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Ana Filipa Ferreira, Maria Soares, Sandra Almeida Reis, João Ramalho-Santos, Ana Paula Sousa, and Teresa Almeida-Santos

Mitochondrial supplementation was proposed as a complementary treatment to assisted reproductive technologies to improve oocyte competence and support post-fertilization development. This strategy is based on the fact that poor-quality/aged oocytes contain lower and dysfunctional mitochondria. However, the efficacy and safety of mitochondrial supplementation are still controversial. Therefore, this review summarizes the clinical/biological outcomes of mitochondrial supplementation, aiming to improve oocyte competence or explore the safety of this technique, and was based on an online search using PubMed and Web of Science, until September 2019. The studies included reported outcomes related to the efficacy and safety of mitochondrial supplementation either in human or animal models (bovine, porcine and mouse). Extracted data were organized according to study objective, the mitochondrial source and the main outcomes: fertilization/pregnancy rates, embryo development and adverse outcomes. Clinical pregnancy was not improved in the only randomized controlled trial published, although an increase was demonstrated in other non-randomized studies. Fertilization rate and embryo development were not different from control groups in the majority of studies, although performed in different contexts and using diverse sources of mitochondria. The safety of mitochondria transfer is still a concern, however, the euploid rate and the absence of reported congenital malformation from the clinical studies are reassuring. In summary, mitochondrial supplementation does not seem to cause harm although the benefit of improving oocyte competence is still unclear due to the diversity of methodological approaches and low-quality of the data available. Analyzed data support the need to investigate further, in both pre-clinical and clinical contexts.

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Jacqueline M Wallace, John S Milne, and Raymond P Aitken

The competition for nutrients when pregnancy coincides with continuing growth in biologically immature adolescent girls increases their risk of preterm delivery and low birthweight and is partly replicated in the overnourished adolescent sheep paradigm. Although overfeeding to promote rapid maternal growth robustly leads to a reduction in average birthweight relative to slow-growing control-fed adolescents of equivalent age, the extent of prenatal compromise is variable. This retrospective analysis of a large cohort of identically managed pregnancies determined whether maternal anthropometry predicts the severity of fetal growth-restriction (FGR) in growing adolescents. Singleton pregnancies were established by embryo transfer in adolescents subsequently control-fed (n = 96) or overnourished. The latter pregnancies were classified as non-FGR (n = 116) or FGR (n = 96) if lamb birthweight was above or below the optimally fed control mean minus 2SD. A similar approach categorised placental growth-restriction (PlGR) and preterm delivery. Gestation length, placental mass and lamb birthweight were FGR < non-FGR < control (post hoc P < 0.01). Relative to the non-FGR group, overnourished dams with FGR were marginally leaner and lighter at conception (P = 0.023/P = 0.014) and had greater gestational weight gain (GWG) during the first-third of pregnancy (P < 0.001). GWG during this early period was also higher in PlGR compared with non-PlGR, and in very preterm vs term deliveries (P < 0.01). Likewise maternal leptin concentrations (fat accrual biomarker) were FGR > non-FGR by day 60, and changes in leptin throughout pregnancy predicted attenuated fetal cotyledon mass and birthweight (P = 0.01 to <0.001). The anthropometric antecedents of FGR in still-growing adolescent sheep originate in early pregnancy coincident with early placental development.

Open access

Heather Flanagan, Chih-Jen Lin, Lisa L Campbell, Paddy Horner, Andrew W Horne, and Norah Spears

Ectopic pregnancy (EP) is defined as the implantation of an embryo outside of the uterus and is a leading cause of first trimester maternal mortality and morbidity. This article discusses a possible role for epithelial to mesenchymal transition in the pathogenesis of EP, given the notable similarity of protein expression between the two processes.

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Natalie M Hohos, Emily M Elliott, Asma Giornazi, Elena Silva, John D Rice, and Malgorzata E Skaznik-Wikiel

High-fat diet (HFD) consumption in female rodents causes impaired estrous cyclicity, fewer pups per litter, and dysregulation of key ovulatory genes suggesting that HFD-induced subfertility may be due to ovulatory dysfunction. To test this hypothesis female mice were fed chow or HFD for 10 weeks at which point ovulation and ovarian gene expression of endothelin-2 (Edn2), a gene critical for ovulation, were assessed. After 10 weeks of HFD, both mice that remained lean and those that became obese had fewer ovulated oocytes than chow controls (P = 0.041, P = 0.0030, respectively). In chow controls, Edn2 was expressed as expected with basal levels during diestrus and proestrus, increased 11.6-fold during estrus, and decreased to basal levels during metestrus. In HFD mice, Edn2 was dysregulated across the entire estrous cycle as were other Edn2 system components (endothelin converting enzyme 1 (Ece-1), and the endothelin receptors (Ednra, Ednrb)). Interestingly, we found dysregulation of key ovarian steroidogenic genes after HFD. We also found that estradiol treatment in prepubertal mice increased Edn2 expression in the ovary (P = 0.030), suggesting that impaired steroidogenesis may be involved in the HFD-induced dysregulation of ovarian Edn2. In conclusion, HFD leads to ovulatory dysfunction regardless of the development of obesity, which appears to be mediated through dysregulation of ovarian Edn2 expression.

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Barry E Perlman, Audrey A Merriam, Alexander Lemenze, Qingshi Zhao, Salma Begum, Mohan Nair, Tracy Wu, Ronald J Wapner, Jan K Kitajewski, Carrie J Shawber, and Nataki C. Douglas

In the 1st trimester of human pregnancy, low oxygen tension or hypoxia, is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multuple cell types, the relationship between hypoxia and Notch in 1st trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human 1st trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a -secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed 2nd trimester chorionic villous sampling (CVS) samples and 3rd trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies, and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.

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Teruhito Ishihara, Oliver W Griffith, Gerard A Tarulli, and Marilyn B Renfree

Male germ cells undergo two consecutive processes – pre-spermatogenesis and spermatogenesis – to generate mature sperm. In eutherian mammals, epigenetic information such as DNA methylation is dynamically reprogrammed during pre-spermatogenesis, before and during mitotic arrest. In mice, by the time germ cells resume mitosis, the majority of DNA methylation is reprogrammed. The tammar wallaby has a similar pattern of germ cell global DNA methylation reprogramming to that of the mouse during early pre-spermatogenesis. However, early male germline development in the tammar or in any marsupial has not been described previously, so it is unknown whether this is a general feature regulating male germline development or a more recent phenomenon in mammalian evolutionary history. To answer this, we examined germ cell nuclear morphology and mitotic arrest during male germline development in the tammar wallaby (Macropus eugenii), a marsupial that diverged from mice and humans around 160 million years ago. Tammar pro-spermatogonia proliferated after birth and entered mitotic arrest after day 30 postpartum (pp). At this time, they began moving towards the periphery of the testis cords and their nuclear size increased. Germ cells increased in number after day 100 pp which is the time that DNA methylation is known to be re-established in the tammar. This is similar to the pattern observed in the mouse, suggesting that resumption of germ cell mitosis and the timing of DNA methylation reprogramming are correlated and conserved across mammals and over long evolutionary timescales.

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Zhiyong Zou, Karen Forbes, Lynda K Harris, and Alexander E P Heazell

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for estrogen related receptor-gamma (ESRRG) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ESRRG is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA (miRNA) or other potential upstream regulators of ESRRG negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, miRNAs regulate ESRRG expression in human trophoblast. Thus, if ESRRG is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ESRRG and upstream regulation of ESRRG-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ESRRG pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

Free access

Madelyn K Spooner, Yasser Y Lenis, Rachel Watson, Daniela Jaimes, and Amanda L Patterson

Uterine remodeling during pregnancy and repair postpartum are fundamental to the successful propagation of eutherian species. The most drastic remodeling occurs in species with invasively implanting embryos, including humans and mice. During embryo implantation, embryonic trophoblasts breach the epithelium, penetrating into the stroma. Stromal cell decidualization, which is critical for the establishment and maintenance of early pregnancy, occurs throughout the implantation site. Trophoblasts further invade into and remodel uterine spiral arteries, which is necessary for placental formation. The uterus increases in size up to 24-fold, which is largely attributed to myometrial expansion. Uterine changes that occur during pregnancy must then be resolved postpartum. Following parturition, the uterus repairs the remodeled tissue in the process of uterine involution. During involution, the majority of the endometrium is regenerated to replace the tissue that is shed postpartum. The myometrium returns to the pre-gravid state which is thought to occur through apoptosis and autophagy of smooth muscle cells. Although we understand the general process of postpartum uterine involution, the detailed mechanisms, particularly the role of putative stem cells, are poorly understood. This review discusses the evidence for the existence of epithelial, stromal and myometrial stem cells and their role in uterine involution. Gaps in knowledge and areas for future research are also considered. Studies of both postpartum and menstrual uterine repair, which likely involve similar mechanisms, are described under the broad definition of uterine involution. Although the primary focus of this review is human, mouse models are discussed to provide additional information.

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Pasqualino Loi, Luca Palazzese, Pier Augusto Scapolo, Josef Fulka, Helena Fulka, and Marta Czernik

The birth of Dolly through somatic cell nuclear transfer (SCNT) was a major scientific breakthrough of the last century. Yet, while significant progress has been achieved across the technics required to reconstruct and in vitro culture nuclear transfer embryos, SCNT outcomes in terms of offspring production rates are still limited. Here we provide a snapshot of the practical application of SCNT in farm animals and pets. Moreover, we suggest a path to improve SCNT through alternative strategies inspired by the physiological reprogramming in male and female gametes in preparation for the totipotency required after fertilization. Almost all papers on SCNT focused on nuclear reprogramming in the somatic cells after nuclear transfer. We believe that this is misleading, and even if it works sometimes, it does so in an uncontrolled way. Physiologically, the oocyte cytoplasm deploys nuclear reprogramming machinery specifically designed to address the male chromosome, the maternal alleles are prepared for totipotency earlier, during oocyte nuclear maturation. Significant advances have been made in remodeling somatic nuclei in vitro through the expression of protamines, thanks to a plethora of data available on spermatozoa epigenetic modifications. Missing are the data on large-scale nuclear reprogramming of the oocyte chromosomes. The main message our article conveys is that the next generation nuclear reprogramming strategies should be guided by insights from in-depth studies on epigenetic modifications in the gametes in preparation for fertilization.