Mitochondrial activator BGP-15 protects sperm quality against oxidative damage and improves embryo developmental competence

Objective: To study the efficacy of mitochondrial activator BGP-15 to preserve sperm quality and competence against cellular damage.

Design: Spermatozoa from mice or humans were treated in vitro with BGP-15 and sperm quality markers assessed. Spermatozoa from young (8-12 weeks old) or reproductively old (>14 months old) mice were treated with BGP-15 for 1h and assessed for sperm quality and pre-implantation embryo development after in vitro fertilization (IVF). The safety of BGP-15 on offspring outcomes was assessed through embryo transfers. In parallel studies, spermatozoa from healthy (not infertile) men were incubated in hydrogen peroxide, to induce oxidative stress, plus increasing doses of BGP-15 , and sperm quality evaluated. Spermatozoa from patients undergoing assisted reproductive technology treatment (ART) were incubated in the optimized dose of BGP-15 for 30 min and sperm quality assessed.

Subjects and animals: C57BL/6 mice (N=4-15 per group) for sperm quality and embryo development. CBAF1 mice (n=6 per group) produced embryos for transfer. Human spermatozoa were from men with no infertility diagnosis (n=14-20), or men undergoing ART (n=33) at a local fertility clinic.

Exposure: Mouse spermatozoa were treated with 10μM BGP-15. Human spermatozoa were treated with BGP-15 at doses from 1μM to 100μM.

Main outcome measures: Sperm quality measures (mouse and human): motility, mitochondrial membrane potential (JC-1 dye), DNA fragmentation ('HALO' assay) and DNA oxidation (8-OHdG immunodetection). Mouse embryo and offspring measures: on-time development after IVF, morphokinetic analysis and blastocyst inner cell mass and trophectoderm cell number; growth and development from birth to 21 days post-natal.

Results: BGP-15 increased sperm motility, increased mitochondrial membrane potential and decreased DNA oxidation in old mice. BGP-15 improved on-time development of 2-cell and blastocyst embryos, and increased ICM blastomere number. Embryos from BGP-15-treated mouse spermatozoa produced normal offspring. In human spermatozoa subjected to in vitro oxidative stress, BGP-15 increased motility by 45% (p=0.03) and prevented DNA fragmentation (by 45%; p<0.0001) and oxidative damage (by 60%; p<0.0001). In spermatozoa from men attending a fertility clinic, BGP-15 increased motility by 12% (p=0.02), and reduced both DNA oxidation and fragmentation by >20% (p<0.05).

Conclusion: BGP-15 protects sperm against cellular damage and has the potential to improve ART outcomes.