Unlocking the Secrets of Fertilization Inhibition

A research team led by Yale scientists has uncovered the mechanics of a natural biological process that prevents sperm from interacting with an egg, effectively blocking fertilization.

Their discovery, made using rodent models, offers new possibilities for addressing infertility and developing contraceptive treatments. The findings were published in the Proceedings of the National Academy of Sciences.

“This research has direct implications for both infertility and contraception, particularly in the fields of immuno-infertility and immuno-contraception,” said Steven Tang, Assistant Professor of Molecular Biophysics and Biochemistry at Yale University and the study’s corresponding author.

In the U.S., fertility challenges affect approximately 9% of men and 11% of women of reproductive age. Some of these issues stem from improper recognition, adhesion, or fusion between sperm and egg cells. A key part of this process involves IZUMO1, a protein on the surface of sperm, and JUNO, a receptor on the egg, which must connect for fertilization to occur.

A naturally occurring sperm antibody, OBF13, can interfere with this connection. First identified 40 years ago at Osaka University in Japan, OBF13 binds to IZUMO1 and disrupts fertilization, though the exact mechanism remains unclear until now.

Using X-ray crystallography, the Yale team analyzed how IZUMO1 interacts with OBF13. They found that the antibody binds to sperm in a way that alters its ability to engage with an egg. The study also identified a high-affinity version of OBF13 that more effectively inhibits fertilization.

Additionally, researchers pinpointed key amino acid sites on JUNO that determine its ability to bind with IZUMO1. When these sites are accessible, fertilization can still occur despite the presence of OBF13 or its variant.

“In this study, we present the first high-resolution structure of an anti-sperm antibody-antigen complex,” Tang explained. “This insight will help us identify new IZUMO1 regulators, guide the development of antibodies and small-molecule inhibitors, and support contraceptive drug screening.”

This research not only advances our understanding of fertilization but also paves the way for potential new treatments for infertility and non-hormonal contraception options.