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

• Published in: Pharmacological reports 2019-08, Vol.71 (4), p.591-602
• Main Authors: Gungor-Ordueri, Nazli Ece, Kuscu, Nilay, Tasatargil, Arda, Burgucu, Durmus, Karacan, Meric, Celik-Ozenci, Ciler
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - blood; Antibiotics, Antineoplastic - toxicity; Apoptosis; Body Weight - drug effects; Doxorubicin; Doxorubicin - blood; Doxorubicin - toxicity; Drug Safety and Pharmacovigilance; Infertility, Male - chemically induced; Male; Male infertility; Mice, Inbred C57BL; Mice, Knockout; Organ Size - drug effects; Original Article; PARP-1; Pharmacotherapy; Pharmacy; PJ34; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Sperm Motility - drug effects; Testicular damage; Testis - drug effects; Testis - metabolism; Testis - pathology
• ISSN: 1734-1140; 2299-5684
• DOI: 10.1016/j.pharep.2019.02.018

Doxorubicin (DOX), is a chemotherapeutic agent, which evokes oxidative stress and cell apoptosis in testicular tissue. It is known that the activation of the nuclear enzyme poly (ADP-ribose) polymerase (PARP), leading to apoptosis induced by DOX. The aim of the present study is to investigate whether PARP pathway has a role in DOX-induced testicular damage and infertility utilizing pharmacological PARP-1 inhibitor, PJ34, and PARP-1 knockout mice model. Firstly, we assessed the activation of PARP pathway after DOX-induction at various hours by immunohistochemistry and western blot analysis. Secondly, we evaluated the role of PARP pathway in DOX-induced testicular damage, sperm motility, and fertility with pharmacological inhibition of PARP by using PJ34. Finally, we aimed to correlate a functional relationship between PARP-1 and DOX using PARP-1 knockout mice in DOX-induced testicular damage. Doxorubicin levels in plasma and testis tissue were also assessed. In DOX-induced group; PARP-1, PAR and apoptotic pathway protein expressions, increased significantly. In DOX + PJ34 group; PAR, cytochrome c, and AIF levels decreased significantly. Testicular weights, sperm motility, and mean the number of pups per litter decreased in DOX-induced group after 28 days, however they were similar to the control group in DOX-PJ34 group. In PARP-1 KO group, seminiferous tubule morphology was impaired significantly after 28 days of DOX-administration. Our study indicates that DOX-induced testicular damage may be related to over-activation of PARP-1. PJ34 application was effective in preventing severe testicular damage caused by DOX-injection and may be considered for fertility protection against DOX-induced testicular damage.