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This Article Full Text Full Text (PDF) All Versions of this Article: 79/5/849    most recent biolreprod.108.067884v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal My Folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by O'Leary, S. Articles by Robertson, S. A. Search for Related Content PubMed PubMed Citation Articles by O'Leary, S. Articles by Robertson, S. A. Agricola Articles by O'Leary, S. Articles by Robertson, S. A.

Immunization with Recombinant Murine Cytomegalovirus Expressing Murine Zona Pellucida 3 Causes Permanent Infertility in BALB/c Mice Due to Follicle Depletion and Ovulation Failure¹

Research Centre for Reproductive Health,³ Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia, Australia 5005 Discipline of Microbiology and Immunology,⁴ School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley, Western Australia, Australia 6009

ABSTRACT

Zona pellucida (ZP) glycoproteins are promising candidate antigens for use in immunocontraceptive vaccines because of their crucial role in mammalian fertilization. A single intraperitoneal immunization with recombinant murine cytomegalovirus engineered to express murine ZP3 (rMCMV-mZP3) induces permanent infertility with no evident systemic illness in female BALB/c mice. To investigate the mechanisms underpinning reproductive failure elicited by rMCMV-mZP3, ovarian parameters and reproductive function were evaluated at time points spanning 10 days to 5 wk after virus inoculation. Fertility was substantially impaired by 14 days after inoculation with rMCMV-mZP3 and was fully ablated by 21 days. Pregnancies established after inoculation but before complete infertility showed no adverse effects on fetal viability assessed at Day 17.5 post coitum (pc). Infertile mice retained estrous cycling activity and remained receptive to mating; however, at Day 3.5 pc there were fewer developing embryos and corpora lutea, plasma progesterone content was reduced, and there was no evidence of excess unfertilized oocytes. Consistent with this, profound ovarian pathology was evident from 10 days after rMCMV-mZP3 inoculation, with a decline first in mature ovarian follicles and then in immature ovarian follicles and with diminished expression of genes regulating follicle development, including Nobox, Gdf9, and Gja1 (connexin43). Follicle loss was associated with mild focal oophoritis and with recruitment of inflammatory leukocytes, predominantly CD4⁺ and CD8⁺ T cells evident from 10 days after virus inoculation. These data indicate that vaccination with rMCMV-mZP3 causes permanent infertility in BALB/c mice principally due to induction of ovarian autoimmune pathology leading to progressive oocyte depletion and eventual ovulation failure..

follicular development, immunocontraception, immunology, infertility, murine cytomegalovirus, ovarian follicle, ovary, pregnancy, zona pellucida

¹Supported by ARC Discovery Project 0559839 and by the Pest Animal Control Co-operative Research Centre.

Correspondence: ²Sarah A. Robertson, Research Centre for Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, South Australia, Australia 5005. FAX: 61 8 8303 4099; e-mail: sarah.robertson{at}adelaide.edu.au