Control of oocyte release by progesterone receptor-regulated gene expression

The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes

Can fetal alcohol exposure increase the risk of hypertension? A new study in children and adolescents diagnosed with fetal alcohol spectrum disorder suggests it can

Prenatal alcohol exposure (PAE) is increasingly recognized as being associated with a wide range of physical health problems, in addition to the well-defined neurocognitive difficulties that have been reported (Mattson et\ua0al., 2019). In line with other prenatal perturbations, including smoking, inadequate nutrition and exposure to stress, exposure of the fetus to alcohol during critical stages of development may contribute to 'developmental origins of health and disease' (DOHaD), as first proposed by Barker and colleagues (1995). DOHaD suggests that a suboptimal environment in early development may increase susceptibility to conditions such as hypertension, insulin resistance and obesity, which are risk factors for prevalent non-communicable chronic diseases such as cardiovascular disease and type II diabetes (Hanson and Gluckman, 2011). This article is protected by copyright. All rights reserved

Adverse health outcomes associated with fetal alcohol exposure: a systematic review focused on immune-related outcomes

Prenatal alcohol exposure (PAE) has well known teratogenic effects on the developing fetus, potentially resulting in neurological impairments. However, there is increasing interest regarding other potential adverse health outcomes related to prenatal alcohol exposure.To undertake a systematic review to identify all the available clinical and preclinical literature investigating immune related outcomes in offspring with PAE.Systematic review searching four electronic databases (PubMed, CINAHL, Web of Science, and Embase). Potential articles were screened against strict inclusion/exclusion criteria. This review specifically focused on evaluating studies related to immune-related outcomes following PAE.Twelve clinical studies were included in the current review. Six included allergy outcomes, 4 included infection outcomes and 2 studies included both. Thirty-nine preclinical studies were identified examining a wide range of immune outcomes.The current review provides some preliminary clinical evidence that PAE can influence immune function, including atopic allergy and infection outcomes. However, there was variability in results across studies, particularly in the atopy area. Preclinical studies demonstrated some changes in lymphocytes and cytokines in offspring following PAE. More research investigating the effects of PAE on immune responses are warranted. This article is protected by copyright. All rights reserved

Abundance estimators and truth: Accounting for individual heterogeneity in wild house mice

We compared the actual abundance of 12 confined populations of wild house mice (Mus musculus) with closed population estimates based on mark-recapture data. Goodness-of-fit tests consistently detected individual heterogeneity in capture probability. Estimators designed to take such heterogeneity into account were expected to perform best, and generally did. However, of the 9 abundance estimators we considered, only Chao's modified moment estimator had no obvious bias and produced confidence intervals that always included the actual population size. The reliability of the 9 estimators and minimum number known alive (MNA), as indices of abundance, was quantified by (1) linear regression, and (2) calculating a Spearman rank correlation coefficient between the ranking obtained using the index and the true ranking. We found Petersen estimates to provide the most accurate ranking, and MNA also performed well. Since Chao's modified moment estimator was designed for populations with high levels of heterogeneity and low average capture probability, we concluded that this is an accurate description of trap response for confined mice populations. Body-length frequency distributions and sex ratios for mice caught once, more than once, and not at all revealed that body length and sex could explain some of the observed individual heterogeneity. Males were more likely to enter traps than females, and large mice were more likely to be trapped than small mice. Field populations of house mice are monitored regularly throughout southeastern Australia because high densities cause considerable damage to wheat crops and place substantial stress on farming communities. We found that field populations trapped during the breeding season exhibit heterogeneity in capture probability similar to that for confined populations, with the same relationships between capture probability, sex, and body length. However, these relationships did not hold for the same field population later in the season when breeding and recruitment had ceased. Chao's modified moment estimator was applied to field data and found to be stable when populations were trapped for ≥5 nights, but unreliable trapped for <5 nights

Increased beta-oxidation and improved oocyte developmental competence in response to L-Carnitine during ovarian in vitro follicle development in mice

Oocyte developmental competence is acquired throughout folliculogenesis and is associated with appropriate differentiation and responsiveness to the luteinizing hormone (LH) surge. The recent development of a novel system for culturing ovarian follicles in a three-dimensional alginate matrix shows promise in phenocopying in vivo folliculogenesis. However, oocytes from follicles grown in vitro have a reduced capacity to complete nuclear maturation and be fertilized compared to oocytes matured in vivo. Oocyte metabolism is closely linked with oocyte quality, and we have recently shown that beta-oxidation of lipids is essential for oocyte developmental competence. Thus we investigated whether upregulation of beta-oxidation by treatment with the fatty acid transport cofactor l-carnitine could improve folliculogenesis and developmental competence of mouse follicles following three-dimensional culture. Ovarian hormones (androstenedione, estradiol, and progesterone) and the induction of cumulus matrix proteins (hyaluronan and ADAMTS1) were similar to in vivo follicles, indicating that appropriate differentiation of follicular cells occurs in cultured follicles after an LH/human chorionic gonadotropin (hCG) stimulus. l-carnitine did not alter survival, growth, or differentiation of follicles. However, l-carnitine supplementation significantly increased beta-oxidation, and markedly improved both fertilization rate and blastocyst development. Together, these results show that appropriate responsiveness of the follicle to the LH/hCG surge occurs following three-dimensional follicle culture but limitations on key metabolic requirements remain. l-carnitine supplementation during in vitro follicle culture increased lipid metabolism and improved oocyte developmental competence.Kylie R. Dunning, Lisa K. Akison, Darryl L. Russell, Robert J. Norman, and Rebecca L. Robke

Transient invasive migration in mouse cumulus oocyte complexes induced at ovulation by luteinizing hormone

Ovulation, the release of the oocyte from the ovarian follicle, is initiated by the luteinizing hormone surge. It is clear that highly controlled degradation of the follicle and ovarian wall is required for passage of the oocyte and accompanying cumulus cells from the follicle, but the mechanism has not yet been elucidated. Here we show that cumulus oocyte complexes (COCs) adopt transient adhesive, migratory, and matrix-invading capacities at the time of ovulation. We characterized cell adhesion, migration, and invasion in preovulatory and postovulatory mouse COCs collected over a time course post-human chorionic gonadotropin (hCG) administration. Adhesion of dispersed cumulus cells and intact COCs to extracellular matrix proteins present in the ovarian wall(collagens, laminin, and fibronectin) increased significantly after hCGtreatment and declined immediately after ovulation. Cumulus cell migration was low in unexpanded, equine chorionic gonadotropin- only treated COCs, but increased 4, 8, and 10 h post-hCG, reaching a peak at 12 h post-hCG that coincided with ovulation. The ability of cumulus cells to migrate was rapidly diminished in COCs isolated from the oviduct within 2 h postovulation. Cell migration was cumulus cell specific and was not observed in granulosa cells. Invasion through three-dimensional collagen I and matrigel barriers by preovulatory expanded COCs was equivalent to that of a known invasive breast cancer cell line (MB-231). Cumulatively, these results demonstrate that cumulus cells in the expanded COC transition to an adhesive, motile, and invasive phenotype in the periovulatory period that may be required for successful release of the oocyte from the ovary at ovulation.Lisa K. Akison, Emily R. Alvino, Kylie R. Dunning, Rebecca L. Robker and Darryl L. Russel

Progesterone receptor-dependent regulation of genes in the oviducts of female mice

Oviducts play a critical role in gamete and embryo transport, as well as supporting early embryo development. Progesterone receptor (PGR) is a transcription factor highly expressed in oviductal cells, while its activating ligand, progesterone, surges to peak levels as ovulation approaches. Progesterone is known to regulate oviduct cilia beating and muscular contractions in vitro, but how PGR may mediate this in vivo is poorly understood. We used PGR null mice to identify genes potentially regulated by PGR in the oviducts during the periovulatory period. Histologically, oviducts from PGR null mice showed no gross structural or morphological defects compared with normal littermates. However, microarray analysis of oviducts at 8 h posthuman chorionic gonadotropin revealed >1,000 PGR-dependent genes. Using reverse-transcription polymerase chain reaction (RT-PCR) we selected 10 genes for validation based on their potential roles in oocyte/embryo transport and support. Eight genes were confirmed to be downregulated (Adamts1, Itga8, Edn3, Prlr, Ptgfr, Des, Myocd, and Actg2) and one upregulated (Agtr2) in PGR null oviducts. Expression of these genes was also assessed in oviducts of naturally cycling mice during ovulation and day 1 and day 4 of pregnancy. Adamts1, Itga8, Edn3, Prlr, and Ptgfr were significantly upregulated in oviducts at ovulation/mating. However, most genes showed basal levels of expression at other times. The exceptions were Prlr and Ptgfr, which showed pulsatile increases on day 1 and/or day 4 of pregnancy. This is the first, comprehensive study to elucidate putative PGR-regulated genes in the oviduct and reveals key downstream targets potentially mediating oocyte and embryo transport.Lisa K. Akison, Michael J. Boden, David J. Kennaway, Darryl L. Russell, and Rebecca L. Robke