Related Experiment Videos
Further studies on 6-mercaptopurine-induced muscle atrophy in rats, mice, and hamsters treated as neonates
Insights
Neonatal exposure to 6-mercaptopurine monohydrate (6-MP) causes muscle atrophy in rats, appearing by two months and detectable grossly by four months. This effect is species-specific and occurs only after early-life treatment.
Area of Science:
- Toxicology
- Neuromuscular Biology
- Developmental Biology
Background:
- Previous studies indicated 6-mercaptopurine monohydrate (6-MP) causes muscle atrophy in Sprague-Dawley rats later in life.
- The precise onset and characteristics of this atrophy required further investigation.
Purpose of the Study:
- To determine the earliest onset and gross signs of 6-MP-induced muscle atrophy.
- To investigate the species-specificity and critical treatment period for 6-MP-induced muscle atrophy.
Main Methods:
- Sprague-Dawley rats received daily subcutaneous injections of 6-MP (2 mg base/kg) from 2 to 22 days of age.
- Muscle tissues were examined via light microscopy and gross observation at various time points (2, 4, and 16 months).
- Additional experiments involved different rat strains (Wistar), treatment timings, and species (mice, hamsters).
Main Results:
- Muscle atrophy was observed via light microscopy as early as 2 months of age in Sprague-Dawley rats treated neonatally.
- Grossly detectable muscle atrophy, characterized by a flattened croup, appeared by 4 months of age.
- The atrophy specifically affected hindquarter muscles (thigh, soleus, psoas) but not foreleg, intercostal, or tongue muscles, nor the sciatic nerve or internal organs.
- Neonatal 6-MP treatment induced similar atrophy in Wistar rats, but not in mice or hamsters, suggesting species-specificity.
- Weanling rats treated with 6-MP showed no muscle abnormalities at 8 months, indicating the neonatal period is critical.
Conclusions:
- Neonatal exposure to 6-MP is critical for inducing muscle atrophy.
- The onset of 6-MP-induced muscle atrophy can be detected microscopically at 2 months and grossly at 4 months in rats.
- 6-MP-induced muscle atrophy exhibits species-specificity, primarily affecting rats following neonatal treatment.
Abstract:
In previous studies, we found that Sprague-Dawley rats injected with 6-mercaptopurine monohydrate (6-MP) at 2 mg base/kg sc daily from 2 to 22 days of age had atrophy of thigh and sublumbar muscles when killed at 16 months of age. The first sign of this muscle atrophy was detected grossly (flattened croup with or without paresis) at 12 months of age. In one experiment of the present work, using the same treatment in rats as above, we found that the earliest onset of muscle atrophy observed by light microscopy occurred at 2 months of age. By 4 months the atrophy could be detected grossly. The atrophy did not uniformly involve all muscles of the hindquarters; the thigh (especially the semitendinosus), leg (soleus but not the extensor carpi group), and lumbar vertebral (including the psoas) muscles were involved. Foreleg (biceps), intercostal, and tongue muscles as well as the sciatic nerve and internal organs appeared unaffected. In another experiment, weanling Sprague-Dawley rats given large daily doses of 6-MP from 25 to 45 days of age had normal muscles when killed at 8 months. In a third experiment, Wistar rats injected with 6-MP (2 mg base/kg sc) daily from 2 to 22 days of age and killed at 6 months had muscle atrophy similar to that seen in Sprague-Dawley rats. In the last experiment, mice and hamsters given large daily doses of 6-MP from 2 to 22 days of age had normal muscles when killed at 10 months. It appears from these results that the 6-MP-induced muscle atrophy occurs only after treatment during the neonatal period and that the atrophy may be species specific.