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.

Effects of bisphenol A analogues on reproductive functions in mice.

This study was performed to examine whether bisphenol (BP) A analogues, BPE and BPS, negatively impacts reproductive functions using mice as a model. CD-1 mice were exposed to control treatment (corn oil), BPA, BPE and BPS (50μg/kg or 10mg/kg) from birth to postnatal day (PND) 60 by s.c.

Niclosamide As a Potential Nonsteroidal Therapy for Endometriosis That Preserves Reproductive Function in an Experimental Mouse Model.

Endometriosis causes severe chronic pelvic pain and infertility. Because the standard medication and surgical treatments of endometriosis show high recurrence of symptoms, it is necessary to improve current treatment options. In the initial study, we examined whether niclosamide can be a useful drug for endometriosis in a preclinical setting.

WNT7A Regulation by miR-15b in Ovarian Cancer.

WNT signaling is well known to play an important role in the regulation of development, cell proliferation and cell differentiation in a wide variety of normal and cancerous tissues. Despite the wealth of knowledge concerning when and where various WNT genes are expressed and downstream events under their control, there is surprisingly little published evidence of how they are regulated. We have recently reported that aberrant WNT7A is observed in serous ovarian carcinomas, and WNT7A is the sole ligand accelerating ovarian tumor progression through CTNNB1 (β-catenin)/TCF signaling in the absence of CTNNB1 mutations.

Rhox8 Ablation in the Sertoli Cells Using a Tissue-Specific RNAi Approach Results in Impaired Male Fertility in Mice.

The reproductive homeobox X-linked, Rhox, genes encode transcription factors that are selectively expressed in reproductive tissues. While there are 33 Rhox genes in mice, only Rhox and Rhox8 are expressed in Sertoli cells, suggesting that they may regulate the expression of somatic-cell gene products crucial for germ cell development. We previously characterized Rhox5-null mice, which are subfertile, exhibiting excessive germ cell apoptosis and compromised sperm motility.

The RHOX homeodomain proteins regulate the expression of insulin and other metabolic regulators in the testis.

Defects in cellular metabolism have been widely implicated in causing male infertility, but there has been little progress in understanding the underlying mechanism. Here we report that several key metabolism genes are regulated in the testis by Rhox5, the founding member of a large X-linked homeobox gene cluster. Among these Rhox5-regulated genes are insulin 2 (Ins2), resistin (Retn), and adiponectin (Adipoq), all of which encode secreted proteins that have profound and wide-ranging effects on cellular metabolism.