Induction of hyperchromic microcytic anaemia by repeated oral administration of methotrexate in rats

• Published in: Journal of toxicological sciences Vol. 37; no. 5; pp. 957 - 968
• Main Authors: Kojima, Sayuri, Yoshida, Toshinori, Sasaki, Junya, Takahashi, Naofumi, Kuwahara, Maki, Shutoh, Yasufumi, Saka, Machiko, Nakashima, Nobuaki, Kosaka, Tadashi, Harada, Takanori
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Society of Toxicology 2012; Japan Science and Technology Agency
• Subjects: Anemia; Anemia - blood; Anemia - chemically induced; Anemia - pathology; Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - toxicity; Antitumor agents; Bone marrow; Bone Marrow Cells - drug effects; Bone Marrow Cells - pathology; Cancer; Cell Count; Drugs; Erythrocyte Indices; Erythrocytes; Female; Hematocrit; Hemoglobin; Hemoglobins - metabolism; Hemopoiesis; Hyperchromic microcytic anaemia; Leukocytes (neutrophilic); Lymphopenia; Male; Methotrexate; Methotrexate - administration & dosage; Methotrexate - toxicity; Oral administration; Pancytopenia; Pancytopenia - blood; Pancytopenia - chemically induced; Pancytopenia - pathology; Peripheral blood; Rats; Rats, Wistar; Reticulocytes; Sex; Spleen - drug effects; Spleen - pathology; Thrombocytopenia; Thymus Gland - drug effects; Thymus Gland - pathology; Germany, Niedersachsen, Hannover
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.37.957

Anaemia is a significant prognostic factor in cancer patients receiving anticancer drugs such as methotrexate (MTX). This study focuses on the effects of toxicological changes on the hematopoietic systems in male and female Wistar Hannover rats when MTX is orally administered at a dose of 0, 0.05, 0.15, or 0.45 mg/(kg·day) for a period of 28 days. Both male and female rats receiving 0.45 mg/kg MTX showed a decrease in the haemoglobin concentration (Hb), haematocrit, and erythrocyte count. Female rats showed a decrease in mean corpuscular volume (MCV) and an increase in cell mean Hb (CHCM) in total erythrocytes, including the mature erythrocytes. These results indicate that MTX causes the production of small, mature erythrocytes that contain a high concentration of Hb. MTX reduced the number of peripheral reticulocytes but produced the cells with a large size and a high concentration of Hb, as demonstrated by the reticulocyte MCV and CHCM as well as the content of haemoglobin per reticulocyte (CHr). Consistent with these findings, bone marrow haematopoiesis was impaired by MTX, as there was a reduction in erythroid count in rats of both sexes. The number of cells of the myeloid lineage reduced in female rats, followed by a reduction in the total leukocyte and neutrophil counts in peripheral blood. Thrombocytopenia was detected in a small population of rats. These results indicate that MTX induces hyperchromic microcytic anaemia and pancytopenia, and the use of MCV and CHCM in mature erythrocytes and reticulocytes, along with the CHr, gives a better understanding of the development and nature of anaemia.