Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next‐generation adult rats

Aiken, Catherine; Tarry-Adkins, Jane L.; Spiroski, Ana-Mishel; Nuzzo, Anna Maria; Ashmore, Tom; Rolfo, Alessandro; Sutherland, Megan R.; Camm, Emily J.; Giussani, Dino A.; Ozanne, Susan E.

doi:10.1096/fj.201802772r

Cited by 24 publications

(15 citation statements)

References 58 publications

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“…Interestingly, downregulation of genes that control DNA repair and damage response pathways may result from antecedent hypoperfusion injury before birth. The developing ovary is highly sensitive to such gestational hypoxia, with implications for the fertility of nextgeneration offspring [35][36][37]. Exposure to chronic hypoxia during fetal development accelerates ovarian aging and decreases reserve in adulthood.…”

Section: Resultsmentioning

confidence: 99%

Intraovarian vascular enhancement via stromal injection of platelet-derived growth factors: Exploring subsequent oocyte chromosomal status and in vitro fertilization outcomes

Wood

Sills

2020

Clin Exp Reprod Med

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The inverse correlation between maternal age and pregnancy rate represents a major challenge for reproductive endocrinology. The high embryo ploidy error rate in failed <i>in vitro</i> fertilization (IVF) cycles reflects genetic misfires accumulated by older oocytes over time. Despite the application of different follicular recruitment protocols during IVF, gonadotropin modifications are generally futile in addressing such damage. Even when additional oocytes are retrieved, quality is frequently poor. Older oocytes with serious cytoplasmic and/or chromosomal errors are often harvested from poorly perfused follicles, and ovarian vascularity and follicular oxygenation impact embryonic chromosomal competency. Because stimulation regimens exert their effects briefly and immediately before ovulation, gonadotropins alone are an ineffective antidote to long-term hypoxic pathology. In contrast, the tissue repair properties (and particularly the angiogenic effects) of platelet-rich plasma (PRP) are well known, with applications in other clinical contexts. Injection of conventional PRP and/or its components (e.g., isolated platelet-derived growth factors as a cell-free substrate) into ovarian tissue prior to IVF has been reported to improve reproductive outcomes. Any derivative neovascularity may modulate oocyte competence by increasing cellular oxygenation and/or lowering concentrations of intraovarian reactive oxygen species. We propose a mechanism to support intrastromal angiogenesis, improved follicular perfusion, and, crucially, embryo ploidy rescue. This last effect may be explained by mRNA upregulation coordinated by PRP-associated molecular signaling, as in other tissue systems. Additionally, we outline an intraovarian injection technique for platelet-derived growth factors and present this method to help minimize reliance on donor oocytes and conventional hormone replacement therapy.

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Section: Resultsmentioning

confidence: 99%

Intraovarian vascular enhancement via stromal injection of platelet-derived growth factors: Exploring subsequent oocyte chromosomal status and in vitro fertilization outcomes

Wood

Sills

2020

Clin Exp Reprod Med

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“…In reconstituted ovaries derived from pluripotent stem cells, hypoxia induced oocytes to remain dormant via overexpression of Foxo3 (Shimamoto et al 2019). Hypoxia also lowers the primordial follicular reserve in rats, potentially due to a reduced capacity for DNA damage and telomere repair (Aiken et al 2019). The involvement of hypoxia also extends to the other stages of follicular development.…”

Section: F36mentioning

confidence: 99%

HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation

2021

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The ovarian follicle provides the oocyte with the ideal environment for growth and development in preparation for ovulation and fertilisation. The follicle undergoes many structural changes as it grows, including changes in vasculature, cell proliferation and differentiation and the formation of a follicular fluid-filled antrum. These changes collectively create a low oxygen environment within the follicle. Thus, the oocyte itself develops in a potentially hypoxic environment. The survival of hypoxic tissues is controlled by hypoxia-inducible factors (HIFs) that are activated in a low oxygen state. The understanding of HIF pathways is growing across all fields of biology, and its role in ovarian development is steadily gaining clarity. One of the genes upregulated by HIF is vascular endothelial growth factor, the main inducer of angiogenesis which is required for follicle development and luteal formation. Ovulation is also intrinsically linked to HIF activity through the ovulatory luteinizing hormone surge increasing HIF expression. The role for HIF in oocyte maturation is less understood, as efforts to replicate the low oxygen environment of the in vivo follicle are not achievable by culturing in low oxygen alone. There is potential for other factors present in vivo, but lost in vitro, to be involved in oxygen regulation. One factor of interest is haemoglobin, the oxygen-binding protein, which brings the exciting possibility of sensitive oxygen regulation, consequently affecting HIF-regulated gene expression. A thorough understanding of oxygen regulation within the follicle would provide vital applications for the field of assisted reproductive technologies, in particular in vitro oocyte maturation.

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“…Moreover, the authors in a later job reported that the offspring, shown a reduction in the number of primordial follicles available and an increase in oxidative stress markers such as Gp91 phox and P22 phox . Therefore, prolonged exposure to fetal hypoxia causes a reduction in fertility that accelerates with the aging of the ovary [56]. However, an understanding of these molecular pathways would be necessary to develop effective interventions to protect the female offspring of a high-risk pregnancy.…”

Section: Animal Models Of Prenatal Hypoxiamentioning

confidence: 99%

“…[50] Fetal hypoxia in addition to accelerated aging of the ovary is also responsible for a reduction in fertility through an increase of oxidative stress. [56] eNOS; endothelial nitric oxide synthase, eNOS −/− mice; mice lacking the eNOS, COMT −/− mice; mice deficient in the enzyme catechol-O-methyl transferase, NO; nitric oxide, Ang II; angiotensin II, CIH; chronic intermittent hypoxia, SOD1; superoxide dismutase1, ROS; reactive oxygen species, CAT; catalase.…”

Section: Animal Models Sample Size O 2 Concentration Main Messagementioning

confidence: 99%

Prenatal Hypoxia and Placental Oxidative Stress: Insights from Animal Models to Clinical Evidences

et al. 2020

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Hypoxia is a common form of intrauterine stress characterized by exposure to low oxygen concentrations. Gestational hypoxia is associated with the generation of reactive oxygen species. Increase in oxidative stress is responsible for damage to proteins, lipids and DNA with consequent impairment of normal cellular functions. The purpose of this review is to propose a summary of preclinical and clinical evidences designed to outline the correlation between fetal hypoxia and oxidative stress. The results of the studies described show that increases of oxidative stress in the placenta is responsible for changes in fetal development. Specifically, oxidative stress plays a key role in vascular, cardiac and neurological disease and reproductive function dysfunctions. Moreover, the different finding suggests that the prenatal hypoxia-induced oxidative stress is associated with pregnancy complications, responsible for changes in fetal programming. In this way, fetal hypoxia predisposes the offspring to congenital anomalies and chronic diseases in future life. Several antioxidant agents, such as melatonin, erythropoietin, vitamin C, resveratrol and hydrogen, shown potential protective effects in prenatal hypoxia. However, future investigations will be needed to allow the implementation of these antioxidants in clinical practice for the promotion of health in early intrauterine life, in fetuses and children.

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Chronic gestational hypoxia accelerates ovarian aging and lowers ovarian reserve in next‐generation adult rats

Cited by 24 publications

References 58 publications

Intraovarian vascular enhancement via stromal injection of platelet-derived growth factors: Exploring subsequent oocyte chromosomal status and in vitro fertilization outcomes

Intraovarian vascular enhancement via stromal injection of platelet-derived growth factors: Exploring subsequent oocyte chromosomal status and in vitro fertilization outcomes

HYPOXIA AND REPRODUCTIVE HEALTH: Hypoxia and ovarian function: follicle development, ovulation, oocyte maturation

Prenatal Hypoxia and Placental Oxidative Stress: Insights from Animal Models to Clinical Evidences

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