Antibodies to human ZP3 induce reversible contraception in transgenic mice with 'humanized' zonae pellucidae

The initial spermatozoon-egg interaction of mammalian fertilization is mediated by the zona pellucida, an extracellular 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and mouse to form chimeric zonae pellucidae, and genetically engineered mice in which the endogenous mouse ZP3 has been replaced by human ZP3 have 'humanized' zonae, but normal fertility. Administration of monoclonal 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.