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Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes

Dalileh Nabi, Davide Bosi, Neha Gupta, Nidhi Thaker, Rafael Fissore, and Lynae M Brayboy

In brief

Oocyte quality remains the most important and unsolved issue in reproduction. Our data show that multidrug resistance transporters and oocyte mitochondria are involved in determining oocyte quality in a mouse model.

Abstract

Multidrug resistance transporter-1 (MDR-1) is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and by-products. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1a mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle to germinal vesicle breakdown transition, an increased percentage of symmetric divisions, chromosome misalignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more SNPs in the exomic DNA and twice the amount of mitochondrial DNA (mtDNA) SNPs compared to the wild-type ones. Ca2+ analysis revealed the inability of MDR-1 mutant oocytes to manage Ca2+ storage content and oscillations in response to several stimuli, and ATP quantification shows that mutant oocytes trend toward lower ATP levels compared to wild types. Finally, 1-year-old mutant ovaries express a lower amount of SIRT1, SIRT3, SIRT5, SIRT6 and SIRT7 compared to wild-type levels. These results together emphasize the importance of MDR-1 in mitochondrial physiology and highlight the influence of MDR-1 on oocyte quality and ovarian aging.

DOI:
https://doi.org/10.1530/REP-22-0192
Volume 165: Issue 1,
Pages:
79–91 (13 total)
Restricted access

Nicotinamide riboside supplementation ameliorated post-ovulatory oocyte quality decline

Hui Li, Huan Wang, Jianmin Xu, Xinxin Zeng, Yingpu Sun, and Qingling Yang

In brief

Oocyte quality and its NAD+ level decrease with time during in vitro culture. This study shows that nicotinamide riboside (NR) supplementation improves early embryonic development potential in post-ovulatory oocytes by decreasing the reactive oxygen species (ROS) levels and reducing DNA damage and apoptosis which could potentially increase the success rate of assisted reproductive technology (ART).

Abstract

The quality of post-ovulatory oocytes deteriorates over time, impacting the outcome of early embryonic development during human ART. We and other groups have found that NAD+, a prominent redox cofactor and enzyme substrate, decreases in both aging ovaries and oocytes. In this study, we found that the NAD+ levels decreased in the post-ovulatory mouse oocytes during in vitro culture and this decrease was partly prevented by NR supplementation. NR treatmenty restored MII oocyte quality and enhanced the early embryonic development potential of post-ovulatory oocytes via alleviating mitochondrial dysfunction and maintaining normal spindle/chromosome structure. Also, treatment with NR decreased ROS levels and reduced DNA damage and apoptosis in post-ovulatory oocytes. Taken together, our findings indicated that NR supplementation increases the oocyte quality and early embryonic development potential in post-ovulatory oocytes which could potentially increase the success rate of ART.

DOI:
https://doi.org/10.1530/REP-22-0095
Volume 165: Issue 1,
Pages:
103–111 (9 total)
Restricted access

Processes involved in prostaglandin F2alpha autoamplification in heifers

Rafael R Domingues, OJ Ginther, Victor Gomez-Leon, Polyana Nunes da Silva, Thadeu Castro, August Hoppmann, and Milo C Wiltbank

In brief

Endometrial and luteal synthesis of prostaglandin F2alpha (PGF2A) occurs before and during luteolysis and is critical for luteal regression. This study demonstrates that PGF2A stimulates further PGF2A synthesis (autoamplification) apparently from the corpus luteum.

Abstract

Understanding the endocrine profile of prostaglandin F2alpha (PGF2A) autoamplification is fundamental to comprehend luteal and endometrial responses to PGF2A. On day 10 of postovulation (preluteolysis), heifers (n  = 6/group) were treated intrauterine with saline or PGF2A (0.5 mg; hour 0). A third group received flunixin meglumine + PGF (FM+PGF) to prevent endogenous synthesis of PGF2A. Exogenous PGF2A was metabolized at hour 2 as measured by PGF2A metabolite (PGFM). From hours 5 to 48, concentrations of PGFM were greatest in the PGF group, smallest in the FM+PGF, and intermediate in the control suggesting endogenous synthesis of PGF2A only in PGF group. Progesterone (P4) concentrations decreased transiently between hours 0 and 1 in PGF and FM+PGF groups but rebounded to pretreatment concentrations by hours 6 and 4, respectively. No control or FM+PGF heifers underwent luteolysis during the experimental period. Conversely, in the PGF group, one heifer had complete luteolysis (P4 < 1 ng/mL), two heifers had partial luteolysis followed by P4 and CL resurgence by hour 48, and three heifers did not undergo luteolysis. Endogenous PGF2A appears to be of luteal origin due to the lack of pulsatile pattern of PGFM and lack of endometrial upregulation of oxytocin receptor (typical of endometrial synthesis of PGF2A), whereas luteal downregulation of PGF receptor and HPGD indicates a classic luteal response to PGF2A signaling although other specific mechanisms were not investigated. The hypothesis was supported that a single PGF2A treatment simulating the peak of a natural luteolytic pulse and the uteroovarian transport of PGF2A stimulates measurable endogenous PGF2A production.

DOI:
https://doi.org/10.1530/REP-22-0242
Volume 165: Issue 1,
Pages:
93–101 (9 total)
Free access

Repurposing existing drugs as a therapeutic approach for the prevention of preterm birth

Bridget M Arman, Natalie K Binder, Natasha de Alwis, Tu’uhevaha J Kaitu’u-Lino, and Natalie J Hannan

In brief

Preterm birth is the leading cause of perinatal morbidity and mortality; however, current therapies offer limited efficacy to delay birth and improve neonatal outcomes. This review explores the potential of repurposing drugs with known safety profiles to quench uterine contractions and inflammation, identifying promising agents for clinical trials.

Abstract

Preterm birth is the leading cause of neonatal morbidity and mortality globally. Despite extensive research into the underlying pathophysiology, rates of preterm birth have not significantly reduced. Currently, preterm labour management is based on optimising neonatal outcomes. Treatment involves administering drugs (tocolytics) to suppress uterine contractions to allow sufficient time for transfer to an appropriate facility and administration of antenatal corticosteroids for fetal lung maturation. Current tocolytics are limited as they are associated with adverse maternal and fetal effects and only delay delivery for a short period. There has been a serious lack of therapeutic development for preterm birth, and new approaches to protect against or delay preterm birth are urgently needed. Repurposing drugs for the prevention of preterm birth presents as a promising approach by reducing the time and costs associated with pharmaceutical drug development. In this review, we explore the evidence for the potential of therapies, specifically proton pump inhibitors, tumour necrosis factor inhibitors, prostaglandin receptor antagonists, aspirin, and statins, to be repurposed as preventatives and/or treatments for preterm birth. Importantly, many of these innovative approaches being explored have good safety profiles in pregnancy. We also review how delivery of these drugs can be enhanced, either through targeted delivery systems or via combination therapy approaches. We aim to present innovative strategies capable of targeting multiple aspects of the complex pathophysiology that underlie preterm birth. There is an urgent unmet need for preterm birth therapeutic development, and these strategies hold great promise for improving neonatal outcomes.

DOI:
https://doi.org/10.1530/REP-22-0226
Volume 165: Issue 1,
Pages:
R9–R23
Free access

RNA m6A modifications in mammalian gametogenesis and pregnancy

Xuesong Sui, Arne Klungland, and Lu Gao

In brief

RNA modifications play key roles in regulating various biological processes. This article discusses and summarizes the recent advances of RNA m6A modifications related to mammalian gametogenesis, early embryonic development, and miscarriage.

Abstract

The epitranscriptome is defined as the collection of post-transcriptional chemical modifications of RNA in a cell. RNA methylation refers to the chemical post-transcriptional modification of RNA by selectively adding methyl groups under the catalysis of a methyltransferase. The N6 methyladenosine (m6A) is one of the most common of the more than 100 known RNA modifications. Recent research has revealed that RNA m6A modifications are reversible. Additionally, m6A containing RNA can be selectively identified by immunoprecipitation followed by high-throughput sequencing (MeRIP-SEQ). These two developments have inspired a tremendous effort to unravel the biological role of m6A. The role of RNA m6A modifications in immune regulation, cell division, stem cell renewal, gametogenesis, embryonic development, and placental function has gradually emerged, which is of great significance for the study of post-transcriptional regulation of gene expression in reproductive biology. This review summarizes the current knowledge about RNA m6A modification in a variety of mammalian reproductive events.

DOI:
https://doi.org/10.1530/REP-22-0112
Volume 165: Issue 1,
Pages:
R1–R8
Restricted access

The role of steroidogenic factor 1 (SF-1) in steroidogenic cell function of the testes and ovaries of mature mice

Olivia E Smith, Fanny Morin, Vickie Roussel, Micka C Bertucci, Alexandre Boyer, and Bruce D Murphy

In brief

The nuclear receptor steroidogenic factor 1 (SF-1) is essential for mature mouse gonad steroidogenic gene expression, for Leydig and Sertoli cell function, and depletion of SF-1 in steroidogenic cells of the testis compromises steroidogenesis, spermatogenesis and male fertility.

Abstract

Steroidogenic factor 1 (SF-1 or NR5A1) plays an essential role in the development of fetal gonads and regulates genes involved in steroid biosynthesis. Since SF-1 is expressed in multiple cell types in mouse gonads, we developed three novel conditional knockout (cKO) mouse models employing Cre-recombinase and floxed alleles of SF-1 (Nr5a1f/f) to identify its role in testes and ovaries of mature mice: Cytochrome P450 17α-hydroxylase (Cyp17Cre/+;Nr5a1f/f, Leydig and theca cell-specific), aromatase (Cyp19Cre/+;Nr5a1f/f, Sertoli and granulosa cell-specific), as well as a combination of both (Cyp17+Cyp19-Cre;Nr5a1f/f). Compared to control animals, Cyp19-Cre;Nr5a1f/f cKO males showed normal fertility and testicular function. The Cyp17Cre/+;Nr5a1f/f cKO males had smaller testis, with drastically reduced Leydig cell volumes and impaired steroidogenesis, though their reproductive performance remained comparable to controls. Some 50% of Cyp17Cre/++Cyp19Cre/+;Nr5a1f/f double-cKO (dKO) males were infertile, while the remaining 50% showed significantly reduced fertility. These dKO males also had smaller testis with degenerative seminiferous tubules, abnormal Leydig cell morphology and lower levels of intra-testicular testosterone. Abnormal Sertoli cell localization was noted in dKO testes, with increased Sox9, p27 and inhibin subunit ßb and decreased androgen receptor expression. Female mice from all genotypes showed normal reproductive capacity, though steroidogenic gene expression levels were significantly decreased in both Cyp17Cre/+;Nr5a1f/f cKO and dKO females. These results show the essential role of SF-1 in mature mouse gonad steroidogenic gene expression, for Leydig and Sertoli cell function, and that depletion SF-1 in all steroidogenic cells of the testis compromises steroidogenesis, spermatogenesis and male fertility.

DOI:
https://doi.org/10.1530/REP-22-0049
Volume 165: Issue 1,
Pages:
1–17 (17 total)
Restricted access

Role of the hypothalamus in ghrelin effects on reproduction: sperm function and sexual behavior in male mice

María Belén Poretti, Santiago Bianconi, Eugenia Luque, Ana Carolina Martini, Laura Vincenti, Veronica Cantarelli, Pedro Torres, Marina Ponzio, Helgi B Schiöth, and Valeria Paola Carlini

In brief

Ghrelin signals to the hypothalamus inhibit reproduction during times of food scarcity. In this study, we demonstrate that ghrelin impairs sperm quality in male mice.

Abstract

Ghrelin (GHRL) is an orexigenic peptide that has been investigated as one of the signals responsible for the reproductive performance of mammals under fluctuating metabolic conditions. Central GHRL administration impairs spermatogenesis in mice by regulating the hypothalamic–pituitary–gonadal axis function. In the present study, the hypothalamus role as a mediator of GHRL effects on sperm fertilizing capacity and male sexual behavior was evaluated. After 42 days of hypothalamic GHRL infusion or artificial cerebrospinal fluid, in vitro and in vivo sperm fertilizing capacity, testicular α-tubulin, speriolin gene expression and spermatic α-tubulin protein were evaluated. Hypothalamic expression of genes Kiss1, Gpr54 and Gnrh was also studied. The second group of animals was infused with one time only GHRL or artificial cerebrospinal fluid into the hypothalamus to evaluate the effects on sexual behavior. Results demonstrated that chronic GHRL administration to male mice significantly increased the percentages of pre-implantation embryo loss and the number of post-implantation embryo loss. In relation to the gene expression, our results show a relative decrease of Kiss1, Gpr54 and Spatc1. Although no significant differences were observed in the quantitative expression of α-tubulin protein, qualitative changes in its expression pattern were observed. In addition, a dual effect on sexual behavior was observed: 40% of the treated animals showed a significant reduction in the number of mounts and intromissions, while a 60% showed a significant decrease in ejaculation latency vs control animals. In conclusion, our results provide evidence that central GHRL administration possibly induces failure in embryo development and/or implantation in the females mated with treated males, possibly because of a negative effect in the α-tubulin pattern.

DOI:
https://doi.org/10.1530/REP-22-0098
Volume 165: Issue 1,
Pages:
123–134 (12 total)
Open access

Xenograft model of heterotopic transplantation of human ovarian cortical tissue and its clinical relevance

Limor Man, Nicole Lustgarten Guahmich, Eleni Kallinos, Laura Park, Richard Bodine, Nikica Zaninovic, Glenn Schattman, Zev Rosenwaks, and Daylon James

In brief

Xenografts of human ovarian cortical tissue provide a tractable model of heterotopic autotransplantation that is used for fertility preservation in patients undergoing ablative chemo/radiotherapy. This study describes the behavior of hundreds of xenografts to establish a framework for the clinical function of ovarian cortex following autotransplantation over short- and long-term intervals.

Abstract

More than 200 live births have been achieved using autotransplantation of cryopreserved ovarian cortical fragments, yet challenges remain to be addressed. Ischemia of grafted tissue undermines viability and longevity, typically requiring transplantation of multiple cortical pieces; and the dynamics of recruitment within a graft and the influence of parameters like size and patient age at the time of cryopreservation are not well-defined. Here, we describe results from a series of experiments in which we xenografted frozen/thawed human ovarian tissue (n  = 440) from 28 girls and women (age range 32 weeks gestational age to 46 years, median 24.3 ± 4.6). Xenografts were recovered across a broad range of intervals (1–52 weeks post-transplantation) and examined histologically to quantify follicle density and distribution. The number of antral follicles in xenografted cortical fragments correlated positively with the total follicle number and was significantly reduced with increased patient age. Within xenografts, follicles were distributed in focal clusters, similar to the native ovary, but the presence of a leading antral follicle coincided with increased proliferation of surrounding follicles. These results underscore the importance of transplanting ovarian tissue with a high density of follicles and elucidate a potential paracrine influence of leading antral follicles on neighboring follicles of earlier stages. This temporal framework for interpreting the kinetics of follicle growth/mobilization may be useful in setting expectations and guiding the parameters of clinical autotransplantation.

DOI:
https://doi.org/10.1530/REP-22-0114
Volume 165: Issue 1,
Pages:
31–47 (17 total)
Restricted access

C/EBP-β contributes to pig endometrial LE receptivity by targeting cell remodeling genes during implantation

Yan Sun, Yifen Yang, Ziran Jiang, Feiyu wang, Kun Han, Linjun Hong, Jianhua Cao, and Mei Yu

In brief

Transforming the endometrial luminal epithelium (LE) into a receptive state is a requisite event for successful embryo implantation. This study suggests the role of a transcription factor in regulating endometrial LE receptivity.

Abstract

The endometrial luminal epithelium (LE) undergoes extensive remodeling during implantation to establish receptivity of the uterus in response to the conceptus signals, such as interleukin 1β (IL1B). But the mechanisms remain to be fully understood. This study investigated the role of CCAAT/enhancer-binding protein β (C/EBP-β) in regulating pig endometrial LE receptivity. Our results showed that C/EBP-β was expressed and activated only in the endometrial LE in an implantation-dependent manner. In addition, C/EBP-β was highly activated at the pre-attachment stage compared to the attachment stage, and its activation was correlated with the expression of IL1B-dependent extracellular signal-regulated kinases1/2-p90 ribosomal S6 kinase signaling axis. Subsequent chromatin immunoprecipitation (ChIP)-sequencing analysis revealed that the binding of C/EBP-β within the promoter was positively associated with the transcription of genes related to cell remodeling. One such gene is matrix metalloproteinase 8 (MMP8), which is responsible for extracellular matrix degradation. The expression of MMP8 was abundant at the pre-attachment stage but dramatically declined at the attachment stage in the endometrial LE. Consistent with C/EBP-β, the expression and activation of MMP8 were limited to the endometrial LE in an implantation-dependent manner. Using ChIP-qPCR and electrophoresis mobility shift assay approaches, we demonstrated that C/EBP-β regulated the expression of the MMP8 gene during implantation. Furthermore, we detected that MMP8 and one of its substrates, type II collagen, showed a mutually exclusive expression pattern in pig endometrial LE during implantation. Our findings indicate that C/EBP-β plays a role in pig endometrial LE receptivity by regulating cell remodeling-related genes, such as MMP8, in response to conceptus signals during implantation.

DOI:
https://doi.org/10.1530/REP-22-0270
Volume 164: Issue 6,
Pages:
269–281 (13 total)
Free access

Does single-strand DNA break repair capacity influence oocyte maintenance and quality?

Saranya Giridharan, Karla J Hutt, and Amy L Winship

Human genome-wide association studies and evidence from animal models link ovarian ageing to double-strand (ds)DNA break repair capacity. Is there a connection between single-strand (ss)DNA repair mechanisms and ovarian function? We hypothesize that endogenous cellular processes subject oocytes to ssDNA lesions, and thus, ssDNA repair capacity is fundamental to their survival and maintenance.

DOI:
https://doi.org/10.1530/REP-22-0325
Volume 164: Issue 6,
Pages:
V15–V18