Effects of poly (ADP-ribose) polymerase inhibition on DNA integrity and gene expression in ovarian follicular cells in mice with endotoxemia

A mouse model of lipopolysaccharide (LPS)-induced inflammation was used to investigate pharmacological inhibition of nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) on oocyte maturation, apoptotic and necrotic death as well as DNA integrity of follicular cells. In addition, the relative expression of cumulus genes (HAS2, COX2 and GREM1) associated with oocyte developmental competence was assessed.

Mice were treated with PARP-1 inhibitor, 4-hydroxyquinazoline (4-HQN), 1h before LPS administration. After 24h oocyte in vitro maturation was detected. Granulosa cell DNA damage was determined by the alkaline comet assay. Live, necrotic and apoptotic cells were identified  usingdouble vital staining by fluorescent dyes Hoechst 33342 and propidium iodide. The expression levels of cumulus genes were assessed using reverse transcriptase polymerase chain reaction.

The administration of 4-HQN to LPS-treated mice ameliorated oocyte meiotic maturation and exerted a significant cytoprotective effect. 4-HQN attenuated LPS-induced DNA damage and favored cell survival by decreasing necrosis and apoptosis in granulosa cells. Exposure to 4-HQN increased mRNA expression levels for HAS2, COX2 and GREM1 in cumulus cells.

 The obtained results indicated the involvement of PARP-1 in the pathogenesis of ovarian dysfunction caused by LPS. We suppose that this enzyme can be an attractive target for the therapy of inflammatory disorders in ovary. The protective action of PARP-1 inhibition could be at least partly associated with the diminish of necrotic death of follicular cells as well as in other cells. However, the detailed mechanisms of favorable effect of PARP inhibitors on endotoxin-induced ovarian disorders  need to be further explored.