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Nonoxynol-9 Induces Apoptosis of Endometrial Explants by Both Caspase-Dependent and -Independent Apoptotic Pathways¹

Departments of Obstetrics and Gynecology,³ Pediatrics,⁴ Pathology,⁵ Keck School of Medicine, University of Southern California, Los Angeles, California 90033

Contraceptive microbicides formulated as vaginal gels offer the possibility of women-controlled contraception and prevention of HIV infection. The effects of these gels on the upper reproductive tract are largely unknown. The purpose of this study was to determine whether nonoxynol-9 (N-9) induces apoptosis in human endometrium using endometrial explant as a model. Apoptosis was determined by gel electrophoresis for the detection of DNA fragmentation and by immunohistochemistry using the M30 CytoDEATH and anti-cleaved caspase-3 (CASP3) antibodies for the detection of caspase activity. The ability of the broad-spectrum caspase inhibitor and CASP3-specific inhibitor to prevent N-9-induced cell death was measured. Expression of apoptosis-related genes such as BCL2, BAX, Fas receptor (FAS), and Fas ligand (FASLG) was quantified using real-time polymerase chain reaction (PCR) analysis. This study demonstrated that N-9 induced DNA fragmentation and caspase activity in endometrial explants in a dose- and time-dependent manner. Caspase inhibitors did not fully prevent the N-9-induced DNA fragmentation. Real-time PCR analysis revealed that FAS and FASLG were largely increased following N-9 treatment. Together, these results suggested that apoptosis triggered by N-9 in endometrial explants is mediated upstream via FAS and FASLG, followed by CASP3 activation leading to final cell death. It appears that other factors besides caspases are also involved in the N-9-induced apoptosis.

apoptosis, caspase activation, endometrial explants, female reproductive tract, gene expression, gene regulation, nonoxynol-9, uterus

² Correspondence: John K. Jain, Department of Obstetrics and Gynecology, The Keck School of Medicine of the University of Southern California, 1240 Mission St., Room 1M20, Los Angeles, CA 90033. FAX: 323 226 2850; jjain{at}usc.edu

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