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Decreased piRNAs in Infertile Semen Are Related to Downregulation of Sperm MitoPLD Expression.

ABSTRACT: Currently, the molecular mechanisms underlining male infertility are still poorly understood. Our previous study has demonstrated that PIWI-interacting RNAs (piRNAs) are downregulated in seminal plasma of infertile patients and can serve as molecular biomarkers for male infertility. However, the source and mechanism for the dysregulation of piRNAs remain obscure. In this study, we found that exosomes are present in high concentrations in human seminal plasma and confirmed that piRNAs are predominantly present in the exosomal fraction of seminal plasma. Moreover, we showed that piRNAs were significantly decreased in exosomes of asthenozoospermia patients compared with normozoospermic men. By systematically screening piRNA profiles in sperms of normozoospermic men and asthenozoospermia patients, we found that piRNAs were parallelly reduced during infertility. At last, we investigated the expression of some proteins that are essential for piRNAs biogenesis in sperms and therefore identified a tight correlation between the levels of spermatozoa piRNA and MitoPLD protein, suggesting that the loss-of-function of MitoPLD could cause a severe defect of piRNA accumulation in sperms. In summary, this study identified a parallel reduction of piRNAs and MitoPLD protein in sperms of asthenozoospermia patients, which may provide pathophysiological clues about sperm motility.

SUBMITTER: Hong Y

PROVIDER: S-EPMC8315149 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Low serum testosterone is found in approximately 15% of subfertile men. Although testosterone is essential in spermatogenesis, it is unclear whether low testosterone levels may have a negative impact on the semen parameters of men belonging to infertile couples with a total sperm count greater than 5 million. Furthermore, it is debatable whether the initial evaluation of the subfertile male should include an endocrine assessment. This was a retrospective, single-center cohort study conducted at a tertiary fertility clinic. Male partners of infertile couples undergoing in vitro fertilization (IVF), with a total sperm count greater than 5 million, were included. All men provided morning blood samples, and none had been on exogenous testosterone or other relevant medications. Low total testosterone (TT) was defined as <264 ng/dL. Free T was calculated using TT and sex hormone-binding globulin (SHBG) levels (nmol/L) by a constant albumin concentration of 43 g/L. In total, 853 patients were included: 116 had low TT (<264 ng/dL) and 737 had normal TT (?264 ng/dL). Semen volume, sperm cell count, progressive (A + B) motility and morphology (?4% strict Kruger) were lower in the low TT group but not significantly different between low and normal TT groups (3.2 ± 1.79 vs. 3.23 ± 1.64, p = 0.87; 76.82 ± 83.18 vs. 67.55 ± 57.70, p = 0.7; 54.89 ± 19.45 vs. 56.25 ± 19.03, p = 0.6; 5.77 ± 3.23 vs. 6.89 ± 3.94, p = 0.23). The percentage of patients with below-reference sperm volume (<1.5 mL), cell count (<15 × 106/mL), motility (A + B) (<32%) and morphology (<4%) was higher in the low TT group but not statistically different compared to the normal TT group. Multivariable regression analysis revealed that low TT and free T levels had no significant effect on the aforementioned semen parameters (coefficient: 3.94, 0.88, 1.37, 0.39; p = 0.53, 0.8, 0.3, 0.2; coefficient: 0.001, 0.06, 0.007, 0.0002; p = 0.73, 0.52, 0.85, 0.98). Despite our robust methodological approach, the presence of biases related to retrospective design cannot be excluded. Our findings highlighted the lack of association between low TT levels and semen parameter alterations in male partners of infertile couples undergoing IVF, with a total sperm count greater than 5 million. However, it is important to emphasize that more patients in the low TT group had subnormal semen parameters, albeit the difference was not statistically significant. Larger, prospective studies are warranted in order to validate these findings, as well as to investigate the existence of a TT threshold below which semen parameters might be negatively affected.

Project description:WBP2NL/PAWP, a protein found in the post-acrosomal region of mammalian spermatozoa, has been proposed as a sperm-borne oocyte-activating factor (SOAF) contributing to Ca2+ release within the oocyte and subsequent fertilization and embryo development. However, its relevance as either a diagnostic or a prognostic marker of fertilization failure has been questioned in the recent literature. We analyzed WBP2NL/PAWP gene and protein expression level and localization in patients without previous intracytoplasmic sperm injection (ICSI) cycles in order to assess its association with both sperm characteristics and ability to fertilize.Raw frozen-thawed semen samples from 33 couples referred for oocyte donation were included in the study during 2015. Relative protein expression versus ?-tubulin (western blot, WB), proportion of post-acrosomal WBP2NL/PAWP-positive spermatozoa over the total number of sperm cells (immunofluorescence), and WBP2NL/PAWP gene expression (RT-qPCR) were analyzed and correlated with semen analysis parameters (number, motility, and morphology) and with reproductive outcomes.WBP2NL/PAWP protein was expressed in all samples with high variability: relative protein expression (1.77 ± 0.8, range [0.4-3.7]), proportion of positive cells (49.6% ± 16.1, range [22-89]), and relative gene expression (7.3 ± 8.2). No significant correlation (R 2 < 0.1) was found between gene and protein expression, neither between WBP2NL/PAWP gene or protein expression, and fertilization rate or other reproductive outcomes (i.e., pregnancy). In contrast, we found significant correlation between sperm morphology and WBP2NL/PAWP semiquantitative analysis in WB (r = -0.42, p < 0.05) and for sperm motility and WBP2NL/PAWP expression in IF (r = 0.52, p < 0.05).Taken into account that WBP2NL/PAWP gene and protein levels and distribution did not correlate with fertilization rates, this study questions the interest of WBP2NL/PAWP protein and gene expression analysis in sperm cells as a prognostic factor for the outcome of ICSI cycles. Larger studies focusing on WBP2NL/PAWP protein and gene expression are needed in order to evaluate the role of WBP2NL/PAWP as a prognostic factor for ART.

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Decreased piRNAs in Infertile Semen Are Related to Downregulation of Sperm MitoPLD Expression.

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