Developmental toxicity of 4-substituted amphetamines in mice

Area of Science:

• Pharmacology
• Developmental Toxicology
• Reproductive Toxicology

Background:

• Amphetamines are widely abused drugs with known detrimental health consequences.
• Understanding the specific risks of various amphetamine derivatives is crucial for public health.
• 4-substituted amphetamines represent a class with diverse chemical structures and potential toxicological profiles.

Purpose of the Study:

• To compare the effects of different 4-substituted amphetamines on intrauterine development, pregnancy outcomes, and postnatal survival in a mouse model.
• To evaluate maternal toxicity and reproductive wastage associated with exposure to 4-hydroxyamphetamine (4-HA), 4-methoxyamphetamine (4-MEA), 4-ethoxyamphetamine (4-ETA), 4-propoxyamphetamine (4-PPA), and 4-benzyloxyamphetamine (4-BEA).

Main Methods:

• Swiss-Webster mice were administered single daily doses (0, 50, or 100 mg/kg) of 4-substituted amphetamines from day 6 to 18 of gestation.
• Maternal toxicity, delivery outcomes, fetal development (including resorptions), and pup survival and growth were assessed.
• Postnatal development and mortality were monitored for the first three weeks of life.

Main Results:

• Maternal mortality occurred at 100 mg/kg for 4-HA, 4-MEA, 4-ETA, and 4-BEA.
• Increased resorptions were observed with 4-MEA and 4-ETA.
• Prolonged delivery, stillbirths, reduced litter size/weight, increased cannibalism, and higher pup mortality were noted with various 4-substituted amphetamines.
• Reduced body weight gain in offspring exposed to 4-HA and 4-PPA.

Conclusions:

• 4-substituted amphetamines exhibit varied maternal toxicity and pregnancy wastage.
• These compounds adversely affect parturition, pup survival, and postnatal development.
• The findings highlight the significant risks associated with exposure to these amphetamine derivatives during pregnancy.