Abstract
PurposeTo characterize, by specific biomarkers and nucleic acid sequencing, the structural and genomic sperm characteristics of partial (PG) and complete globozoospermic (CG) men in order to identify the best reproductive treatment.MethodsWe assessed spermatozoa from 14 consenting men ultrastructurally, as well as for histone content, sperm chromatin integrity, and sperm aneuploidy. Additional genomic, transcriptomic, and proteomic evaluations were carried out to further characterize the CG cohort. The presence of oocyte-activating sperm cytosolic factor (OASCF) was measured by a phospholipase C zeta (PLCζ) immunofluorescence assay. Couples were treated in subsequent cycles either by conventional ICSI or by ICSI with assisted gamete treatment (AGT) using calcium ionophore (Ionomycin, 19657, Sigma-Aldrich, Saint Louis, MO, USA).ResultsUltrastructural assessment confirmed complete acrosome deficiency in all spermatozoa from CG men. Histone content, sperm chromatin integrity, and sperm aneuploidy did not differ significantly between the PG (n = 4) and CG (n = 10) cohorts. PLCζ assessment indicated a positive presence of OASCF in 4 PG couples, who underwent subsequent ICSI cycles that yielded a 36.1% (43/119) fertilization with a 50% (2/4) clinical pregnancy and delivery rate. PLCζ assessment failed to detect OASCF for 8 CG patients who underwent 9 subsequent ICSI cycles with AGT, yielding a remarkable improvement of fertilization (39/97; 40.2%) (P = 0.00001). Embryo implantation (6/21; 28.6%) and clinical pregnancies (5/7; 71.4%) were also enhanced, resulting in 4 deliveries. Gene mutations (DPY19L2, SPATA16, PICK1) were identified in spermatozoa from CG patients. Additionally, CG patients unable to sustain a term pregnancy had gene mutations involved in zygote development (NLRP5) and postnatal development (BSX). CG patients who successfully sustained a pregnancy had a mutation (PIWIL1) related to sperm phenotype. PLCZ1 was both mutated and underexpressed in these CG patients, regardless of reproductive outcome.ConclusionsSperm bioassays and genomic studies can be used to characterize this gamete’s capacity to support embryonic development and to tailor treatments maximizing reproductive outcome.
Highlights
Infertility is known to affect 15% of couples of reproductive age
Transmission electron microscopy (TEM) confirmed the characteristic round-headed shape and acrosomal absence in 100% of the spermatozoa assessed from the complete globozoospermic (CG) group
We focused on the presence of oocyte-activating sperm cytosolic factor (OASCF) due to the absence of acrosome and perinuclear theca
Summary
Infertility is known to affect 15% of couples of reproductive age. Other minor contributors include infections (3%), hormones (2.3%), immunology (2.3%), ejaculatory dysfunction (1.2%), cancer (0.5%), and, as more recently recognized, systemic diseases (0.4%) [2]. All of these etiologies affect spermatozoa production and compromise the typical semen parameters. Concentration and kinetic characteristics of the male gamete are widely understood to be associated with its ability to fertilize an oocyte, sperm phenotype as evaluated by sperm morphology— in relation to the sperm head— indicates spermatozoa competence
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