Evaluation of Short-term Myelotoxicity Study in Dietary Reduced Rats

Abstract

This study attempted to prove our hypothesis that a short-term toxicity study, using a 4-day dosing regimen as an example, is suitable for evaluating myelotoxicity in rats. We compared the hematological, bone marrow cytological and histopathological results of 5-fluorouracil (5-FU) treated and pair-feeding groups after a 4-day administration period. Several experimental groups were defined for this 4-day study as well as for our previously reported 14-day study (Miyata et al., 2009); these included 5-FU treated groups receiving 12, 15 and 18 mg/kg/day (FU12, FU15 and FU18), pair-feeding groups (R12, R15 and R18 receiving the same amount of food as the FU12, FU15 and FU18 groups, respectively) and a nontreated control group. Although severe reductions in body weight gain and food consumption were reported in the 14-day study, only slight reductions were observed in the 4-day study. In the 4-day study, a decrease in blood reticulocytes and a decreasing trend of marrow erythroid cells were only observed in the FU18 group, and no effects were observed in the pair-feeding groups. The erythroblastic changes observed in this 4-day study were thought to reflect the direct influence of 5-FU administration. Since concerns regarding the influence of secondary changes related to undernutrition were minimized in the 4-day study, it was thought to clarify the direct influence of 5-FU administration on erythroblastic cells. Thus, a 4-day study protocol might be helpful for distinguishing secondary changes related to undernutrition.

Feature on Erythropoiesis in Dietary Restricted Rats

“…However, decreases in peripheral blood reticulocytes and bone marrow erythroids, increases in the marrow M/E ratio and SI level, and a decrease in the UIBC were observed as changes that suppressed erythropoiesis in the R33 and R66 groups and as changes that were reflected by the decrease in body weight gain. These erythropoietic changes agreed with the result of our previous studies [1,2,22] in that they sensitively reflected the influence of undernutrition. The marrow M/E ratio increased because of a decrease in the marrow erythroid counts.…”

“…We previously reported that increases in reticulocytes were observed more frequently in the 5-FU administration group (oral gavages, 15 and 18 mg/kg/day for 14 days with a 7-day recovery period) than in the corresponding pair-feeding group at the end of the recovery period, though a severe reduction in reticulocytes was observed in those groups at the end of the administration period [1,22]. These findings were not observed in a pair-feeding group in a 4-day study protocol, since concerns regarding the influence of secondary changes related to undernutrition were minimized for this short-term study protocol [2]. Burkhard et al [5] reported that anemia induced in weanling rats by feeding them an iron-deficient diet resulted in a decrease in reticulocytes with bone marrow erythroid hypoplasia, and an increase in reticulocytes was seen in these rats after a hemolytic event.…”

“…The phenomenon that decreased food consumption was designated as 'undernutrition' in this study as well as our previous studies [1,2,22]. In this study, dietary restriction groups in which feeding was restricted by 33% or 66% for 14 days were used for the experimental design.…”

The Influence of Dietary Restrictions and Malnutrition on Morphological Construction of Bone Marrow

“…This is indicative of big vulnerability of haematopoiesis to changes, especially among young animals which bone marrow cells are in constant increased proliferation and differentiation. It can be assumed that adult rats with decreased body weight caused by taking compound or medicine will be more relevant to assess their myelotoxicity [2,3]. Tang et al (2016) have carried out an interesting and innovative research in which consequences of 30% food restriction among adult animals were analysed.…”

Effect of Selected Diets/Xanthone Derivatives on Morphotic Image of Bone Marrow and Other Tissues

“…Most researchers analyzing the impact of malnutrition on hematopoiesis focused on changes in the process of erythropoiesis. However, there are also studies on other hemopoietic pathways -granulocytopoiesis, and lymphocytopoiesis [10].…”