Conditional ablation of Insr and Igf1r using Esr2-Cre leads to abnormal ovarian follicle development and infertility in mice.

Conditional ablation of Igf1r in early folliculogenesis has demonstrated the necessity of insulin signaling to progress to the antral stage, whereas ablation of both Insr and Igfr1 in the periovulatory window allows the formation of the antrum but reduces the efficiency of ovulation and subsequent luteinization. For this study, we examined the independent and shared actions in single and double knockouts (DKO) for Insr and Ifg1r using Esr2-Cre. As this recombinase is active during neonatal ovarian development and the initial wave of folliculogenesis, we hypothesized that abnormalities in ovary formation and establishment of the initial follicle pool would occur, which could alter female reproductive lifespan.

RHOX Homeobox Transcription Factor Regulation of in Rodent Granulosa Cells.

The family of homeobox transcription factors comprises established regulators of gonad function, but their downstream targets have been relatively elusive, particularly in the female reproductive tract. Here, we characterize as a downstream target of the two granulosa cell-specific factors, and , in the ovary. While INS2 is classically produced by islet cells in the pancreas, we found that gene expression is present in the mural granulosa cell layer of large antral follicles, and it was not significantly reduced in -null mice.

Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.

The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning.

Transgenerational effects of perinatal cannabis exposure on female reproductive parameters in mice.

The use of cannabis during pregnancy and nursing is a growing public health concern, and the multigenerational impacts of perinatal cannabis exposure remain largely unknown. To address this knowledge gap, we sought to examine the long-term consequences of perinatal cannabis use on reproductive function and how it might impact subsequent generations. Pregnant female mice were exposed to control vehicle or cannabis extract [25, 100, or 200 mg/ml Δ9-tetrahydrocannabinol (THC) in the cannabis extract] from gestational day 1 to postnatal day 21 (twice/day), encompassing the duration of pregnancy through weaning.

Multiple lesion inductions intensify central sensitization driven by neuroinflammation in a mouse model of endometriosis.

Introduction: Endometriosis is an inflammatory disease associated with chronic pelvic pain (CPP). Growing evidence indicates that endometriotic lesions are not the sole source of pain. Instead, central nervous system (CNS) dysfunction created by prolonged peripheral and central sensitization plays a role in developing endometriosis-associated CPP.

Environmentally-relevant doses of bisphenol A and S exposure in utero disrupt germ cell programming across generations resolved by single nucleus multi-omics.

Background: Exposure to endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to bridge transgenerational reproductive defects resulting from EDCs. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice.

The involvement of peritoneal GATA6 macrophages in the pathogenesis of endometriosis.

Endometriosis is a chronic inflammatory disease that causes debilitating pelvic pain in women. Macrophages are considered to be key players in promoting disease progression, as abundant macrophages are present in ectopic lesions and elevated in the peritoneum. In the present study, we examined the role of GATA6 peritoneal macrophages on endometriosis-associated hyperalgesia using mice with a specific myeloid deficiency of GATA6.

Normal Ovarian Function in Subfertile Mouse with Cre-Driven Ablation of and .

Insulin receptor signaling promotes cell differentiation, proliferation, and growth which are essential for oocyte maturation, embryo implantation, endometrial decidualization, and placentation. The dysregulation of insulin signaling in women with metabolic syndromes including diabetes exhibits poor pregnancy outcomes that are poorly understood. We utilized the Cre/LoxP system to target the tissue-specific conditional ablation of insulin receptor () and insulin-like growth factor-1 receptor () using an anti-Mullerian hormone receptor 2 () Cre-driver which is active in ovarian granulosa and uterine stromal cells.

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia.

Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD cause an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia.

High-fat diets promote peritoneal inflammation and augment endometriosis-associated abdominal hyperalgesia.

Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD alter an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia.

Niclosamide targets the dynamic progression of macrophages for the resolution of endometriosis in a mouse model.

Due to the vital roles of macrophages in the pathogenesis of endometriosis, targeting macrophages could be a promising therapeutic direction. Here, we investigated the efficacy of niclosamide for the resolution of a perturbed microenvironment caused by dysregulated macrophages in a mouse model of endometriosis. Single-cell transcriptomic analysis revealed the heterogeneity of macrophages including three intermediate subtypes with sharing characteristics of traditional "small" or "large" peritoneal macrophages (SPMs and LPMs) in the peritoneal cavity.

Progesterone Actions and Resistance in Gynecological Disorders.

Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women's lives.

Effects of Dietary Soy Protein Isolate Versus Isoflavones Alone on Poststroke Skilled Ladder Rung Walking and Cortical mRNA Expression Differ in Adult Male Rats.

Dietary soy protein isolate (SPI) and the isoflavones daidzein and genistein have been shown to provide neuroprotection from stroke. However, the mechanisms remain uncertain. We sought to determine whether the addition of isoflavones to a diet containing caseinate (CAS) as the protein source would induce behavioral neuroprotection similar to that seen previously in rats fed SPI.

Vapor Cannabis Exposure Generationally Affects Male Reproductive Functions in Mice.

This study was performed to examine whether vapor exposure to cannabis plant matter negatively impacts male reproductive functions and testis development in mice. Adult CD-1 male mice (F0) were exposed to air (control) or 200 mg of vaporized cannabis plant matter 3×/day over a 10-day period. Subsequently, F0 males were bred with drug-naïve CD-1 females to generate F1 males, and F1 offspring were used to generate F2 males.

Efficacy of niclosamide on the intra-abdominal inflammatory environment in endometriosis.

Endometriosis, a common gynecological disease, causes chronic pelvic pain and infertility in women of reproductive age. Due to the limited efficacy of current therapies, a critical need exists to develop new treatments for endometriosis. Inflammatory dysfunction, instigated by abnormal macrophage (MΦ) function, contributes to disease development and progression.

Niclosamide's potential direct targets in ovarian cancer†.

Recent evidence indicates that niclosamide is an anti-cancer compound that is able to inhibit several signaling pathways. Although niclosamide has previously been identified by high-throughput screening platforms as a potential effective compound against several cancer types, no direct binding interactions with distinct biological molecule(s) has been established. The present study identifies key signal transduction mechanisms altered by niclosamide in ovarian cancer.

Insulin signaling is an essential regulator of endometrial proliferation and implantation in mice.

Insulin signaling is critical for the development of preovulatory follicles and progression through the antral stage. Using a conditional knockout model that escapes this blockage, we recently described the role of insulin signaling in granulosa cells during the periovulatory window in mice lacking Insr and Igf1r driven by Pgr-Cre. These mice were infertile, exhibiting defects in ovulation, luteinization, steroidogenesis, and early embryo development.

Niclosamide suppresses macrophage-induced inflammation in endometriosis†.

Endometriosis is a common gynecological disease, which causes chronic pelvic pain and infertility in women of reproductive age. Due to limited efficacy of current treatment options, a critical need exists to develop new and effective treatments for endometriosis. Niclosamide is an efficacious and FDA-approved drug for the treatment of helminthosis in humans that has been used for decades.

Inactivation of TRP53, PTEN, RB1, and/or CDH1 in the ovarian surface epithelium induces ovarian cancer transformation and metastasis.

Ovarian cancer (OvCa) remains the most common cause of death from gynecological malignancies. Genetically engineered mouse models have been used to study initiation, origin, progression, and/or mechanisms of OvCa. Based on the clinical features of OvCa, we examined a quadruple combination of pathway perturbations including PTEN, TRP53, RB1, and/or CDH1.

Periovulatory insulin signaling is essential for ovulation, granulosa cell differentiation, and female fertility.

Recent studies have demonstrated an essential role for insulin signaling in folliculogenesis as conditional ablation of Igf1r in primary follicles elicits defective follicle-stimulating hormone responsiveness blocking development at the preantral stage. Thus the potential role of insulin action in the periovulatory window and in the corpus luteum is unknown. To examine this, we generated conditional Insr,Igf1r, and double receptor knockout mice driven by Pgr-Cre.

Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Male Reproductive Functions in Mice.

This study was performed to examine the transgenerational effects of bisphenol (BP) A analogs, BPE, and BPS on male reproductive functions using mice as a model. CD-1 mice (F0) were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5 or 50 µg/kg/day) from gestational day 7 (the presence of vaginal plug = 1) to birth.

Prenatal Exposure to Bisphenol A, E, and S Induces Transgenerational Effects on Female Reproductive Functions in Mice.

This study was performed to examine the transgenerational effects of bisphenol (BP) A analogs, BPE, and BPS on female reproductive functions using mice as a model. CD-1 mice (F0) were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5 or 50 µg/kg/day) from gestational day 7 (the presence of vaginal plug = 1) to birth.

Prenatal Exposure to Bisphenol A Analogues on Female Reproductive Functions in Mice.

This study was performed to examine whether prenatal exposure to bisphenol (BP) A analogues, BPE and BPS, negatively impacts female reproductive functions and follicular development using mice as a model. CD-1 mice were orally exposed to control treatment (corn oil), BPA, BPE, or BPS (0.5, 20, or 50 µg/kg/day) from gestational day 11 (the presence of vaginal plug = 1) to birth.

Endometriotic inflammatory microenvironment induced by macrophages can be targeted by niclosamide†.

Endometriosis causes severe chronic pelvic pain and infertility. We have recently reported that niclosamide treatment reduces growth and progression of endometriosis-like lesions and inflammatory signaling (NF${\rm \small K}$B and STAT3) in a mouse model. In the present study, we examined further inhibitory mechanisms by which niclosamide affects endometriotic lesions using an endometriotic epithelial cell line, 12Z, and macrophages differentiated from a monocytic THP-1 cell line.

Prenatal Exposure to Bisphenol A Analogues on Male Reproductive Functions in Mice.

This study was performed to examine whether prenatal exposure to bisphenol (BP) A analogues, BPE and BPS, negatively impacts male reproductive functions and testis development using mice as a model. CD-1 mice were orally exposed to control treatment (corn oil), BPA, BPE, and BPS (0.5, 20, or 50 µg/kg/day) from gestational day 11 (the presence of vaginal plug = 1) to birth.