Search for other papers by Jessica Dalton-O’Reilly in
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Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Saint Mary’s Hospital, Manchester, United Kingdom
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In brief
Animal models have been developed to aid understanding of the increased incidence of adverse pregnancy complications observed in women of advanced maternal age (AMA). This systematic review of murine models of AMA demonstrates consistent effects of decreased litter size and fetal weight; this supports the future use of these models to determine pathophysiological mechanisms and test therapeutic strategies to improve poor pregnancy outcomes in AMA.
Abstract
Advanced maternal age (AMA; ≥35 years of age) is associated with an increased risk of adverse pregnancy outcomes. To explore causes of adverse pregnancy outcomes in AMA, and to test candidate therapies, an increasing number of murine AMA models have been developed. The aim of this study was to systematically review the literature to assess whether murine AMA models demonstrate a reproducible effect on pregnancy outcomes. PubMed, Ovid, Web of Science and Google Scholar were searched. Studies that reported on pregnancy outcomes in AMA mice and rats were included; the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) tool evaluated the risk of bias. Eleven mouse and six rat studies were included. AMA mice and rats had reduced litter size (standardised mean difference (SMD): −1.59, 95% confidence interval (CI): −1.84, −1.34 for mice; SMD: −1.66, 95% (CI): −2.09, −1.23 for rats) and reduced fetal weight (SMD: −0.87, 95% CI: −1.24, −0.49 for mice; SMD: −1.05, 95% CI: −1.40, −0.69 for rats). Placental weight was increased in AMA mice (SMD: 0.62, 95% CI: 0.16, 1.08). Subgroup analysis indicated that C57Bl/6 mice had less heterogeneity than other, mostly outbred, mouse strains with regards to litter size (C57 strain I 2 = 68.2% vs other strain types I 2 = 85.7%). The risk of bias was high, mostly due to the lack of methodological detail and unclear reporting of findings. Murine models of AMA demonstrate similar adverse pregnancy outcomes to those observed in large human epidemiological studies. The reproducible phenotypes in AMA murine models allow the exploration of mechanisms underpinning poor pregnancy outcomes and the pursuit of therapeutic interventions.
Search for other papers by Caroline Gomes Lucas in
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Search for other papers by Riley M Sullivan in
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Search for other papers by Caroline A Pfeiffer in
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In brief
Aromatase catalyzes the synthesis of estrogens and has been shown to have an important role during the establishment of pregnancy in the pig. This study confirmed the differential expression of the three aromatase isoforms.
Abstract
Although three porcine aromatase isoforms have been identified, their gene expression profiles in reproduction are still poorly understood. Here, we identified by Sanger sequencing unique nucleotide signatures for the three paralogous copies of Cyp19 and analyzed by RT-PCR the occurrence of the Cyp19 and Cyp17a1 transcripts at different tissues and stages of conceptus and fetal–placental development. Cyp19a1 and Cyp19a3 expressions were detected in conceptuses and gonads, respectively. Cyp19a2 transcripts were identified on both the conceptuses and the placenta samples. Transcripts for Cyp17a1 were detected predominantly in conceptus and gonads. In the endometrium of day 21 pregnant females, as well as days 12 and 17 pseudopregnant females, we did not detect the expression of Cyp19a1, Cyp19a2, or Cyp19a3. In our study, we have demonstrated distinct transcriptional regulation for the three functional Cyp19 paralogs and a potential role for Cyp17a1 in controlling the secretion of estrogen from the conceptus and the placenta.
Search for other papers by Xiaoqin Li in
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Search for other papers by Zhilan Lu in
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Search for other papers by Xiushuai Du in
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Search for other papers by Jin Liu in
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Search for other papers by Wenchang Zhang in
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In brief
Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring. This article shows that pregnant woman should be protected from cadmium exposure.
Abstract
Exposure to cadmium (Cd) during pregnancy can potentially harm the reproductive system of male offspring, although the full extent of its heritable effects remains partially unresolved. In this study, we examined the inter-generational impacts of Cd using a distinct male-lineage generational model. Pregnant Sprague–Dawley female rats (F0) were administered control or cadmium chloride (0.5, 1 and 2 mg/day) via intra-gastric administration from gestation day 1 to 20. Subsequently, the first filial generation (F1) male rats were mated with untreated females (not exposed to Cd) to produce the second filial generation (F2). Histopathological analysis of the F1 and F2 generations revealed abnormal testicular development, while ultrastructural examination indicated damage to Sertoli cells. Cd exposure also led to alterations in serum hormone levels (gonadotropin-releasing hormone, follicle-stimulating hormone) and reduced follicle-stimulating hormone receptor (FSHR) protein expression in Sertoli cells in the F1 generation. Furthermore, Cd affected the mRNA and protein expression of FSHR pathway factors and DNA methyltransferase, albeit with distinct patterns and inconsistencies observed between the F1 and F2 generations. Overall, our findings indicate that prenatal Cd exposure, using a male-lineage transmission model, can induce inter-generational effects on male reproduction, particularly by causing toxicity in Sertoli cells. This effect appears to be primarily mediated through disruptions in the FSHR pathway and changes in DNA methyltransferase activity in the male testes.
Citrus Research and Education Center, University of Florida Institute of Food and Agricultural Sciences, Lake Alfred, Florida, USA
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Search for other papers by Zongliang Jiang in
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Search for other papers by Peter J Hansen in
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In brief
It is not known when a functional circadian clock is established in the developing embryo. Lack of expression of key genes involved in the clock mechanism is indicative that a functional circadian clock mechanism is absent in the mammalian preimplantation embryo through the blastocyst stage of development.
Abstract
An embryonic circadian clock could conceivably organize cellular and developmental events temporally and in synchrony with other circadian rhythms in the mother. The hypothesis that a functional molecular clock exists in the preimplantation bovine, pig, human, and mouse embryo was tested by using publicly available RNAseq datasets to examine developmental changes in expression of the core genes responsible for the circadian clock – CLOCK, ARNTL, PER1, PER2, CRY1, and CRY2. In general, the transcript abundance of each gene decreased as development advanced to the blastocyst stage. The most notable exception was for CRY2, where transcript abundance was low and constant from the two-cell or four-cell to the blastocyst stage. Developmental patterns were generally the same for all species although there were some species-specific patterns such as an absence of PER1 expression in the pig, an increase in ARNTL expression at the four-cell stage in human, and an increase in expression of Clock and Per1 from the zygote to two-cell stage in the mouse. Analysis of intronic reads (indicative of embryonic transcription) for bovine embryos indicated an absence of embryonic transcription. Immunoreactive CRY1 was not detected in the bovine blastocyst. Results indicate that the preimplantation mammalian embryo lacks a functional intrinsic clock although specific components of the clock mechanism could conceivably play a role in other functions in the embryo.
Search for other papers by Joaquín Lilao-Garzón in
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Servicio Endocrinología y Nutrición. Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Spain
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Search for other papers by Silvia Muñoz-Descalzo in
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In brief
Fertility has decreased due to advanced maternal age and the rising prevalence of the metabolic syndrome. Using quantitative image analysis methods, we show that these factors are associated with delayed preimplantation embryo development in a mouse model.
Abstract
Delayed maternal age, obesity and diabetes are associated with reduced fertility. We investigated how age and obesity/metabolic syndrome impact fertility and hypothesized that its decrease is due to defects in preimplantation embryo development. Three groups of female C57Bl6 mice (12 weeks, 9 months and 1 year old) were fed either a high-fat diet for 8 weeks, to induce obesity and the metabolic syndrome, or a control chow diet. Body weight and composition, glucose tolerance and insulin resistance were assessed. Fecundity was evaluated by mating and pregnancy rates, as well as by the number of embryos. Embryo quality was assessed morphologically, and cell fate composition was analysed in preimplantation embryos by state-of-the-art single-cell quantitative confocal image analysis. The high-fat diet was associated with increased adiposity, glucose intolerance and insulin resistance, especially in the older mice. Fecundity was affected by age more than by the diet. Both age and high-fat diet were associated with reduced cell fate allocation, indicating a delay in the preimplantation embryo development, and with increased expression of GATA3, an inhibitor of placentation. These results support that age and the metabolic syndrome reduce fertility through mechanisms which are present at conception or very early in pregnancy.
Search for other papers by Aisha Sati in
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Sorbonne Université, CNRS INSERM Neuroscience Paris Seine - Institut de Biologie Paris Seine Neuroplasticity of Reproductive Behaviours Team, Paris, France
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Search for other papers by Rebecca E Campbell in
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In brief
Neuroendocrine dysfunction and transgenerational susceptibility associated with polycystic ovary syndrome (PCOS) suggest that programmed changes within the brain contribute to adult development of the syndrome. This review discusses a potentially important role for microglia in mediating prenatal androgen-programmed changes in the female brain that contribute to PCOS-like features.
Abstract
Several lines of evidence support a role for the brain in both the development and maintenance of polycystic ovary syndrome (PCOS), the most common cause of anovulatory infertility worldwide. Persistently elevated luteinizing hormone secretion and impaired gonadal steroid hormone feedback in PCOS patients suggest impairments within the neuronal networks that regulate the reproductive axis. Evidence from preclinical models has linked androgen excess during prenatal life with altered structure and function of the developing female brain that might underpin syndrome development in adulthood. Studies investigating the mechanisms by which excess androgens program changes in the female brain have highlighted an important role for microglia. This review discusses how these non-neuronal cells shape the developing female brain in response to excess androgens and focuses on how microglia may be involved in the development of the neuroendocrine dysfunctions associated with PCOS.
Touchlight Genetics Ltd. Hampton, London, UK
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Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA
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Search for other papers by Vijay Suresh Akhade in
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Search for other papers by M R S Rao in
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In brief
Mrhl lncRNA regulates the Wnt signaling pathway in mouse spermatogonial cells, resulting in the commitment of B-type spermatogonia to meiotic entry through Mrhl lncRNA-mediated regulation of Sox8. Mrhl lncRNA regulates chromatin dynamics of the Sox8 promoter/enhancer interaction through chromatin looping.
Abstract
Proliferation and meiotic division of spermatogonial stem cells are highly regulated biological processes that occur during spermatogenesis. In addition to protein-coding genes, the mammalian genome encodes thousands of lncRNAs which are spatio-temporally expressed and play key role(s) in cellular differentiation and development. Mrhl lncRNA is one such mono-exonic polyadenylated non-coding RNA encoded within the 15th intron of the mouse Phkb gene. Mrhl lncRNA is expressed in mouse testis amongst other tissues. The RNA is nuclear localized and predominantly bound to chromatin in GC-1 spg cells (derived from B-type spermatogonia). It regulates multiple genes belonging to different biological processes including Wnt signaling. Wnt activation of GC-1 spg cells downregulates Mrhl lncRNA expression, in turn activating the expression of meiotic marker genes and downregulating stem cell markers. We have mapped the genomic loci bound by Mrhl lncRNA and identified 37 genes to be regulated by its physical association. Sox8 gene, one among these, is regulated through its interaction at its promoter through RNA:DNA:DNA triplex structure and chromatin looping mediated by the architectural proteins CTCF and YY1. Here, we summarize our major findings on this novel lncRNA starting from its discovery to biological function(s), particularly during meiotic commitment/initiation in mouse spermatogenesis.
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
National Demonstration Center for Experimental Veterinary Medicine Education (Huazhong Agricultural University), Wuhan, China
Search for other papers by Xia Zhang in
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
Search for other papers by Jilong Zhou in
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Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction (Huazhong Agricultural University), Ministry of Education, Wuhan, China
Hubei Hongshan Laboratory, Wuhan, P. R. China
Search for other papers by Yi-Liang Miao in
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In brief
Normal gene expression during early embryonic development and in the placenta is crucial for a successful pregnancy. Nicotine can disrupt normal gene expression during development, leading to abnormal embryonic and placental development.
Abstract
Nicotine is a common indoor air pollutant that is present in cigarette fumes. Due to its lipophilic nature, nicotine can rapidly transport through membrane barriers and spread throughout the body, which can lead to the development of diseases. However, the impact of nicotine exposure during early embryonic development on subsequent development remains elusive. In this study, we found that nicotine significantly elevated reactive oxygen species, DNA damage and cell apoptosis levels with the decrease of blastocyst formation during early embryonic development. More importantly, nicotine exposure during early embryonic development increased placental weight and disrupted placental structure. In molecular level, we also observed that nicotine exposure could specifically cause the hypermethylation of Phlda2 promoter (a maternally expressed imprinted gene associated with placental development) and reduce the mRNA expression of Phlda2. By RNA sequencing analysis, we demonstrated that nicotine exposure affected the gene expression and excessive activation of the Notch signaling pathway thereby affecting placental development. Blocking the Notch signaling pathway by DAPT treatment could recover abnormal placental weight and structure induced by nicotine exposure. Taken together, this study indicates that nicotine causes the declining quality of early embryos and leads to placental abnormalities related to over-activation of the Notch signaling pathway.
Search for other papers by Ziqian Min in
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Shenzhen Research Institute of Hunan University, Shenzhen, China
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In brief
Bacterial infection can induce testicular inflammation and damage male fertility. This paper reveals the role of nuclear receptor subfamily 2 group C member 2 (NR2C2) in macrophage cells in orchitis caused by bacterial endotoxin lipopolysaccharide (LPS) infection.
Abstract
Bacterial infection and induced inflammation are important causes of male infertility. Here, we described the characteristics of expression and the regulatory role of NR2C2 in testicular inflammatory injury induced by infection with the bacterial endotoxin LPS. We found that NR2C2 was highly expressed in the testes and the expression of NR2C2 was upregulated in testicular macrophages in the LPS-induced mouse orchitis model in vivo. In primary testicular macrophages and RAW264.7 cells in vitro, RNA interference with the Nr2c2 gene downregulated the expression of inflammatory factors such as IL-1β and IL-6. In addition, the knockdown of NR2C2 in macrophages alleviated the inhibitory effect of the inflammatory supernatant secreted by the macrophages on the proliferation of spermatogonia GC-1 SPG cells. Mechanistically, NR2C2 activated NF-κB signaling by binding with DR elements in the promotor of the Nfκb gene and promoted the development of inflammation. These data are the first to confirm that during LPS-induced bacterial infection, NR2C2 plays a proinflammatory role by activating IL-1β and IL-6 via the NF-κB pathway in macrophages, consequently inhibiting the proliferation of spermatogonia and damaging the quality of sperm. Our findings reveal the important role of NR2C2 in testicular inflammatory injury induced via LPS and provide a new potential target and a molecular basis for the treatment of male infertility caused by bacterial infection.
Search for other papers by Pia Seßenhausen in
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In brief
Nicotinic acetylcholine receptor alpha 7 (nAChRa7), encoded by Chrna7, is expressed by various murine ovarian cells. Morphological and molecular investigations, including a proteomic study of adult Chrna7 knockout (KO) mouse ovaries, reveal the roles of these receptors in the local regulation of the ovary.
Abstract
Nicotinic acetylcholine receptor alpha 7 (nAChRa7), encoded by Chrna7, is involved in cellular functions ranging from synaptic transmission in neurons to regulation of inflammation, cell growth and metabolism to cell death in other cells. Our qPCR results and other studies indicated that nAChRa7 is expressed in the adult mouse ovary, while in situ hybridization and single-cell sequencing data suggested this expression may be shared by several ovarian cells, including fibroblast-like and steroidogenic stroma cells, macrophages and oocytes of small follicles. To explore a possible involvement of nAChRa7 in ovarian functions, we evaluated ovarian morphology of Chrna7-null mutant adult mice (KO) and wildtype mice (WT; 3 months, metestrus) by performing immunohistochemistry, qPCR studies, measurements of serum progesterone and proteomic analyses. The evaluation of serial sections indicated fewer primordial follicles but similar numbers of primary, secondary and tertiary follicles, as well as corpora lutea in KO and WT mice. Atresia was unchanged. Serum progesterone and mRNA levels of proliferation and most apoptosis markers were not changed, yet two typical macrophage markers were elevated. Furthermore, the proteomes of KO ovaries were significantly altered with 96 proteins increased and 32 decreased in abundance in KOs compared to WTs. Among the elevated proteins were markers for stroma cells. Hence, the lack of nAChRa7 causes changes in small follicle counts and alterations of the ovarian stroma cells. The ovarian phenotype of Chrna7 mutant mice links this channel protein to the local regulation of ovarian cells, including stroma cells.
