To characterize our model further, we investigated age- and dose-related differences in sensitivity to 2-BE. We exposed groups of 6- and 12-week-old F344 rats (5 animals/group) to 62.5, 125, and 250 mg/kg/day of 2-BE for up to 4 days. Blood was collected on days 2-4 for complete blood count and measurement of intracellular adhesion molecule-1 (ICAM-1). Histopathological evaluation was performed to find evidence of disseminated thrombosis. The maximum hemolytic response, resulting in decreased erythrocyte count and higher mean cell volume (MCV) occurred in the 12-week-old rats treated with the highest dose of 2-BE (250 mg/kg, p<0.0001). The highest increase in ICAM-1 levels occurred in the 12-week-old rats treated with 125 and 250 mg/kg 2-BE (p<0.0001). No intravascular thrombi were noted in the 6-week-old 2-BE-treated animals. The majority of intravascular thrombi occurred in the 12-week-old rats treated with 250 mg/kg 2-BE. Because our findings show age- and dose-related sensitivities, we suggest that 12-week-old rats and doses of 250 mg/kg be used in the 2-BE model.
authors.affiliation: Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lewis
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Ortel
authors.forename: Mike
authors.initials: M
authors.lastname: Streicker
authors.forename: Glenda
authors.initials: G
authors.lastname: Moser
authors.forename: Susan
authors.initials: S
authors.lastname: Elmore
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Ward
authors.forename: Shyamal
authors.initials: S
authors.lastname: Peddada
authors.forename: Abraham
authors.initials: A
authors.lastname: Nyska
mesh_terms: D000375:Aging / Q000097:blood*; D000743:Anemia, Hemolytic / Q000097:blood / Q000139:chemically induced*; D000818:Animals; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D004909:Erythrocyte Indices; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D005026:Ethylene Glycols / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced*
chemical_list: D005026:Ethylene Glycols; D018799:Intercellular Adhesion Molecule-1; C017096:n-butoxyethanol