Article

Age and dose sensitivities in the 2-butoxyethanol F344 rat model of hemolytic anemia and disseminated thrombosis.

Hadassah Medical Center, Hebrew University, Jerusalem, Israel.
Experimental and Toxicologic Pathology (Impact Factor: 2.01). 04/2007; 58(5):311-22. DOI: 10.1016/j.etp.2006.11.003
Source: PubMed

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.

Download full-text

Full-text

Available from: Deborah Lewis, Aug 21, 2015
0 Followers
 · 
189 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally-accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature and differential diagnosis for classifying microscopic lesions observed in the hepatobiliary system of laboratory rats and mice, with color microphotographs illustrating examples of some lesions. The standardized nomenclature presented in this document is also available for society members electronically on the internet (http://goreni.org). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous and aging lesions as well as lesions induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions of the hepatobiliary system in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists.
    Toxicologic Pathology 12/2010; 38(7 Suppl):5S-81S. DOI:10.1177/0192623310386499 · 1.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Female rats develop haemolytic anaemia and disseminated thrombosis and infarction in multiple organs, including bone, when exposed to 2-butoxyethanol (BE). There is growing evidence that vascular occlusion of the subchondral bone may play a part in some cases of osteoarthritis. The subchondral bone is the main weight bearer as well as the source of the blood supply to the mandibular articular cartilage. Vascular occlusion is thought to be linked to sclerosis of the subchondral bone associated with disintegration of the articular cartilage. The aim of this study was to find out whether this model of haemolysis and disseminated thrombosis supports the vascular hypothesis of osteoarthritis. Six female rats were given BE orally for 4 consecutive days and the two control rats were given tap water alone. The rats were killed 26 days after the final dose. The mandibular condyles showed histological and radiological features consistent with osteoarthritis in three of the four experimental rats and in neither of the control rats. These results may support the need to explore the vascular mechanism of osteoarthritis further.
    British Journal of Oral and Maxillofacial Surgery 01/2011; 49(1):21-5. DOI:10.1016/j.bjoms.2009.11.011 · 1.13 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Disseminated intravascular coagulation (DIC) is a severe clinical condition with activation of coagulation and fibrinolysis. Its diagnosis is based on the International Society of Thrombosis and Haemostasis (ISTH) scoring system of DIC. Animal models of DIC, used to investigate pathophysiology and evaluate treatments, have not been developed in a standardized way, which impedes comparison between models and translation to the human setting. In the current review of animal models of DIC an overview of species, inducers, and dosing regimens is provided. Diagnostic approaches are compared in the light of the ISTH score and treatments tested in animal models of DIC are summarized. Systematic analysis revealed that the rat is by far the preferred species amongst animal models of DIC and lipopolysaccharides (LPS) the preferred inducer of DIC. An overview of the reporting of ISTH DIC score parameters elucidated that only about 25% of the studies measure all of the four parameters necessary for the implementation the ISTH scoring system. Furthermore, most therapeutic interventions tested in animal models of DIC are administered prophylactically, which may be irrelevant to the clinical setting and could explain why compounds effective in preclinical animal models often fail in clinical trials. It is concluded that Implementation of a scoring system in animal models of DIC may increase the ability to compare DIC amongst animal models and improve the translational aspect of treatment effect.
    Thrombosis Research 08/2011; 128(2):103-16. DOI:10.1016/j.thromres.2010.12.002 · 2.43 Impact Factor
Show more