Characterization of 5-Fluorouracil Daily Oral Dosing versus Dietary Restriction on Femoral Growth Plates in Rats

Abstract

We evaluated the growth plates (GPs) of rats after a 14-day reduction in food consumption caused by either daily oral dosing with 5-fluorouracil (5-FU: a positive control reducing food consumption and affecting the GPs) or a direct reduction in food consumption to determine whether the observed changes were attributable to a direct effect of drug toxicity. Histomorphometric analyses of the femoral GP were performed for a nontreated (NT) control group, three groups treated with 5-FU (12, 15, and 18 mg/kg/day) and three groups with food intake restricted to levels corresponding to those consumed by the rats in the three 5-FUtreated groups. Compared with the NT group, the GP widths and the number of chondrocytes in the proliferative zone decreased significantly in all the 5-FU-treated groups and the dietary restriction groups. Importantly, no significant differences between the 5-FU-treated groups and the groups with matched dietary restrictions were seen for most parameters. Thus, the 14-day dietary restriction caused significant changes in the proliferative zone of the GP, and similar changes observed in the 5-FU-treated groups were presumed to result from the comparable reduction in food intake rather than being a direct toxic effect of the drug.

Utility of measuring long bone length in toxicity studies: results of a 14-day repeated dose oral toxicity study of dexamethasone in young, periadolescent and adult rats

“…The percentage reduction in food intake in the 14-day diet-restricted periadolescent animal group was 15%, and no changes in the bone length or histopathology were observed in these animals. The percent reduction in food intake in the 14-day diet-restricted adult animal group was 40.3%, and a statistically significant decrease in the bone length of the femur was observed in this group without any associated histopathological changes, consistent with previous reports (Levin et al, 1993;Moriyama et al, 2008;Noguchi et al, 2019). These results also suggest that the femur is a more sensitive site for measurement of the bone length than the tibia, humerus or sternum in adult animals, similar to the results obtained in the DEXtreated adult animal group.…”

Dietary restriction inhibits bone formation in alveolar bone modeling and remodelling

“…The effects of undernutririon in bone activity were obtained in models of active ossification (5,6), but no reports are available on the effect of DR in bone remodeling.…”

“…Numerous studies have been published about its impact on the long bones development. It was shown that malnutrition, caused by prolonged fasting or dietary restriction (DR) affects total epiphyseal growth plate height, as well as the number of chondrocytes per column in the proliferative and hypertrophic zones of the epiphyseal growth plate and the size of hypertrophic chondrocytes (4,5,6).…”

“…Mandibular growth and develop is caused by endochondral ossification of the mandibular condyle and it is well documented that this type of ossification is particularly sensitive to nutritional deficiencies (4,6). Thus, DR in rats results in bone growth arrest and alterations in the size and biomechanical properties of the mandible (7,8,9).…”