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Renjie Wang, Wei Pan, Lei Jin, Yuehan Li, Yudi Geng, Chun Gao, Gang Chen, Hui Wang, Ding Ma and Shujie Liao

Artificial intelligence (AI) has experienced rapid growth over the past few years, moving from the experimental to the implementation phase in various fields, including medicine. Advances in learning algorithms and theories, the availability of large datasets and improvements in computing power have contributed to breakthroughs in current AI applications. Machine learning (ML), a subset of AI, allows computers to detect patterns from large complex datasets automatically and uses these patterns to make predictions. AI is proving to be increasingly applicable to healthcare, and multiple machine learning techniques have been used to improve the performance of assisted reproductive technology (ART). Despite various challenges, the integration of AI and reproductive medicine is bound to give an essential direction to medical development in the future. In this review, we discuss the basic aspects of AI and machine learning, and we address the applications, potential limitations and challenges of AI. We also highlight the prospects and future directions in the context of reproductive medicine.

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Rebekka Einenkel, Katrin Regina Helene Packhäuser, Jens Ehrhardt, Anne Tüngler, Marek Zygmunt and Damián Oscar Muzzio

Alterations in the immunologic balance during pregnancy have been associated with poor pregnancy outcomes. The underlying mechanisms are complex and mouse models delivered valuable information on inflammatory imbalance in disturbed pregnancies and served as model to test potential anti-inflammatory therapies. CD83 is a transmembrane protein (mCD83) with a soluble form (sCD83) which possesses strong anti-inflammatory properties. During murine pregnancy, upregulated mCD83 expression induces sCD83 release after in vitro stimulation with LPS, phorbol myristate acetate (PMA) and ionomycin. The release mechanism of sCD83 and its control are yet to be elucidated. In this study, the expression of mCD83 and sCD83 has been extensively studied in the CBA/J × DBA/2J mouse model of pro-inflammatory-mediated pregnancy disturbances. mCD83 was higher expressed on splenic B cells, uterus-draining lymph nodes T cells and dendritic cells from mice with poor pregnancy outcome (PPOM) compared to mice with good pregnancy outcome (GPOM). PPOM, however, was accompanied by lower sCD83 serum levels. In vitro treatment of splenic B cells with progesterone led to a reduction of TIMP1 expression, mCD83 expression and sCD83 release, while TIMP1 treatment had a positive effect on sCD83 availability. These results suggest that tissue and matrix components are involved in the regulation of CD83 in murine pro-inflammatory pregnancies.

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Imke Bommer, Lorena Juriol, Damián Muzzio, Natalin Valeff, Jens Ehrhardt, Franziska Matzner, Katharina Ziegler, Kristin Malinowsky, María Silvia Ventimiglia, Marek Zygmunt and Federico Jensen

The amniotic fluid provides mechanical protection and immune defense against pathogens to the fetus. Indeed, components of the innate and adaptive immunity, including B cells, have been described in the amniotic fluid. However, limited information concerning phenotype and functionality of amniotic fluid B cells is available. Hence, we aimed to perform a full phenotypical and functional characterization of amniotic fluid B cells in normal pregnancy and in a mouse model of preterm birth. Phenotypic analysis depicted the presence of two populations of amniotic fluid B cells: an immature population, resembling B1 progenitor cells and a more mature population. Further isolation and in vitro co-culture with a bone marrow stroma cell line demonstrated the capacity of the immature B cells to mature. This was further supported by spontaneous production of IgM, a feature of the B1 B cell sub-population. An additional in vitro stimulation with lipopolysaccharide induced the activation of amniotic fluid B cells as well as the production of pro and anti-inflammatory cytokines. Furthermore, amniotic fluid B cells were expanded in the acute phase of LPS-induced preterm birth. Overall our data add new insight not only on the phenotype and developmental stage of the amniotic fluid B1 B cells but especially on their functionality. This provides important information for a better understanding of their role within the amniotic fluid as immunological protective barrier, especially with regard to intraamniotic infection and preterm birth.

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Alessandra Santillo, Massimo Venditti, Sergio Minucci, Gabriella Chieffi Baccari, Sara Falvo, Luigi Rosati and Maria Maddalena Di Fiore

D-Aspartate (D-Asp) is an endogenous amino acid that plays a central role in the development of the central nervous system (CNS) and functioning of the neuroendocrine system. In line with its functions, it is abundantly present in the CNS and reproductive systems of vertebrates and invertebrates. It has been implicated in the biosynthesis and/or secretion of hormones and factors that are involved in various reproductive functions, such as GnRH from the hypothalamus and testosterone from the testis. We conducted an in vivo study consisting of acute (i.p. injection of 2 µmol/g body weight) and chronic (15 days drinking solution) administration of D-Asp to adult rats to understand the signaling pathways elicited by D-Asp in the rat testis. We found that D-Asp upregulated the expression of prolyl endopeptidase (PREP), a serine protease having a pivotal role in the regulation of mammalian spermatogenesis and spermiogenesis. Immunofluorescence analysis revealed its overexpression in Leydig cells, Sertoli cells and spermatogonia. Moreover, PREP was found to co-localize with GluA2/3, an AMPA receptor subunit, whose protein expression also increased after D-Asp treatments. Finally, we found a significant increase in ERK and Akt activities in the testis of rats treated with D-Asp. Since PREP is known to be involved in regulating GnRH levels and in germ cell differentiation, we hypothesize D-Asp to play a pivotal role in regulating hormone homeostasis and spermatogenesis through activation of PREP, AMPAR, ERK and Akt.

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Tine-Tsan Lin, Po-Chiang Lan, Yi-Jui Hsieh and Yung-Song Wang

Japanese eels are commercially valuable species in Asian aquaculture. This study evaluated whether salmon pituitary extract (SPE) or 17β-estradiol (E2) treatment can induce cytotoxic activity in eel ovarian follicles. Follicular cells died after exposure SPE for 24-h culture in an in vitro culture. Moreover, the E2 treatment also significantly reduced follicular cell counts. These results reveal that the inhibition of follicular cell numbers by SPE may occur through SPE-induced steroidogenesis. Results of a quantitative PCR analysis indicated that adding E2 to the culture decreased bcl2 and increased dnmt1 mRNA expression in Japanese eel follicular cells after 24 h. The results of a promoter assay revealed that E2 significantly increase dnmt1 promoter activity through estrogen receptor-binding site. An in silico analysis predicted several putative transcription factors targeting the bcl2 gene promoter region. Methylation of the bcl2 promoter accounted for the downregulation of bcl2 by E2-mediated dnmt1. The DNA methylation level of the bcl2 gene was significantly higher in E2-treated follicular cells than that in the control group. Finally, the E2-induced hypermethylation pattern of the bcl2 promoter and the reduction in follicular cell numbers were suppressed by adding an MTase inhibitor. Our findings demonstrate that estrogen has a negative effect on the reproductive system of female eels by regulating an epigenetic mechanism during artificial maturation.

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Luiz Sergio Almeida Camargo, Tiphaine Aguirre-Lavin, Pierre Adenot, Thamiris Dornelas Araujo, Vivian Rachel Araujo Mendes, Iuri Drumond Louro, Nathalie Beaujean and Eliza Diniz Souza

Heat stress compromises bovine oocyte developmental competence, but the effects of high temperature during oocyte maturation on embryo chromatin organization is unknown. In this study bovine oocytes were exposed to heat shock (41°C) for 12 h during in vitro maturation and then submitted to in vitro fertilization. The heat shock did not affect (P > 0.05) the cleavage but reduced (P < 0.01) the blastocyst rate on Day 7 and Day 8. No effect (P > 0.05) on total cell number was found, but the heat shock increased (P < 0.05) the proportion of apoptotic cells in blastocysts at Day 8. Immunofluorescence analysis of H3K9me3 and HP1 was performed in embryos at 52 h post in vitro fertilization. An accumulation of H3K9me3 in the nuclei of embryos derived from heat-shocked oocytes at four-cell and eight-cell stages was found. Also, a non-expected higher proportion (P < 0.05) of four-cell stage embryos displaying nuclei with increased HP1 fluorescence was observed, suggesting an abnormal chromatin compaction in embryos from heat-shocked oocytes. Embryos at eight-cell stage derived from heat-shocked oocytes displayed lower (P < 0.05) relative amount of HSP40 transcripts than control ones. In conclusion, heat shock before fertilization has an effect on embryo chromatin, influencing the accumulation of H3K9me3 and HP1 in early embryos as well as further development.

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Lydia K Wooldridge, Sally E Johnson, Rebecca R Cockrum and Alan D Ealy

Supplementing interleukin-6 (IL6) to in vitro-produced bovine embryos increases inner cell mass (ICM) cell numbers in blastocysts. A series of studies were completed to further dissect this effect. Treatment with IL6 increased ICM cell numbers in early, regular and expanded blastocysts but had no effect on morulae total cell number. Treatment with IL6 for 30 min induced signal transducer and activator of transcription 3 (STAT3) phosphorylation and nuclear translocation in all blastomeres in early morulae and specifically within the ICM in blastocysts. Also, IL6 supplementation increased SOCS3 mRNA abundance, a STAT3-responsive gene, in blastocysts. Chemical inhibition of Janus kinase (JAK) activity from day 5 to day 8 prevented STAT3 activation and the IL6-induced ICM cell number increase. Global transcriptome analysis of blastocysts found that transcripts for IL6 and its receptor subunits (IL6R and IL6ST) were the most abundantly expressed IL6 family ligand and receptors. These results indicate that IL6 increases ICM cell numbers as the ICM lineage emerges at the early blastocyst stage through a STAT3-dependent mechanism. Also, IL6 appears to be the primary IL6 cytokine family member utilized by bovine blastocysts to control ICM cell numbers.

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Cindy Riou, Aurélien Brionne, Luiz Cordeiro, Grégoire Harichaux, Audrey Gargaros, Valérie Labas, Joël Gautron and Nadine Gérard

Avian uterine fluid (UF) and uterovaginal sperm storage tubules (SST) are key components in accepting sperm in SST, maintaining sperm function for several weeks, releasing sperm from SST and their ascent through the uterus. To improve the understanding of sperm storage processes requires investigating UF and SST. This study aimed to identify proteins modulated by sperm in the hen’s genital tract and to highlight their role during sperm storage. Two genetic lines of hens exhibiting long (F+) or short (F−) sperm storage ability were used. GeLC MS/MS analysis was used to establish a quantitative inventory of proteins regulated after insemination in both lines. The proteomic data are available via ProteomeXchange with identifier PXD013514. Immunohistochemistry was used to identify high (ANXA4/ANXA5/OCX32) and low (HSPA8/PIGR) fertility markers in the uterovaginal junction. Our results demonstrated that sperm induced a significant and rapid change in the UF proteomic content and also in the SST epithelium. In F+ hens, mobilization of the ANXA4 protein in the apical part of SST cells after insemination was associated with increased levels of some proteoglycans and binding proteins, and also antimicrobial eggshell matrix protein (OCX32) in the UF. We also observed increased levels of lipid transporters involved in egg formation (VTG1-2, APOA1-4-H). In F− hens, insemination induced increased levels of PIGR in both UF and SST, of ANXA5 in SST, of UF enzymes exhibiting metallopeptidase activity and mucins. In conclusion, sperm induced significant changes in the UF proteomic content. This study also provides evidence that the SST immune system plays a major role in regulating sperm storage.

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Meritxell Jodar

The paternal contribution to the new individual is not just limited to half the diploid genome. Recent findings have shown that sperm delivers to the oocyte several components, including a complex population of RNAs, which may influence early embryo development and the long-term phenotype of the offspring. Although the majority of sperm RNAs may only represent spermatogenic leftovers with no further function, the male gamete provides a specific set of RNAs to the oocyte that is able to modulate gene expression in the preimplantation embryo. Those sperm transcripts include coding and non-coding RNAs that might either be translated by the oocyte machinery or directly regulate embryo gene expression at the transcriptional or post-transcriptional level. Interestingly, some sperm RNAs seem to be acquired during post-testicular maturation through active communication between sperm and epididymal and seminal exosomes released by the epididymis and the male accessory sex glands, respectively. Exosomes contained in the seminal plasma seem to not only interact with the spermatozoa but also with cells from the female reproductive tract, modulating their gene expression and influencing female immune response triggered by the semen. This review also considers the findings that indicate the role of semen RNAs in preimplantation embryo development and offspring phenotypes. In this regard, different studies supporting the hypothesis of paternal epigenetic inheritance of altered metabolic phenotypes associated with environmental exposures are discussed. Lastly, potential mechanisms that could explain the impact of semen RNAs to both early embryogenesis and paternal epigenetic inheritance are suggested.

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Luís Crisóstomo, Luís Rato, Ivana Jarak, Branca M Silva, João F Raposo, Rachel L Batterham, Pedro F Oliveira and Marco G Alves

In recent decades, the prevalence of metabolic diseases has concomitantly increased with a decline on fertility rates and sperm quality. High-fat diets (HFD) are seldom considered part of the problem, but the molecular mechanisms underlying its effects on male fertility remain poorly understood. Herein we postulated that HFD alter sperm quality. We evaluated the effects of switching from a HFD to a normal diet in early adulthood on metabolic disease onset, testicular metabolism and sperm quality. Thirty-six male C57BL6/J mice were divided in: a control group fed with standard chow; a group fed with HFD for 200 days; and a group fed with HFD for 60 days and then with standard chow (HFDt). Biometric data and whole-body metabolism were assessed. Epididymal sperm was studied for concentration, motility, viability and morphology. 1H-NMR metabolomics approach was performed on testicular extracts to trace the metabolic changes. Diet switch reduced body weight and fat mass, preventing metabolic syndrome onset. However, sperm viability, motility and morphology were deteriorated by HFD consumption and not restored by diet switch. HFD induced irreversible changes in pyruvate and glutamate metabolism, ethanol degradation and ammonia recycling in testis. Furthermore, HFDt changed purine and cysteine metabolism, urea cycle, and glutathione content. Overall, HFD caused irreversible changes in testicular metabolism even after switching to normal diet. HFD feeding until early adulthood decreases sperm quality, which cannot be restored by diet switch or weight loss, even when development of metabolic syndrome is avoided.