Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?

Conflitti, Anna Chiara; Cicolani, Gaia; Buonacquisto, Alessandra; Pallotti, Francesco; Faja, Fabiana; Bianchini, Serena; Blaconà, Giovanna; Bruno, Sabina Maria; Linari, Antonella; Lucarelli, Marco; Montanino, Diletta; Muzii, Ludovico; Lenzi, Andrea; Lombardo, Francesco; Paoli, Donatella

doi:10.3390/ijms24021007

Cited by 14 publications

(14 citation statements)

References 57 publications

(79 reference statements)

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“…Similarly, Shi et al, (2020) observed a negative correlation between spermatogenic miR-34c levels and embryo developmental kinetics, but a positive correlation with blastocyst formation rates, number of high-quality blastocysts, and pregnancy [ 170 ]. Human sperm containing higher levels of miR-34c had a 14-fold increased probability of obtaining a viable embryo [ 73 ]. Interestingly, miR-34b/c levels in sperm were only associated with a decrease in miscarriages, and increased implantation and pregnancy rates at certain Ct thresholds, determined using receiver operating characteristic curve (ROC) analysis [ 171 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although sperm are mainly transcriptionally silent, a transcriptomic analysis previously conducted by our group demonstrated that exposing sperm to THC significantly changed the abundance of several fertility-associated miRs, including miR-346, miR-324, and miR-33b [22]. Mature, sperm-borne miRs are transferred to the zygote and dictate the success of embryonic development [68,73,74,76,77,[157][158][159][160][161]. Few have simultaneously evaluated cannabinoid-induced changes to fertility-associated miRs in sperm and embryos.…”

Section: Plos Onementioning

confidence: 99%

“…Considering that 30% of human genes are regulated by miRs [62], aberrant expression may rapidly alter the proteome of cells, and lead to the inheritance of maladaptive paternal phenotypes [63][64][65][66]. Multiple groups have shown that miR profiles significantly differ between high and low fertility sperm from both humans and bovine [60,61,[67][68][69][70][71][72][73][74][75][76][77][78], suggesting that these molecules may be used as biomarkers for fertility status. Specific miRs are known to be essential for embryo development.…”

Section: Introductionmentioning

confidence: 99%

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THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications

Kuzma-Hunt,

Sabry,

Davis

et al. 2024

PLoS ONE

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Global cannabis use has risen 23% since 2010, with 209 million reported users, most of whom are males of reproductive age. Delta-9-tetrahydrocannabinol (THC), the main psychoactive phytocannabinoid in cannabis, disrupts pro-homeostatic functions of the endocannabinoid system (ECS) within the male reproductive system. The ECS is highly involved in regulating morpho-functional and intrinsic sperm features that are required for fertilization and pre-implantation embryo development. Previous work by our group demonstrated that THC altered sperm capacitation and the transcriptome, including several fertility-associated microRNAs (miRs). Despite the prevalent use of cannabis among males of reproductive age, clinical and pre-clinical research investigating the impact of paternal cannabis on sperm function and the outcomes of artificial reproductive technologies (ARTs) remains inconclusive. Therefore, the present study investigates the impact of in vitro THC exposure on morpho-functional and intrinsic sperm functions, including contributions to embryo development following IVF. Bovine sperm were used as a translational model for human and treated with concentrations of THC that reflect plasma levels after therapeutic (0.032μM), and low (0.32μM)-high (4.8μM) recreational cannabis use. After 6-hours of treatment, THC did not alter the acrosomal reaction, but 4.8μM significantly reduced mitochondrial membrane potential (MMP) (p<0.05), primarily through agonistic interactions with CB-receptors. Fertilization of bovine oocytes with THC-treated sperm did not alter developmental rates, but blastocysts generated from sperm treated with 0.32–4.8μM THC had fewer trophoblasts (p<0.05), while blastocysts generated from sperm exposed to any concentration of THC had fewer cells in the inner cell mass (ICM), particularly within the 0.032μM group (p<0.001). Fertility associated miRs, including miR-346, miR-324, miR-33b, and miR-34c were analyzed in THC-exposed sperm and associated blastocysts generated by IVF, with lower levels of miRs-346, -324, and -33b found in sperm treated with 0.32μM THC, while miR-34c levels were higher in sperm treated with 0.032μM THC (p<0.05). Levels of miR-346 were also lower in sperm treated with 0.032μM THC, but higher in blastocysts generated from sperm exposed to 0.32μM THC (p<0.05). Our findings suggest that THC may alter key morpho-functional and epigenetic sperm factors involved in fertilization and embryo development. This is the first study to demonstrate that sperm exposed to THC in vitro negatively affects embryo quality following IVF.

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Section: Discussionmentioning

confidence: 99%

Section: Plos Onementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications

Kuzma-Hunt,

Sabry,

Davis

et al. 2024

PLoS ONE

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“…The expression of miR-449b-5p is positively associated with SDF and the expression of miR-34c-5p. High expression of miR-34c-5p and miR-449b-5p in sperm increased the likelihood of retrieving viable embryos, suggesting that these two miRNAs are promising biomarkers for assessing sperm SDF and ART outcomes ( 137 ). Paternal miR-34c is believed to be involved in the early stages of embryonic development.…”

Section: Potential Of Mirnas As Biomarkers For Disease Diagnosis and ...mentioning

confidence: 99%

MicroRNAs in spermatogenesis dysfunction and male infertility: clinical phenotypes, mechanisms and potential diagnostic biomarkers

Shi,

Yu,

Guo

et al. 2024

Front. Endocrinol.

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Infertility affects approximately 10–15% of couples worldwide who are attempting to conceive, with male infertility accounting for 50% of infertility cases. Male infertility is related to various factors such as hormone imbalance, urogenital diseases, environmental factors, and genetic factors. Owing to its relationship with genetic factors, male infertility cannot be diagnosed through routine examination in most cases, and is clinically called ‘idiopathic male infertility.’ Recent studies have provided evidence that microRNAs (miRNAs) are expressed in a cell-or stage-specific manner during spermatogenesis. This review focuses on the role of miRNAs in male infertility and spermatogenesis. Data were collected from published studies that investigated the effects of miRNAs on spermatogenesis, sperm quality and quantity, fertilization, embryo development, and assisted reproductive technology (ART) outcomes. Based on the findings of these studies, we summarize the targets of miRNAs and the resulting functional effects that occur due to changes in miRNA expression at various stages of spermatogenesis, including undifferentiated and differentiating spermatogonia, spermatocytes, spermatids, and Sertoli cells (SCs). In addition, we discuss potential markers for diagnosing male infertility and predicting the varicocele grade, surgical outcomes, ART outcomes, and sperm retrieval rates in patients with non-obstructive azoospermia (NOA).

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“…The detection of biomarkers to predict sperm quality and functional integrity has gained much interest over the last decade for human health and animal production. However, routine spermiograms have largely been unsuccessful in attaining this aim [1], though 2 of 17 techniques based on molecular approaches show promise [2][3][4]. In this regard, sperm chromatin evaluation has recently entered the set of available techniques for studying fertility as a biomarker of sperm fertility [5,6].…”

Section: Introductionmentioning

confidence: 99%

Application of Flow Cytometry Using Advanced Chromatin Analyses for Assessing Changes in Sperm Structure and DNA Integrity in a Porcine Model

Lacalle,

Fernández-Alegre,

Gómez-Giménez

et al. 2024

IJMS

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Chromatin status is critical for sperm fertility and reflects spermatogenic success. We tested a multivariate approach for studying pig sperm chromatin structure to capture its complexity with a set of quick and simple techniques, going beyond the usual assessment of DNA damage. Sperm doses from 36 boars (3 ejaculates/boar) were stored at 17 °C and analyzed on days 0 and 11. Analyses were: CASA (motility) and flow cytometry to assess sperm functionality and chromatin structure by SCSA (%DFI, DNA fragmentation; %HDS, chromatin maturity), monobromobimane (mBBr, tiol status/disulfide bridges between protamines), chromomycin A3 (CMA3, protamination), and 8-hydroxy-2′-deoxyguanosine (8-oxo-dG, DNA oxidative damage). Data were analyzed using linear models for the effects of boar and storage, correlations, and multivariate analysis as hierarchical clustering and principal component analysis (PCA). Storage reduced sperm quality parameters, mainly motility, with no critical oxidative stress increases, while chromatin status worsened slightly (%DFI and 8-oxo-dG increased while mBBr MFI—median fluorescence intensity—and disulfide bridge levels decreased). Boar significantly affected most chromatin variables except CMA3; storage also affected most variables except %HDS. At day 0, sperm chromatin variables clustered closely, except for CMA3, and %HDS and 8-oxo-dG correlated with many variables (notably, mBBr). After storage, the relation between %HDS and 8-oxo-dG remained, but correlations among other variables disappeared, and mBBr variables clustered separately. The PCA suggested a considerable influence of mBBr on sample variance, especially regarding storage, with SCSA and 8-oxo-dG affecting between-sample variability. Overall, CMA3 was the least informative, in contrast with results in other species. The combination of DNA fragmentation, DNA oxidation, chromatin compaction, and tiol status seems a good candidate for obtaining a complete picture of pig sperm nucleus status. It raises many questions for future molecular studies and deserves further research to establish its usefulness as a fertility predictor in multivariate models. The usefulness of CMA3 should be clarified.

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Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?

Cited by 14 publications

References 57 publications

THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications

THC and sperm: Impact on fertilization capability, pre-implantation in vitro development and epigenetic modifications

MicroRNAs in spermatogenesis dysfunction and male infertility: clinical phenotypes, mechanisms and potential diagnostic biomarkers

Application of Flow Cytometry Using Advanced Chromatin Analyses for Assessing Changes in Sperm Structure and DNA Integrity in a Porcine Model

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