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Doxorubicin-induced testicular damage is related to PARP-1 signaling molecules in mice

Nazli Ece Gungor-Ordueri1, Nilay Kuscu2, Arda Tasatargil3

  • 1Department of Histology and Embryology, Medical Faculty of Biruni University, Campus, Istanbul, Turkey.

Pharmacological Reports : PR
|June 8, 2019
PubMed
Abstract

Insights

Doxorubicin causes testicular damage via PARP-1 activation. Inhibiting PARP-1 with PJ34 protected sperm motility and fertility, suggesting a therapeutic role for fertility preservation.

Area of Science:

  • Reproductive toxicology
  • Molecular biology
  • Biochemistry

Background:

  • Doxorubicin (DOX) chemotherapy induces testicular damage and apoptosis through oxidative stress.
  • Poly (ADP-ribose) polymerase (PARP) activation is a key mediator of DOX-induced apoptosis.
  • The role of PARP in DOX-induced testicular dysfunction requires further investigation.

Purpose of the Study:

  • To investigate the role of the PARP pathway in doxorubicin-induced testicular damage and infertility.
  • To evaluate the protective effects of the PARP-1 inhibitor PJ34 against DOX-induced testicular toxicity.
  • To confirm the functional link between PARP-1 and DOX using a PARP-1 knockout mouse model.

Main Methods:

  • Assessed PARP pathway activation post-DOX induction using immunohistochemistry and western blot.
  • Evaluated the impact of PJ34 on DOX-induced testicular damage, sperm motility, and fertility.
  • Utilized PARP-1 knockout mice to establish a direct correlation between PARP-1 and DOX toxicity.
  • Quantified doxorubicin levels in plasma and testicular tissue.

Main Results:

  • DOX treatment significantly increased PARP-1, PAR, and apoptotic protein expression.
  • PJ34 administration reduced PAR, cytochrome c, and AIF levels, mitigating DOX-induced damage.
  • DOX-induced decreases in testicular weight, sperm motility, and fertility were reversed by PJ34.
  • PARP-1 knockout mice exhibited significant seminiferous tubule impairment after DOX administration.

Conclusions:

  • Over-activation of PARP-1 is implicated in doxorubicin-induced testicular damage.
  • Pharmacological inhibition of PARP-1 with PJ34 effectively prevents severe testicular damage.
  • PJ34 shows potential for fertility protection in patients undergoing doxorubicin chemotherapy.
Keywords:
ApoptosisDoxorubicinMale infertilityPARP-1PJ34Testicular damage

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