Paternal exposure to methylphenidate causes behavioral abnormalities in grandchildren

Area of Science:

• Neurodevelopmental disorders
• Epigenetics
• Generational health

Background:

• Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder treated with methylphenidate (MPH).
• Paternal environmental factors can impact offspring health, potentially leading to transgenerational effects.
• Previous studies showed MPH administration to sires affected F1 generation behavior and memory.

Purpose of the Study:

• To investigate the transgenerational effects of paternal methylphenidate (MPH) exposure on the F2 generation.
• To examine the impact on development, behavior, and brain gene expression.
• To explore the extent of MPH-induced epigenetic modifications across generations.

Main Methods:

• Paternal administration of MPH to mice.
• Assessment of F2 generation development, including birth rates, survival, body weight, and motor development.
• Behavioral analyses (anxiety, learning, memory) in F2 offspring.
• Transcriptome analysis of the female F2 cortex.

Main Results:

• MPH exposure did not affect birth rates or survival but reduced F2 body weight.
• Transient delays in motor development were observed, normalizing by weaning.
• Reduced anxiety-like behaviors were noted in the MPH group, especially in females; learning and memory remained unaffected.
• Transcriptome analysis indicated activation of neuroplasticity pathways in female F2 offspring.

Conclusions:

• Paternal MPH exposure can induce behavioral abnormalities in the F2 generation, suggesting transgenerational epigenetic inheritance.
• Observed effects, particularly reduced anxiety, may be mediated by epigenetic changes in germ cells.
• This study highlights the potential for environmental factors, including medication, to influence offspring health beyond direct exposure.