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  1. Article ; Online: Clomiphene citrate administered in peri-conception phase causes fetal loss and developmental impairment in mice.

    Chin, Peck Y / Kieffer, Tom E C / Prins, Jelmer R / Russell, Darryl L / Davies, Michael J / Robertson, Sarah A

    Endocrinology

    2024  

    Abstract: Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this ... ...

    Abstract Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated in mice the consequences for fetal development and pregnancy outcome of peri-conception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 h after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in three independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30 h average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed post-weaning growth and development comparable to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can inhibit implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the peri-conception phase unless its use is well-supervised.
    Language English
    Publishing date 2024-04-12
    Publishing country United States
    Document type Journal Article
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqae047
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Regulatory T cells are paramount effectors in progesterone regulation of embryo implantation and fetal growth.

    Green, Ella S / Moldenhauer, Lachlan M / Groome, Holly M / Sharkey, David J / Chin, Peck Y / Care, Alison S / Robker, Rebecca L / McColl, Shaun R / Robertson, Sarah A

    JCI insight

    2023  Volume 8, Issue 11

    Abstract: Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal ... ...

    Abstract Progesterone (P4) is essential for embryo implantation, but the extent to which the pro-gestational effects of P4 depend on the maternal immune compartment is unknown. Here, we investigate whether regulatory T cells (Treg cells) act to mediate luteal phase P4 effects on uterine receptivity in mice. P4 antagonist RU486 administered to mice on days 0.5 and 2.5 postcoitum to model luteal phase P4 deficiency caused fewer CD4+Foxp3+ Treg cells and impaired Treg functional competence, along with dysfunctional uterine vascular remodeling and perturbed placental development in midgestation. These effects were linked with fetal loss and fetal growth restriction, accompanied by a Th1/CD8-skewed T cell profile. Adoptive transfer at implantation of Treg cells - but not conventional T cells - alleviated fetal loss and fetal growth restriction by mitigating adverse effects of reduced P4 signaling on uterine blood vessel remodeling and placental structure and by restoring maternal T cell imbalance. These findings demonstrate an essential role for Treg cells in mediating P4 effects at implantation and indicate that Treg cells are a sensitive and critical effector mechanism through which P4 drives uterine receptivity to support robust placental development and fetal growth.
    MeSH term(s) Humans ; Pregnancy ; Female ; Animals ; Mice ; Progesterone/pharmacology ; T-Lymphocytes, Regulatory ; Placenta ; Fetal Growth Retardation ; Embryo Implantation/physiology ; Fetal Development
    Chemical Substances Progesterone (4G7DS2Q64Y)
    Language English
    Publishing date 2023-06-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.162995
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Prednisolone in early pregnancy inhibits regulatory T cell generation and alters fetal and placental development in mice.

    Kieffer, Tom Ec / Chin, Peck Y / Green, Ella S / Moldenhauer, Lachlan M / Prins, Jelmer R / Robertson, Sarah A

    Molecular human reproduction

    2020  Volume 26, Issue 5, Page(s) 340–352

    Abstract: Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring ... ...

    Abstract Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring outcomes, are unclear. In this study, mice were administered prednisolone (1 mg/kg) or PBS daily in the pre-implantation phase, and effects on the adaptive immune response, the implantation rate, fetal development and postnatal outcomes were investigated. Prednisolone disrupted the expected expansion of CD4+ T cells in early pregnancy, inhibiting generation of both regulatory T cells (Treg cells) and effector T cells and suppressing IFNG required for T cell functional competence. Prednisolone caused an 8-20% increase in the embryo implantation rate and increased the number of viable pups per litter. In late gestation, fetal and placental weights were reduced in a litter size-dependent manner, and the canonical inverse relationship between litter size and fetal weight was lost. The duration of pregnancy was extended by ~ 0.5 day and birth weight was reduced by ~ 5% after prednisolone treatment. Viability of prednisolone-exposed offspring was comparable to controls, but body weight was altered in adulthood, particularly in male offspring. Thus, while prednisolone given in the pre-implantation phase in mice increases maternal receptivity to implantation and resource investment in fetal growth, there is a trade-off in long-term consequences for fetal development, birth weight and offspring health. These effects are associated with, and likely caused by, prednisolone suppression of the adaptive immune response at the outset of pregnancy.
    MeSH term(s) Animals ; Cell Differentiation/drug effects ; Female ; Fetal Development/drug effects ; Fetus/drug effects ; Fetus/immunology ; Gestational Age ; Lymphopoiesis/drug effects ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Placentation/drug effects ; Prednisolone/pharmacology ; Pregnancy ; Prenatal Exposure Delayed Effects/chemically induced ; Prenatal Exposure Delayed Effects/immunology ; Prenatal Exposure Delayed Effects/physiopathology ; T-Lymphocytes/drug effects ; T-Lymphocytes/physiology
    Chemical Substances Prednisolone (9PHQ9Y1OLM)
    Language English
    Publishing date 2020-03-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1324348-2
    ISSN 1460-2407 ; 1360-9947
    ISSN (online) 1460-2407
    ISSN 1360-9947
    DOI 10.1093/molehr/gaaa019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 4482: Show issues Location:
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  4. Article ; Online: High-fat Diet Alters Male Seminal Plasma Composition to Impair Female Immune Adaptation for Pregnancy in Mice.

    Schjenken, John E / Moldenhauer, Lachlan M / Sharkey, David J / Chan, Hon Y / Chin, Peck Y / Fullston, Tod / McPherson, Nicole O / Robertson, Sarah A

    Endocrinology

    2021  Volume 162, Issue 10

    Abstract: Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response ... ...

    Abstract Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high-fat diet (HFD) or control diet (CD) for 14 weeks. Although HFD consumption caused only minor changes to parameters of sperm quality, the volume of seminal vesicle fluid secretions was increased by 65%, and the concentrations and total content of immune-regulatory TGF-β isoforms were decreased by 75% to 80% and 43% to 55%, respectively. Mating with BALB/c females revealed differences in the strength and properties of the postmating immune response elicited. Transcriptional analysis showed >300 inflammatory genes were similarly regulated in the uterine endometrium by mating independently of paternal diet, and 13 were dysregulated by HFD-fed compared with CD-fed males. Seminal vesicle fluid factors reduced in HFD-fed males, including TGF-β1, IL-10, and TNF, were among the predicted upstream regulators of differentially regulated genes. Additionally, the T-cell response induced by mating with CD-fed males was blunted after mating with HFD-fed males, with 27% fewer CD4+ T cells, 26% fewer FOXP3+CD4+ regulatory T cells (Treg) cells, and 19% fewer CTLA4+ Treg cells, particularly within the NRP1+ thymic Treg cell population. These findings demonstrate that an obesogenic HFD alters the composition of seminal vesicle fluid and impairs seminal plasma capacity to elicit a favorable pro-tolerogenic immune response in females at conception.
    MeSH term(s) Adiposity ; Animals ; Body Composition ; Cytokines/metabolism ; Diet, High-Fat ; Female ; Lymphocyte Subsets ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Phenotype ; Plasma/metabolism ; Pregnancy ; Pregnancy, Animal ; Protein Isoforms ; Reproduction ; Semen/metabolism ; Semen/physiology ; Spermatozoa/physiology ; T-Lymphocytes/cytology ; T-Lymphocytes, Regulatory/immunology ; Transforming Growth Factor beta1/metabolism ; Uterus/pathology
    Chemical Substances Cytokines ; Protein Isoforms ; Tgfb1 protein, mouse ; Transforming Growth Factor beta1
    Language English
    Publishing date 2021-06-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/endocr/bqab123
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring.

    Bromfield, John J / Schjenken, John E / Chin, Peck Y / Care, Alison S / Jasper, Melinda J / Robertson, Sarah A

    Proceedings of the National Academy of Sciences of the United States of America

    2014  Volume 111, Issue 6, Page(s) 2200–2205

    Abstract: Paternal characteristics and exposures influence physiology and disease risks in progeny, but the mechanisms are mostly unknown. Seminal fluid, which affects female reproductive tract gene expression as well as sperm survival and integrity, provides one ... ...

    Abstract Paternal characteristics and exposures influence physiology and disease risks in progeny, but the mechanisms are mostly unknown. Seminal fluid, which affects female reproductive tract gene expression as well as sperm survival and integrity, provides one potential pathway. We evaluated in mice the consequences for offspring of ablating the plasma fraction of seminal fluid by surgical excision of the seminal vesicle gland. Conception was substantially impaired and, when pregnancy did occur, placental hypertrophy was evident in late gestation. After birth, the growth trajectory and metabolic parameters of progeny were altered, most profoundly in males, which exhibited obesity, distorted metabolic hormones, reduced glucose tolerance, and hypertension. Altered offspring phenotype was partly attributable to sperm damage and partly to an effect of seminal fluid deficiency on the female tract, because increased adiposity was also evident in adult male progeny when normal two-cell embryos were transferred to females mated with seminal vesicle-excised males. Moreover, embryos developed in female tracts not exposed to seminal plasma were abnormal from the early cleavage stages, but culture in vitro partly alleviated this. Absence of seminal plasma was accompanied by down-regulation of the embryotrophic factors Lif, Csf2, Il6, and Egf and up-regulation of the apoptosis-inducing factor Trail in the oviduct. These findings show that paternal seminal fluid composition affects the growth and health of male offspring, and reveal that its impact on the periconception environment involves not only sperm protection but also indirect effects on preimplantation embryos via oviduct expression of embryotrophic cytokines.
    MeSH term(s) Animals ; Blood Pressure ; Female ; Genitalia, Female/physiology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred CBA ; Phenotype ; Semen
    Language English
    Publishing date 2014-01-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1305609111
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1148: Show issues Location:
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  6. Article ; Online: Stress response genes are suppressed in mouse preimplantation embryos by granulocyte-macrophage colony-stimulating factor (GM-CSF).

    Chin, Peck Y / Macpherson, Anne M / Thompson, Jeremy G / Lane, Michelle / Robertson, Sarah A

    Human reproduction (Oxford, England)

    2009  Volume 24, Issue 12, Page(s) 2997–3009

    Abstract: Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to promote the development and survival of human and mouse preimplantation embryos; however, the mechanism of action of GM-CSF in embryos is not defined.: Methods: Mouse ... ...

    Abstract Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to promote the development and survival of human and mouse preimplantation embryos; however, the mechanism of action of GM-CSF in embryos is not defined.
    Methods: Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM-CSF (rmGM-CSF), and in vivo developed blastocysts were flushed from Csf2 null mutant and wild-type mice. The effect of GM-CSF on blastocyst expression of stress response and apoptosis genes was evaluated by microarray, qPCR and immunochemistry.
    Results: Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM-CSF in vitro. qPCR analysis confirmed that rmGM-CSF inhibited expression of heat shock protein (HSP) and apoptosis pathway genes Cbl, Hspa5, Hsp90aa1, Hsp90ab1 and Gas5 in in vitro blastocysts. Immunocytochemical analysis of HSP 1 (HSPA1A/1B; HSP70), BAX, BCL2 and TRP53 (p53) in in vitro blastocysts showed that HSPA1A/1B and BCL2 proteins were less abundant when embryos were cultured with rmGM-CSF. BAX and TRP53 were unchanged at the protein level, but Bax mRNA expression was reduced after GM-CSF treatment. In in vivo developed blastocysts, Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes.
    Conclusions: We conclude that GM-CSF inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival, and the protective effects of GM-CSF are particularly evident in in vitro culture media, whereas in vivo other cytokines can partly compensate for absence of GM-CSF.
    MeSH term(s) Animals ; Apoptosis/genetics ; Blastocyst/metabolism ; Blastocyst/pathology ; Embryo Transfer/methods ; Embryonic Development ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Granulocyte-Macrophage Colony-Stimulating Factor/deficiency ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Granulocyte-Macrophage Colony-Stimulating Factor/physiology ; In Vitro Techniques ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microscopy, Fluorescence ; Oligonucleotide Array Sequence Analysis ; Pregnancy ; RNA, Messenger/metabolism ; Recombinant Proteins/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Stress, Physiological/genetics
    Chemical Substances RNA, Messenger ; Recombinant Proteins ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
    Language English
    Publishing date 2009-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 632776-x
    ISSN 1460-2350 ; 0268-1161 ; 1477-741X
    ISSN (online) 1460-2350
    ISSN 0268-1161 ; 1477-741X
    DOI 10.1093/humrep/dep307
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 2892: Show issues Location:
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  7. Article ; Online: Hormonal regulation of the cytokine microenvironment in the mammary gland.

    Dasari, Pallave / Sharkey, David J / Noordin, Effarina / Glynn, Danielle J / Hodson, Leigh J / Chin, Peck Y / Evdokiou, Andreas / Robertson, Sarah A / Ingman, Wendy V

    Journal of reproductive immunology

    2014  Volume 106, Page(s) 58–66

    Abstract: The mammary gland is a unique organ that undergoes hormone-driven developmental changes over the course of the ovarian cycle during adult life. Macrophages play a role in regulating cellular turnover in the mammary gland and may affect cancer ... ...

    Abstract The mammary gland is a unique organ that undergoes hormone-driven developmental changes over the course of the ovarian cycle during adult life. Macrophages play a role in regulating cellular turnover in the mammary gland and may affect cancer susceptibility. However, the immune microenvironment that regulates macrophage function has not been described. Hormonal regulation of the cytokine microenvironment across the ovarian cycle was explored using microbead multiplex assay for 15 cytokines in mammary glands from C57Bl/6 mice at different stages of the oestrous cycle, and in ovariectomised mice administered oestradiol and progesterone. The cytokines that were found to fluctuate over the course of the oestrous cycle were colony-stimulating factor (CSF)1, CSF2, interferon gamma (IFNG) and tumour necrosis factor alpha (TNFA), all of which were significantly elevated at oestrus compared with other phases. The concentration of serum progesterone during the oestrus phase negatively correlated with the abundance of cytokines CSF3, IL12p40, IFNG and leukaemia inhibitory factor (LIF). In ovariectomised mice, exogenous oestradiol administration increased mammary gland CSF1, CSF2, IFNG and LIF, compared with ovariectomised control mice. Progesterone administration together with oestradiol resulted in reduced CSF1, CSF3 and IFNG compared with oestradiol administration alone. This study suggests that the cytokine microenvironment in the mammary gland at the oestrus phase of the ovarian cycle is relatively pro-inflammatory compared with other stages of the cycle, and that the oestradiol-induced cytokine microenvironment is significantly attenuated by progesterone. A continuously fluctuating cytokine microenvironment in the mammary gland presumably regulates the phenotypes of resident leukocytes and may affect mammary gland cancer susceptibility.
    MeSH term(s) Animals ; Cellular Microenvironment/immunology ; Cytokines/metabolism ; Estradiol/pharmacology ; Female ; Granulocyte-Macrophage Colony-Stimulating Factor/metabolism ; Humans ; Inflammation/immunology ; Interferon-gamma/metabolism ; Interleukin-12 Subunit p40/metabolism ; Leukemia Inhibitory Factor/metabolism ; Macrophage Colony-Stimulating Factor/metabolism ; Macrophages/immunology ; Mammary Glands, Animal/metabolism ; Menstrual Cycle/metabolism ; Mice ; Mice, Inbred C57BL ; Ovariectomy ; Progesterone/blood ; Progesterone/pharmacology ; Tumor Necrosis Factor-alpha/metabolism
    Chemical Substances Cytokines ; Interleukin-12 Subunit p40 ; Leukemia Inhibitory Factor ; Lif protein, mouse ; Tumor Necrosis Factor-alpha ; Progesterone (4G7DS2Q64Y) ; Estradiol (4TI98Z838E) ; Macrophage Colony-Stimulating Factor (81627-83-0) ; Interferon-gamma (82115-62-6) ; Granulocyte-Macrophage Colony-Stimulating Factor (83869-56-1)
    Language English
    Publishing date 2014-12
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 424421-7
    ISSN 1872-7603 ; 0165-0378
    ISSN (online) 1872-7603
    ISSN 0165-0378
    DOI 10.1016/j.jri.2014.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 1483: Show issues Location:
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