O-251 Defining the exclusive role of male genome integrity on conceptus development
Authors: Ng L , Kocur O , Xie P , Sung C , Souness S , Rosenwaks Z , Palermo G 
Published: June 2022

Abstract

Study question
To determine the effect of sperm DNA fragmentation on embryo development by ruling out a female factor component.

Summary answer
By utilizing healthy donor oocytes, it is possible to quantify the sole deleterious effect of sperm DNA fragmentation and explore the ooplasmic repair mechanism.

What is known already
In approximately 50% of couples with unexplained ART failure, a subtle male factor is present that is missed in a conventional semen analysis assessing concentration, motility, and morphology. Additional information on male gamete competence can be acquired by assessing Sperm Chromatin Fragmentation (SCF). Indeed, a fragmented male genome can give rise to poorly developing embryos, leading to impaired implantation, lower pregnancy, and higher miscarriage rates. It has been previously seen that an oocyte, according to its age, can repair the damaged DNA contributed by the male gamete.

Study design, size, duration
In last decade, 316 couples, who have an elevated SCF, underwent ICSI cycles and resulted in disappointing clinical outcomes. To exclude an eventual confounding female factor, couples who utilized donor oocytes were identified and clinical outcome was compared to a control. To measure the role of an impaired sperm genome and a concurrent oocyte repair mechanism, we compared clinical outcomes between cycles in the same couples who used their own and subsequently donor oocytes.

Participants/materials, setting, methods
We included 381 couples screened for SCF; 65 underwent ICSI cycles with donor oocytes; of these, 46 underwent a previous ICSI cycle with their own oocytes. Fertilization, implantation, clinical pregnancy, and delivery rates were compared between above-mentioned groups. A TUNEL assay was used to measure SCF (≥500 spermatozoa were assessed/sample at a 15% threshold). Paired t and Chi-square tests were used to compare ages and clinical outcomes, respectively.

Main results and the role of chance
We included 381 couples (maternal age, 37.8 ± 4.2; paternal age, 41.8 ± 8.2), whose male partners had the following semen parameters: average volume of 2.5 mL, concentration of 25.4x106/mL, 33% motility, and normal morphology of 1.7. Of these, 316 had elevated average DNA fragmentation of 25.5% and utilized their own oocytes in 683 ICSI cycles, resulting in a 67.5% fertilization, 12.2% implantation, 27.9% clinical pregnancy, and a 22.5% ongoing/delivery. Of the 381 couples, 65 underwent ICSI utilizing donor oocytes (SCF of 24.3%) resulting in a significantly higher fertilization (78.4%) (P &lt; 0.00001) and embryo implantation rates (34.2%) (P &lt; 0.0001). Similarly, albeit not statistically significant, the clinical pregnancy and ongoing/delivery rates increased from 27.9% to 37.1% and from 22.5% to 30.0%, respectively.
To further explore the exclusive role of the male gamete in embryo development, we identified a cohort of patients (n = 46), with an elevated average DNA fragmentation of 23.6%, who underwent an ICSI cycle using their own oocytes and a subsequent cycle using donor oocytes. Compared to cycles where couples used their own oocytes, fertilization, embryo implantation, clinical pregnancy, and ongoing/delivery rates rose from 67.5% to 76.6% (P &lt; 0.0001), 2.8% to 24.7% (P &lt; 0.00001), 8.4% to 38.8% (P &lt; 0.0001), and 1.2% to 28.6% (P &lt; 0.00001), respectively.

Limitations, reasons for caution
Although this study attempts to control for a concurrent confounding female factor, it cannot be completely excluded. It is difficult to assess the extent and contribution of the ooplasmic repair mechanisms on the male genome.

Wider implications of the findings
Ooplasmic repair mechanisms of healthy female gametes appear to repair or improve the deleterious impact of sperm DNA fragmentation on ART outcomes.

Trial registration number
not applicable