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

F&S science Pub Date : 2024-12-13 DOI:10.1016/j.xfss.2024.12.001

Macarena B Gonzalez, Nicole O McPherson, Haley S Connaughton, Yasmyn E Winstanley, David T Kennedy, Carl A Campugan, Mark A Febbraio, Michael Barry M C E, Ryan D Rose, Rebecca L Robker

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Abstract

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.

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目的研究线粒体激活剂 BGP-15 保护精子质量和能力免受细胞损伤的功效：设计：用 BGP-15 对小鼠或人类的精子进行体外处理，并评估精子质量指标。用 BGP-15 处理幼鼠（8-12 周大）或生殖年龄较大（14 个月以上）的小鼠精子 1 小时，并评估精子质量和体外受精（IVF）后植入前胚胎的发育情况。通过胚胎移植评估了 BGP-15 对后代的安全性。在平行研究中，将健康（非不育）男性的精子放入过氧化氢中培养，以诱导氧化应激，同时加入剂量不断增加的 BGP-15，并对精子质量进行评估。将接受辅助生殖技术治疗（ART）患者的精子在优化剂量的 BGP-15 中培养 30 分钟，并对精子质量进行评估：C57BL/6小鼠（每组4-15只），用于精子质量和胚胎发育。CBAF1小鼠（每组6只）产生胚胎用于移植。人类精子来自没有不育诊断的男性（n=14-20），或在当地不育诊所接受人工生殖技术的男性（n=33）。主要结果测量指标：精子质量测量（小鼠和人类）：运动能力、线粒体膜电位（JC-1 染料）、DNA 断裂（'HALO' 检测）和 DNA 氧化（8-OHdG 免疫检测）。小鼠胚胎和后代测量：体外受精后的按时发育、形态动力学分析、囊胚内细胞质量和滋养层细胞数量；出生至出生后 21 天的生长发育：结果：BGP-15 提高了老龄小鼠的精子活力，增加了线粒体膜电位，减少了 DNA 氧化。BGP-15 改善了 2 细胞胚胎和囊胚的按时发育，并增加了 ICM 胚泡数量。经 BGP-15 处理的小鼠精子胚胎可产生正常的后代。在受到体外氧化应激的人类精子中，BGP-15 可使精子活力提高 45%（p=0.03），并防止 DNA 断裂（45%；p20%）：BGP-15能保护精子免受细胞损伤，并有可能改善抗逆转录病毒疗法的效果。

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