Decidual cell FKBP51-progesterone receptor binding mediates maternal stress-induced preterm birth.

Depression and posttraumatic stress disorder increase the risk of idiopathic preterm birth (iPTB); however, the exact molecular mechanism is unknown. Depression and stress-related disorders are linked to increased FK506-binding protein 51 (FKBP51) expression levels in the brain and/or FKBP5 gene polymorphisms. Fkbp5-deficient (Fkbp5-/-) mice resist stress-induced depressive and anxiety-like behaviors. FKBP51 binding to progesterone (P4) receptors (PRs) inhibits PR function. Moreover, reduced PR activity and/or expression stimulates human labor. We report enhanced in situ FKBP51 expression and increased nuclear FKBP51-PR binding in decidual cells of women with iPTB versus gestational age-matched controls. In Fkbp5+/+ mice, maternal restraint stress did not accelerate systemic P4 withdrawal but increased Fkbp5, decreased PR, and elevated AKR1C18 expression in uteri at E17.25 followed by reduced P4 levels and increased oxytocin receptor (Oxtr) expression at 18.25 in uteri resulting in PTB. These changes correlate with inhibition of uterine PR function by maternal stress-induced FKBP51. In contrast, Fkbp5-/- mice exhibit prolonged gestation and are completely resistant to maternal stress-induced PTB and labor-inducing uterine changes detected in stressed Fkbp5+/+ mice. Collectively, these results uncover a functional P4 withdrawal mechanism mediated by maternal stress-induced enhanced uterine FKBP51 expression and FKPB51-PR binding, resulting in iPTB.

Bortezomib-Induced Ovarian Toxicity in Mice.

Cancer survivors may experience long-term adverse effects of cancer treatments such as premature ovarian failure and infertility. We aimed to investigate the potential effects and toxicity of bortezomib (BTZ) as an effective anticancer drug on ovaries, raise awareness to the negative consequences of the treatment, and help increase the quality of life after treatment. Mice were distributed into bortezomib (BTZ1, BTZ2) and saline-injected control groups (C1, C2) at a dose of 1 mg/kg twice per week for 6 weeks. We sacrificed C1, BTZ1 groups at day 1 and C2, BTZ2 groups at 4 weeks after the last injection. Ovary samples were examined using histopathological and immunohistochemical methods. Ovarian follicle impairment was detected on BTZ-treated mice and was associated with a statistically significant decreased population of primordial and antral follicles compared with control groups. In experimental groups, Caspase-3 and Ki67 expressions were increased, whereas estrogen receptor alpha (ERα) and progesterone receptor (PR) expressions were decreased in various developmental stages of follicles. BTZ specifically targets granulosa cells by inducing granulosa cell apoptosis and may have long-term effects on follicles. Bortezomib treatment may adversely affect ovarian function by accelerating ovarian reserve depletion and changing ERα and PR hormone levels that can cause fertility problems in the long term.

Zika Virus-Infected Decidual Cells Elicit a Gestational Age-Dependent Innate Immune Response and Exaggerate Trophoblast Zika Permissiveness: Implication for Vertical Transmission.

Vertical transmission of the Zika virus (ZIKV) causes severe fetal defects, but the exact pathogenic mechanism is unclear. We identified up to a 10,480-fold higher expression of viral attachment factors AXL, GAS6, and PROS1 and a 3880-fold increase in ZIKV infectiousness/propagation in human term decidual stromal cells versus trophoblasts. Moreover, levels of viral attachment factors and ZIKV are significantly increased, whereas expression of innate immune response genes are significantly decreased, in human first trimester versus term decidual cells. ZIKV-infected decidual cell supernatants increased cytotrophoblasts infection up to 252-fold compared with directly infected cytotrophoblasts. Tizoxanide treatment efficiently inhibited Zika infection in both maternal and fetal cells. We conclude that ZIKV permissiveness, as well as innate immune responsiveness of human decidual cells, are gestational age dependent, and decidual cells augment ZIKV infection of primary human cytotrophoblast cultures, which are otherwise ZIKV resistant. Human decidual cells may act as reservoirs for trimester-dependent placental transmission of ZIKV, accounting for the higher Zika infection susceptibility and more severe fetal sequelae observed in early versus late pregnancy. Moreover, tizoxanide is a promising agent in preventing perinatal Zika transmission as well as other RNA viruses such as coronavirus.

Effects of synthetic (JWH-018) cannabinoids treatment on spermatogenesis and sperm function.

JWH-018 is a synthetic cannabinoid which has been increasingly used by adolescents and adults, and is known to cause severe multi-organ failure. However, little is known about the complications and toxicological effects of JWH-018 on reproduction system. Therefore, the aim of the present study is to investigate the effects of JWH-018 on testis and spermatogenesis. Thirty CD-1 male rats were distributed into six groups, control group (C1 and C2), ethanol group (E1 and E2), and JWH-018 group (JWH1 and JWH2), which were administered 0.9% NaCl, %100 ethanol, and JWH-018 (0.3 mg/kg) respectively for 9 d. We euthanized C1, E1, and JWH1 group mice at day 2 and C2, E2, and JWH2 group mice at 45 d after the last injection to evaluate the acute testis damage and potential recovery of spermatogenesis. The histopathology of seminiferous epithelium was evaluated and organ weight, sperm concentration and motility, membrane integrity, and serum testosterone levels were statistically analyzed. In JWH1, seminiferous tubule degeneration, partial germ cell depletion disorganized seminiferous epitheliums were seen. We also observed significantly decreased sperm concentration, sperm motility, intact membrane, and testosterone levels in JWH1 group compared to other groups. Forty-five days after the JWH-018 treatment, sperm concentration, motility, and testosterone level were increased, suggesting that testis and spermatogenesis can recover. We concluded that the use of JWH-018 may adversely affect male reproductive potential and testis histopathology.

Effects of bortezomib on mouse preimplantation embryo development in vitro.

BACKGROUND: Bortezomib, a selective inhibitor of 26S proteasome, is commonly used as a chemotherapeutic agent against different types of human cancer cells. While cancer during pregnancy is a rare condition, the trends in becoming pregnant at an advanced age increase the risk of cancer associated with pregnancy. Cancers need to be treated carefully without harming the fetus during pregnancy for the patients who desire to continue their pregnancy. The aim of this study is to demonstrate the potential side effects of bortezomib as this drug has so far not been investigated during preimplantation embryo development. MATERIALS AND METHODS: Two cell stage embryos were flushed from mated female CD1 mice and were cultured. Two-cell, eight-cell, and morula stage embryos were exposed to different concentrations of bortezomib in vitro. Morphologic alterations of the embryos were evaluated and the data were statistically analyzed. RESULTS: Our study showed that bortezomib exposure caused a statistically significant decrease in embryo survival and developmental competence and potential rate. We detected those early stages of embryos are more susceptible to bortezomib exposure than later stages. CONCLUSION: We indicated that bortezomib adversely affects preimplantation embryo development in a dose, time, and developmental stage dependent manner. Moreover, bortezomib treatment inhibits preimplantation embryo development and induces cytoplasmic fragmentation and cell-cycle arrest on embryos.

The Abelson tyrosine kinase (c-Abl) localization in preimplantation mouse development.

The Abelson family member of non-receptor tyrosine kinase, c-Abl, has an important role in regulation of cellular processes like cell polarity, invasion, proliferation, survival and cell motility. In the present study, we investigated the localization of c-Abl protein during preimplantation mouse embryo development in vitro using immunofluorescence confocal microscopy. We have shown that c-Abl protein is expressed throughout all stages of preimplantation development. We found that c-Abl is asymmetrically localized in egg cortex, which suggests possible roles in positioning of the metaphase II spindle. We also observed strong c-Abl staining in external cells, especially enriched at the apical poles in morula stage and at the E3.5 stage blastocysts, cell membrane enrichment of c-Abl in trophectoderm (TE), the tissue responsible for implantation and placentation. The results indicate that c-Abl may play roles in preimplantation embryo development, especially in TE formation and differentiation.

Evaluation of potential hepatotoxicity induced by Bortezomib

Bortezomib, an inhibitor of 26S proteasome, is an anti-cancer therapeutic agent used in different cancer types. It leads to the arrest of the cancerous cell cycle by inhibiting angiogenesis and inducing apoptosis. Liver is the vital organ for detoxification and excretion of toxic products. The treatment with chemotherapy is a challenge, drugs are used to destroy cancer cells, but healthy cells can be affected during cancer treatment as well. The main objective of this study was to analyze the histopathological and biochemical effects of bortezomib on liver. Twenty-four female C57BL/6 mice were distributed into 4 groups, bortezomib injected treatment groups (Btz1, Btz2) and saline injected control groups (C1, C2). Bortezomib and saline were treated twice per week for 6 weeks and sacrificed at the end of one day (Btz1, C1) and 4 weeks (Btz2, C2) after the last injection. Liver samples were examined for histopathological analysis and the serum samples processed for biochemical analysis. Tissue samples were fixed, routinely processed, sectioned, and stained with Hematoxylin and Eosin (H&E). Periodic Acid-Schiff (PAS), Sudan Black staining and Masson's trichrome histochemical staining methods were performed to characterize the lesions. Histopathological analysis of the Btz1 and Btz2 groups revealed acute hepatic morphological changes such as hepatocellular swelling (cloudy swelling), necro-inflammatory reaction, and increased mononuclear polyploidy. Based on the negative staining with PAS and Sudan Black staining, hepatocellular swelling was diagnosed as hydropic degeneration. Necro-inflammatory reaction observed in the form of acute hepatitis was composed of mainly mononuclear cell infiltration accompanied by multifocal necrotic foci. Kupffer cell proliferation was observed in parallel with degenerative and necrotic changes. An Increase in hepatocellular mononuclear polyploidy visualized as hepatocytes with a single enlarged nucleus was detected in all liver sections of Btz1 and Btz2 groups. Individual cases of cholestasis (n = 1) and mild hepatic fibrosis (n = 1) were also reported. Significant elevated levels of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were detected in bortezomib treated groups. Few clinical cases reported liver injury related to bortezomib used for cancer treatment. However, the liver was not considered as a target for bortezomib treatment. Our data suggesting that bortezomib caused liver damage and induces elevations in serum levels. The reported hepatic lesions including hepatocellular swelling, acute hepatitis and mononuclear polyploidy were mainly mild and moderate in severity. The increase of polyploidy in liver tissue of mice treated with bortezomib in this study was explained as a reaction of the liver facing the drug-induced hepatic damage. The mechanism leading to the hepatotoxicity of bortezomib treatment is not known but the production of a toxic metabolite through its metabolism in the liver can be suggested. Moreover, no recovery was also observed in histopathological and biochemical analyses suggesting that the bortezomib effect is non-reversible four weeks after the drug was withdrawn. Patients should be informed about the possibility of acute drug-induced hepatitis and hepatotoxicity of this chemotherapeutic agent after the treatment.(AU)