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Unformatted text preview: Human Reproduction vol.14 no.3 pp.593600, 1999 OUTSTANDING CONTRIBUTION Antibodies to human ZP3 induce reversible contraception in transgenic mice with humanized zonae pellucidae Stephen Greenhouse 1,2,3 , Philip E.Castle 1 and Jurrien Dean 1 1 Laboratory of Cellular and Developmental Biology, NIDDK National Institutes of Health, Bethesda, Maryland 20892 and 2 Department of Obstetrics and Gynecology, George Washington University, Washington, DC 20037, USA 3 To whom correspondence should be addressed at: Laboratory of Cellular and Developmental Biology, NIDDK, Building 6, Room B1-26, National Institutes of Health, 6 Center Dr. MSC 2715, Bethesda, MD 20892-2715, USA The initial spermatozoonegg interaction of mammalian fertilization is mediated by the zona pellucida, an extra- cellular matrix composed of three glycoproteins (ZP1, ZP2, ZP3). These proteins are sufficiently conserved between human and mouse to form chimeric zonae pellucidae, and genetically engineered mice in which the endogenous mouse ZP3 has been replaced by human ZP3 have human- ized zonae, but normal fertility. Administration of mono- clonal antibodies to mouse ZP3 does not affect fertility in these animals, but administration of antibodies to human ZP3 results in long-term, reversible contraception. The antibodies coat the zonae pellucidae surrounding growing oocytes within the ovary and their presence in the zona matrix inhibits, but does not eliminate, sperm binding. The contraceptive effect is attributed to steric hindrance that decreases sperm binding and prevents penetration through the zona pellucida. The resumption of fertility is associated with the disappearance of antibodies from the zona matrix. No adverse effect on mating behaviour, ovarian histology or fetal development (if administered after fertilization) is detected in treated females. These results suggest that transgenic mice expressing human proteins will prove useful in assessing contraceptive efficacy of zona epitopes in the rational design of immunocontraception directed at the human zona pellucida. Key words: contraception/human ZP3/knockout mice/mono- clonal antibodies/spermatozoonovum interactions Introduction Effective contraception allows couples to control their fertility and prevent unintended pregnancies, a serious public health issue that spans all age, race and socioeconomic groups. This is particularly evident in developing countries, where maternal and infant mortality rates remain high and poverty European Society of Human Reproduction and Embryology 593 and inadequate health care are responsible for substantial human suffering. Nearly 50% of all pregnancies in the USA, and between 2464% worldwide, are unintended at the time of conception. Estimates indicate that, worldwide, the contra- ceptive needs of 120 million to 238 million couples are not metan impressive number that underscores the exigency for new technologies to control fertility (Harrison and Rosenfeld, 1996; Henshaw, 1998). To date, contraceptive methods are1996; Henshaw, 1998)....
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