Toxicological studies with 6-mercaptopurine in neonates

Area of Science:

• Toxicology
• Neuroscience
• Muscle Biology

Background:

• Previous studies indicated 6-mercaptopurine (6-MP) monohydrate treatment in Sprague-Dawley rats leads to muscle atrophy later in life.
• Gross signs of muscle atrophy, such as a flattened croup, were observed around 12 months of age in prior research.

Purpose of the Study:

• To determine the earliest onset of 6-MP-induced muscle atrophy using light microscopy.
• To investigate the species-specificity and age-dependency of 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 at various time points (2, 4, 6, and 16 months) using light microscopy and gross observation.
• Experiments included Wistar rats, mice, and hamsters, with varying treatment and observation periods.

Main Results:

• Light microscopy revealed muscle atrophy as early as 2 months of age in neonatally treated Sprague-Dawley rats.
• Grossly detectable atrophy occurred by 4 months, primarily affecting hindquarter muscles like the semitendinosus and soleus.
• Foreleg, intercostal, and tongue muscles, as well as sciatic nerves and internal organs, remained unaffected.
• Neonatal treatment was crucial; weanling rats treated with 6-MP showed normal muscle development.
• Wistar rats exhibited similar atrophy, but mice and hamsters did not develop muscle atrophy after neonatal 6-MP exposure.

Conclusions:

• 6-MP-induced muscle atrophy is dependent on neonatal exposure during a critical developmental window.
• The observed muscle atrophy is species-specific, with rats susceptible but mice and hamsters resistant.
• These findings highlight the potential for specific developmental periods to influence drug toxicity and long-term outcomes.