ORCID Profile
0000-0002-5111-8389
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Animal Reproduction | Zoology | Animal Developmental and Reproductive Biology | Reproduction | Animal Production
Expanding Knowledge in the Biological Sciences | Animal Production and Animal Primary Products not elsewhere classified | Reproductive System and Disorders |
Publisher: Springer Science and Business Media LLC
Date: 28-09-2018
DOI: 10.1038/S41467-018-05564-Z
Abstract: Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2 -mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1 -methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1- methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
Publisher: The Endocrine Society
Date: 07-03-2022
Abstract: Inhibins are members of the transforming growth factor-β family, composed of a common α-subunit disulfide-linked to 1 of 2 β-subunits (βA in inhibin A or βB in inhibin B). Gonadal-derived inhibin A and B act in an endocrine manner to suppress the synthesis of follicle-stimulating hormone (FSH) by pituitary gonadotrope cells. Roles for inhibins beyond the pituitary, however, have proven difficult to delineate because deletion of the inhibin α-subunit gene (Inha) results in unconstrained expression of activin A and activin B (homodimers of inhibin β-subunits), which contribute to gonadal tumorigenesis and lethal cachectic wasting. Here, we generated mice with a single point mutation (Arg233Ala) in Inha that prevents proteolytic processing and the formation of bioactive inhibin. In vitro, this mutation blocked inhibin maturation and bioactivity, without perturbing activin production. Serum FSH levels were elevated 2- to 3-fold in InhaR233A/R233A mice due to the loss of negative feedback from inhibins, but no pathological increase in circulating activins was observed. While inactivation of inhibin A and B had no discernible effect on male reproduction, female InhaR233A/R233A mice had increased FSH-dependent follicle development and enhanced natural ovulation rates. Nevertheless, inhibin inactivation resulted in significant embryo-fetal resorptions and severe subfertility and was associated with disrupted maternal ovarian function. Intriguingly, heterozygous Inha+/R233A females had significantly enhanced fecundity, relative to wild-type littermates. These studies have revealed novel effects of inhibins in the establishment and maintenance of pregnancy and demonstrated that partial inactivation of inhibin A/B is an attractive approach for enhancing female fertility.
Publisher: Oxford University Press (OUP)
Date: 30-09-2021
Abstract: PIWI-interacting small RNAs (piRNAs) maintain genome stability in animal germ cells, with a predominant role in silencing transposable elements. Mutations in the piRNA pathway in the mouse uniformly lead to failed spermatogenesis and male sterility. By contrast, mutant females are fertile. In keeping with this paradigm, we previously reported male sterility and female fertility associated with loss of the enzyme HENMT1, which is responsible for stabilising piRNAs through the catalysation of 3′-terminal 2′-O-methylation. However, the Henmt1 mutant females were poor breeders, suggesting they could be subfertile. Therefore, we investigated oogenesis and female fertility in these mice in greater detail. Here, we show that mutant females indeed have a 3- to 4-fold reduction in follicle number and reduced litter sizes. In addition, meiosis-II mutant oocytes display various spindle abnormalities and have a dramatically altered transcriptome which includes a down-regulation of transcripts required for microtubule function. This down-regulation could explain the spindle defects observed with consequent reductions in litter size. We suggest these various effects on oogenesis could be exacerbated by asynapsis, an apparently universal feature of piRNA mutants of both sexes. Our findings reveal that loss of the piRNA pathway in females has significant functional consequences.
Publisher: Cold Spring Harbor Laboratory
Date: 17-06-2022
DOI: 10.1101/2022.06.16.496499
Abstract: Meiotic crossovers are required for accurate chromosome segregation and to produce new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we describe the tumour suppressor FANCM as a meiotic anti-crossover factor in mammals. Crossover analyses with single-gamete and pedigree datasets both reveal a genome-wide increase in crossover frequencies in Fancm -deficient mice. Gametogenesis is heavily perturbed in Fancm loss of function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway. Despite the gametogenesis phenotypes in Fancm mutants both sexes were capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.
Publisher: Oxford University Press (OUP)
Date: 2020
Abstract: What is the evidence to guide the management of women who wish to conceive following abdominopelvic radiotherapy (AP RT) or total body irradiation (TBI)? Pregnancy is possible, even following higher doses of post-pubertal uterine radiation exposure however, it is associated with adverse reproductive sequelae and pregnancies must be managed in a high-risk obstetric unit. In addition to primary ovarian insufficiency, female survivors who are treated with AP RT and TBI are at risk of damage to the uterus. This may impact on its function and manifest as adverse reproductive sequelae. A review of the literature was carried out and a multidisciplinary working group provided expert opinion regarding assessment of the uterus and obstetric management. Reproductive outcomes for postpubertal women with uterine radiation exposure in the form of AP RT or TBI were reviewed. This included Pubmed listed peer-reviewed publications from 1990 to 2019, and limited to English language.. The prepubertal uterus is much more vulnerable to the effects of radiation than after puberty. Almost all available information about the impact of radiation on the uterus comes from studies of radiation exposure during childhood or adolescence. An uncomplicated pregnancy is possible, even with doses as high as 54 Gy. Therefore, tumour treatment doses alone cannot at present be used to accurately predict uterine damage. Much of the data cannot be readily extrapolated to adult women who have had uterine radiation and the publications concerning adult women treated with AP RT are largely limited to case reports. This analysis offers clinical guidance and assists with patient counselling. It is important to include patients who have undergone AP RT or TBI in prospective studies to provide further evidence regarding uterine function, pregnancy outcomes and correlation of imaging with clinical outcomes. This study received no funding and there are no conflicts of interest. N/A.
Publisher: Springer Science and Business Media LLC
Date: 25-08-2022
DOI: 10.1038/S43018-022-00413-X
Abstract: Loss of fertility is a major concern for female reproductive-age cancer survivors, since a common side-effect of conventional cytotoxic cancer therapies is permanent damage to the ovary. While immunotherapies are increasingly becoming a standard of care for many cancers-including in the curative setting-their impacts on ovarian function and fertility are unknown. We evaluated the effect of immune checkpoint inhibitors blocking programmed cell death protein ligand 1 and cytotoxic T lymphocyte-associated antigen 4 on the ovary using tumor-bearing and tumor-free mouse models. We find that immune checkpoint inhibition increases immune cell infiltration and tumor necrosis factor-α expression within the ovary, diminishes the ovarian follicular reserve and impairs the ability of oocytes to mature and ovulate. These data demonstrate that immune checkpoint inhibitors have the potential to impair both immediate and future fertility, and studies in women should be prioritized. Additionally, fertility preservation should be strongly considered for women receiving these immunotherapies, and preventative strategies should be investigated in future studies.
Publisher: Oxford University Press (OUP)
Date: 20-12-2020
Abstract: As cancer survival rates improve, understanding and preventing the adverse off-target and long-term impacts of cancer treatments, including impacts on fertility, have become increasingly important. Cancer therapy-mediated damage to the ovary and depletion of the primordial follicle reserve are well characterised. However, our knowledge of the full extent of damage to the rest of the female reproductive tract, in particular the uterus, is limited. Improving our understanding of the off-target effects of cancer therapies on the entire female reproductive tract is a critical step towards developing truly effective strategies to protect the fertility of cancer survivors. The objective of this narrative review was to critically evaluate the available literature regarding the capacity for the uterus to sustain a healthy pregnancy following exposure to radiotherapy or chemotherapy. The authors performed PubMed (Medline) searches using the following key words: uterus, cancer survivors, radiotherapy, chemotherapy, pregnancy outcome, fertility preservation, infertility. There were no limits placed on time of publication. Overall, there were major limitations to the current available literature, meaning that interpretations should be taken with caution. Despite these drawbacks, data suggest that the uterus may sustain off-target damage, with the extent of damage dependent on the type of cancer treatment and patient age. Specifically, uterine growth is stunted and resistant to hormone replacement therapy in prepubertal girls receiving abdominal, pelvic or whole-body radiotherapy. In contrast, females treated with radiotherapy post-puberty can benefit from hormone replacement therapy, as demonstrated by increased uterine volume and function. No live births have been reported in women previously exposed to radiotherapy after transplantation of cryopreserved ovarian tissue, even when menstruation returns. However, this technique has proven to be a successful fertility preservation method for women previously treated with chemotherapy. Obstetricians commonly report that women who maintain sufficient ovarian function can achieve pregnancy naturally following radiotherapy, but they have thin and/or fibrotic myometrium at delivery, compromising safe delivery and subsequent pregnancy. Furthermore, women exposed to either radiotherapy or chemotherapy have a higher prevalence of preterm birth and low birth weight infants, even in those with normal ovarian function or when oocyte donation is utilised. The mechanisms of potential uterine damage are poorly understood. While the myometrium, vasculature and endometrial progenitor cells are possibly targets, further studies are clearly required and well-controlled animal models could provide the best avenue for these types of future investigations. Female cancer survivors experience greater rates of early pregnancy loss and complications, suggesting that cancer therapy-induced damage to the uterus contributes to infertility. Despite clinical reports dating back to 1989, we highlight a surprising lack of detail in the literature regarding the precise nature and extent of off-target damage inflicted to the uterus in response to cancer therapies. Young women requiring cancer treatment, and the clinicians treating them, must be equipped with accurate information to aid informed decision-making regarding cancer treatment regimens as well as the development and use of effective fertility preservation measures. As the current literature on the impacts of cancer treatments is limited, we hope that our narrative review on this subject will stimulate more research in this important field.
Publisher: Wiley
Date: 24-01-2014
Publisher: Cambridge University Press (CUP)
Date: 30-03-2022
DOI: 10.1017/S2040174421000106
Abstract: Through drinking water, humans are commonly exposed to atrazine, a herbicide that acts as an endocrine and metabolic disruptor. It interferes with steroidogenesis, including promoting oestrogen production and altering cell metabolism. However, its precise impact on uterine development remains unknown. This study aimed to determine the effect of prolonged atrazine exposure on the uterus. Pregnant mice ( n = 5/group) received 5 mg/kg body weight/day atrazine or DMSO in drinking water from gestational day 9.5 until weaning. Offspring continued to be exposed until 3 or 6 months of age ( n = 5–9/group), when uteri were collected for morphological and molecular analyses and steroid quantification. Endometrial hyperplasia and leiomyoma were evident in the uteri of atrazine-exposed mice. Uterine oestrogen concentration, oestrogen receptor expression, and localisation were similar between groups, at both ages ( P 0.1). The expression and localisation of key epithelial-to-mesenchymal transition (EMT) genes and proteins, critical for tumourigenesis, remained unchanged between treatments, at both ages ( P 0.1). Hence, oestrogen-mediated changes to established EMT markers do not appear to underlie abnormal uterine morphology evident in atrazine exposure mice. This is the first report of abnormal uterine morphology following prolonged atrazine exposure starting in utero , it is likely that the abnormalities identified would negatively affect female fertility, although mechanisms remain unknown and require further study.
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2020
DOI: 10.1101/2020.01.20.913376
Abstract: Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report the epigenetic repressor Smchd1 as a novel maternal effect gene that regulates imprinted expression of 16 genes. Most Smchd1-sensitive genes only show loss of imprinting post-implantation, indicating maternal Smchd1’s long-lived epigenetic effect. Sm-chd1-sensitive genes include both those controlled by germline polycomb marks and germline DNA methylation imprints however, Smchd1 differs to other maternal effect genes that regulate the latter group, as Smchd1 does not affect germline DNA methylation imprints. Instead, Smchd1-sensitive genes are united by their reliance on polycomb-mediated histone methylation marks as germline or secondary imprints. We propose that Smchd1 translates these imprints to establish a heritable chromatin state required for imprinted expression later in development, revealing a new mechanism for maternal effect genes.
Publisher: eLife Sciences Publications, Ltd
Date: 13-11-2020
DOI: 10.7554/ELIFE.55529
Abstract: Genomic imprinting establishes parental allele-biased expression of a suite of mammalian genes based on parent-of-origin specific epigenetic marks. These marks are under the control of maternal effect proteins supplied in the oocyte. Here we report epigenetic repressor Smchd1 as a novel maternal effect gene that regulates the imprinted expression of ten genes in mice. We also found zygotic SMCHD1 had a dose-dependent effect on the imprinted expression of seven genes. Together, zygotic and maternal SMCHD1 regulate three classic imprinted clusters and eight other genes, including non-canonical imprinted genes. Interestingly, the loss of maternal SMCHD1 does not alter germline DNA methylation imprints pre-implantation or later in gestation. Instead, what appears to unite most imprinted genes sensitive to SMCHD1 is their reliance on polycomb-mediated methylation as germline or secondary imprints, therefore we propose that SMCHD1 acts downstream of polycomb imprints to mediate its function.
Publisher: eLife Sciences Publications, Ltd
Date: 26-10-2020
Publisher: Springer Science and Business Media LLC
Date: 14-10-2020
DOI: 10.1186/S13048-020-00724-6
Abstract: Accurate evaluation of primordial follicle numbers in mouse ovaries is an essential endpoint for studies investigating how endogenous and exogenous insults, such as maternal aging and chemotherapy, impact the ovarian reserve. In this study, we compared and contrasted two methods for counting healthy primordial follicles following exposure to cyclophosphamide (75 mg/kg), a well-established model of follicle depletion. The first was the fractionator/optical dissector technique, an unbiased, assumption-free stereological approach for quantification of primordial follicle numbers. While accurate, highly reproducible and sensitive, this method relies on specialist microscopy equipment and software, requires specific fixation, embedding and sectioning parameters to be followed, and is largely a manual process that is tedious and time-consuming. The second method was the more widely used serial section and direct count approach, which is relatively quick and easy. We also compared the impacts of different fixatives, embedding material and section thickness on the overall results for each method. Direct counts resulted in primordial follicle numbers that were significantly lower than those obtained by stereology, irrespective of fixation and embedding material. When applied to formalin fixed tissue, the direct count method did not detect differences in follicle numbers between saline and cyclophosphamide treated groups to the same degree of sensitivity as the gold standard stereology method (referred to as the Reference standard). However, when Bouin’s fixative was used, direct counts and stereology were comparable in their ability to detect follicle depletion caused by cyclophosphamide. This work indicates that the direct count method can produce similar results to stereology when Bouin’s fixative is used instead of formalin. The findings presented here will assist others to select the most appropriate experimental approach for accurate follicle enumeration, depending on whether the primary objective of the study is to determine absolute primordial follicle numbers or relative differences between groups.
Publisher: Oxford University Press (OUP)
Date: 28-05-2021
DOI: 10.1093/JNCI/DJAB111
Abstract: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function. Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided. Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data. The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making.
Publisher: Bioscientifica
Date: 04-2023
DOI: 10.1530/RAF-22-0123
Abstract: Cytotoxic chemotherapies have been a mainstay of cancer treatment but are associated with numerous systemic adverse effects, including impacts on fertility and endocrine health. Irreversible ovarian damage and follicle depletion are the side effects of chemotherapy that can lead to infertility and premature menopause, both being major concerns of young cancer patients. Notably, many women will proceed with fertility preservation, but unfortunately existing strategies do not entirely solve the problem. Most significantly, oocyte and embryo freezing do not prevent cancer treatment-induced ovarian damage from occurring, which may result in the impairment of long-term hormone production. Unfortunately, loss of endogenous endocrine function is not fully restored by hormone replacement therapy. Additionally, while GnRH agonists are standard care for patients receiving alkylating chemotherapy to lessen the risk of premature menopause, their efficacy is incomplete. The lack of more broadly effective options stems, in part, from our poor understanding of how different treatments damage the ovary. Here, we summarise the impacts of two commonly utilised chemotherapies – cyclophosphamide and cis -diamminedichloroplatinum(II) (cisplatin) – on ovarian function and fertility and discuss the mechanisms underpinning this damage. Additionally, we critically analyse current research avenues in the development of novel fertility preservation strategies, with a focus on ferto-protective agents. Over the past few decades, advances in the detection and treatment of cancer have dramatically improved survival rates in young women. This means that ensuring patients have a high quality of life after cancer treatment has become a new priority. Therefore, it is important to understand and prevent any long-term negative side effects of cancer treatments, with infertility and early-onset menopause being major concerns for women receiving chemotherapy. The current fertility preservation options available to young women have significant limitations. Therefore, the identification of new approaches to protect fertility has been an intense topic of research in recent years. In this review, we provide information on the negative side effects of two commonly used chemotherapy drugs – cyclophosphamide and cis -diamminedichloroplatinum(II) (cisplatin) – on fertility, and discuss how they cause damage to the ovaries. We also critically analyse recent preclinical studies related to the development of new fertility preservation techniques.
Publisher: Oxford University Press (OUP)
Date: 28-02-2023
Abstract: Regulated cell death is a fundamental component of numerous physiological processes spanning from organogenesis in utero, to normal cell turnover during adulthood, as well as the elimination of infected or damaged cells throughout life. Quality control through regulation of cell death pathways is particularly important in the germline, which is responsible for the generation of offspring. Women are born with their entire supply of germ cells, housed in functional units known as follicles. Follicles contain an oocyte, as well as specialized somatic granulosa cells essential for oocyte survival. Follicle loss—via regulated cell death—occurs throughout follicle development and life, and can be accelerated following exposure to various environmental and lifestyle factors. It is thought that the elimination of damaged follicles is necessary to ensure that only the best quality oocytes are available for reproduction. Understanding the precise factors involved in triggering and executing follicle death is crucial to uncovering how follicle endowment is initially determined, as well as how follicle number is maintained throughout puberty, reproductive life, and ovarian ageing in women. Apoptosis is established as essential for ovarian homeostasis at all stages of development and life. However, involvement of other cell death pathways in the ovary is less established. This review aims to summarize the most recent literature on cell death regulators in the ovary, with a particular focus on non-apoptotic pathways and their functions throughout the discrete stages of ovarian development and reproductive life. Comprehensive literature searches were carried out using PubMed and Google Scholar for human, animal, and cellular studies published until August 2022 using the following search terms: oogenesis, follicle formation, follicle atresia, oocyte loss, oocyte apoptosis, regulated cell death in the ovary, non-apoptotic cell death in the ovary, premature ovarian insufficiency, primordial follicles, oocyte quality control, granulosa cell death, autophagy in the ovary, autophagy in oocytes, necroptosis in the ovary, necroptosis in oocytes, pyroptosis in the ovary, pyroptosis in oocytes, parthanatos in the ovary, and parthanatos in oocytes. Numerous regulated cell death pathways operate in mammalian cells, including apoptosis, autophagic cell death, necroptosis, and pyroptosis. However, our understanding of the distinct cell death mediators in each ovarian cell type and follicle class across the different stages of life remains the source of ongoing investigation. Here, we highlight recent evidence for the contribution of non-apoptotic pathways to ovarian development and function. In particular, we discuss the involvement of autophagy during follicle formation and the role of autophagic cell death, necroptosis, pyroptosis, and parthanatos during follicle atresia, particularly in response to physiological stressors (e.g. oxidative stress). Improved knowledge of the roles of each regulated cell death pathway in the ovary is vital for understanding ovarian development, as well as maintenance of ovarian function throughout the lifespan. This information is pertinent not only to our understanding of endocrine health, reproductive health, and fertility in women but also to enable identification of novel fertility preservation targets.
No related organisations have been discovered for Karla Hutt.
Start Date: 2020
End Date: 12-2023
Amount: $853,284.00
Funder: Australian Research Council
View Funded ActivityStart Date: 2020
End Date: 06-2024
Amount: $588,511.00
Funder: Australian Research Council
View Funded Activity