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Examination of generational impacts of adolescent chemotherapy: Ifosfamide and potential for epigenetic

Ryan P Thompson1, Daniel Beck1, Eric Nilsson1

  • 1Center for Reproductive Biology, School of Biological Sciences, Washington State University, Pullman, WA 99164-4236, USA.

Iscience
|December 5, 2022
PubMed

Insights

Chemotherapy exposure during puberty can cause disease and altered traits in grand-offspring via epigenetic transgenerational inheritance. This study in rodents revealed impacts on puberty, organ health, and anxiety levels across generations.

Area of Science:

  • Reproductive biology
  • Toxicology
  • Epigenetics

Background:

  • Chemotherapy is vital for cancer treatment but can have long-term health consequences.
  • Epigenetic transgenerational inheritance describes how environmental exposures can alter offspring phenotypes without changing DNA sequence.
  • The impact of pubertal chemotherapy exposure on subsequent generations remains incompletely understood.

Purpose of the Study:

  • To investigate if ifosfamide exposure during puberty induces epigenetic transgenerational inheritance of disease and altered phenotypes in rodent grand-offspring.
  • To identify specific pathologies and behavioral changes in descendant generations.
  • To explore the underlying epigenetic mechanisms, specifically DNA methylation patterns.

Main Methods:

  • A rodent model was utilized to assess the effects of ifosfamide exposure during puberty.
  • Phenotypic assessments included pubertal onset, kidney disease, testis pathology, and anxiety levels across F1 and F2 generations.
  • Sperm DNA methylation analysis was performed to identify differential methylated regions (DMRs) in exposed lineages.

Main Results:

  • Significant increases in pathologies like delayed puberty and kidney disease were observed in F1 generation offspring from ifosfamide-exposed females.
  • F2 generation males exhibited early pubertal onset and reduced testis pathology.
  • Both male and female F2 offspring displayed reduced anxiety levels, and differential DNA methylation was identified in sperm from F1 and F2 generations.

Conclusions:

  • Chemotherapy exposure during puberty can lead to epigenetic transgenerational inheritance of disease susceptibility and altered phenotypes in subsequent generations.
  • These findings underscore the potential for lasting health impacts across generations due to environmental exposures.
  • Germ cell cryopreservation before chemotherapy is recommended as a precautionary measure for individuals with children or plans for future offspring.
Keywords:
Developmental geneticsEpigeneticsOmics

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