Hematopoietic-Prostaglandin D2 synthase through PGD2 production is involved in the adult ovarian physiology

<p>Abstract</p> <p>Background</p> <p>The prostaglandin D2 (PGD2) pathway is involved in numerous biological processes and while it has been identified as a partner of the embryonic sex determining male cascade, the roles it plays in ovarian function remain largely unknown. PGD2 is secreted by two prostaglandin D synthases (Pgds); the male-specific lipocalin (L)-Pgds and the hematopoietic (H)-Pgds.</p> <p>Methods</p> <p>To study the expression of the Pgds in the adult ovary, <it>in situ </it>hybridization were performed. Then, to evaluate the role of H-Pgds produced PGD2 in the ovarian physiology, adult female mice were treated with HQL-79, a specific inhibitor of H-Pgds enzymatic activity. The effects on expression of the gonadotrophin receptors <it>FshR </it>and <it>LhR</it>, steroidogenic genes <it>Cyp11A1</it>, <it>StAR </it>and on circulating progesterone and estradiol, were observed.</p> <p>Results</p> <p>We report the localization of <it>H-Pgds </it>mRNA in the granulosa cells from the primary to pre-ovulatory follicles. We provide evidence of the role of H-Pgds-produced PGD2 signaling in the FSH signaling through increased <it>FshR </it>and <it>LhR </it>receptor expression. This leads to the activation of steroidogenic <it>Cyp11A1 </it>and <it>StAR </it>gene expression leading to progesterone secretion, independently on other prostanoid-synthetizing mechanisms. We also identify a role whereby H-Pgds-produced PGD2 is involved in the regulation of follicular growth through inhibition of granulosa cell proliferation in the growing follicles.</p> <p>Conclusions</p> <p>Together, these results show PGD2 signaling to interfere with FSH action within granulosa cells, thus identifying an important and unappreciated role for PGD2 signaling in modulating the balance of proliferation, differentiation and steroidogenic activity of granulosa cells.</p

The new molecular biology of granulosa cell tumors of the ovary

Granulosa cell tumors (GCTs) of the ovary belong to the group of ovarian sex-cord stromal tumors and represent 5 to 10% of ovarian malignancies. GCTs exhibit several morphological, biochemical and hormonal features of normal proliferating pre-ovulatory granulosa cells, such as estrogen biosynthesis. Prognostic factors of this condition are lacking, and alternative treatment options to preserve future fertility are needed. Several groups have shown that two genetic factors implicated in GCTs are of particular interest. The gsp oncogene is a constitutive activating mutation of the prognosis of the tumor. FOXL2 is a transcription factor gene involved in ovarian development and function, whose expression is reduced and which is mutated in the majority of GCTs. FOXL2 appears to play a major role in cell cycle regulation. These recent findings open new pathophysiological insights into GCT development as well as revisitation of granulosa cell and ovarian function

Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin (acetylsalicylic acid), diclofenac and ibuprofen (IBU), and analgesic drugs, such as acetaminophen (APAP, or paracetamol), are widely used to treat inflammation and pain. APAP and IBU are over-the-counter drugs and are among the most commonly taken drugs in the first trimester of pregnancy, even in combination. Furthermore, these drugs and their metabolites are released in the environment, and can be frequently detected in wastewater, surface water, and importantly in drinking water. Although their environmental concentrations are much lower than the therapeutics doses, this suggests an uncontrolled low-dose exposure of the general population, including pregnant women and young children, two particularly at risk populations. Epidemiological studies show that exposure to these molecules in the first and second trimester of gestation can favor genital malformations in new-born boys. To investigate the cellular, molecular and mechanistic effects of exposure to these molecules, ex vivo studies with human or rodent gonadal explants and in vivo experiments in rodents have been performed in the past years. This review recapitulates recent data obtained in rodent models after in utero or postnatal exposure to these drugs. The first part of this review discusses the mechanisms by which NSAIDs and analgesics may impair gonadal development and maturation, puberty development, sex hormone production, maturation and function of adult organs, and ultimately fertility in the exposed animals and their offspring. Like other endocrine disruptors, NSAIDs and APAP interfere with endocrine gland function and may have inter/transgenerational adverse effects. Particularly, they may target germ cells, resulting in reduced quality of male and female gametes, and decreased fertility of exposed individuals and their descendants. Then, this review discusses the effects of exposure to a single drug (APAP, aspirin, or IBU) or to combinations of drugs during early embryogenesis, and the consequences on postnatal gonadal development and adult reproductive health. Altogether, these data may increase medical and public awareness about these reproductive health concerns, particularly in women of childbearing age, pregnant women, and parents of young children

La prostaglandine D2

La prostaglandine D2 (PGD2) fait partie de la famille des prostaglandines, molécules ubiquitaires de signalisation, liant des récepteurs transmembranaires couplés aux protéines G et induisant différentes voies de transduction. Les prostaglandines PGE2 et PGF2α ont un rôle reconnu dans l’ovulation, la fécondation et l’implantation ; cependant, le (ou les) rôle(s) de la PGD2 dans les organes reproducteurs mâle ou femelle ne sont pas définis bien que la prostaglandine D synthase (PGDS), l’enzyme de synthèse de la PGD2, y soit détectée. Dans cet article, nous résumons les travaux récents mettant en évidence deux fonctions de la PGD2, dans la mise en place du testicule embryonnaire et dans l’inhibition de croissance des cellules ovariennes tumorales, via l’activation du facteur SOX9 de différenciation des cellules de Sertoli

Adenomyotic Lesions Are Induced in the Mouse Uterus after Exposure to NSAID and EE2 Mixtures at Environmental Doses

The aim of this study was to assess the long-term effect of exposure to environmentally relevant doses of non-steroidal anti-inflammatory drugs (NSAIDs; ibuprofen, and diclofenac) and 17β-ethinylestradiol (EE2) on the mouse uterus. NSAID-EE2 mixtures were administered in the drinking water from gestational day 8 until 8 weeks post-birth (i.e., during embryo development, lactation, puberty, and sexual maturity). The incidence of adenomyosis lesions (presence of endometrial glands in the inner myometrium) increased up to 60% in the uterus of 8-week-old exposed females (F1) and to 85% in F2 females (exposed father). Histological analysis revealed aberrant proliferation and apoptosis, vacuolization of epithelial cells, and increased incidence of abnormal glands in the luminal and glandular epithelium in F1 and F2 uteri. Moreover, myofibroblast proportion (alpha-smooth muscle actin (α-SMA) expression analysis) and collagen expression (Picrosirius red stain; a fibrosis hallmark) were increased in F1 and F2 endometrium. Connexin-43 was aberrantly distributed in the endometrial stroma and glands of F1 and F2 uteri. Conversely, uterine 17β-estradiol and progesterone levels were not affected in F1 and F2 females. These findings demonstrated that in mice, chronic exposure to NSAID and EE2 mixtures at environmental doses intergenerationally affects uterine physiology, particularly the endometrium. It may serve as a model to study the pathophysiology of human adenomyosis

Sex-specific expression of SOX9 during gonadogenesis in the amphibian Xenopus tropicalis.

International audienceTo investigate the role of SOX9 gene in amphibian gonadogenesis, we analyzed its expression during male and female gonadogenesis in Xenopus tropicalis. The results showed that in both sexes SOX9 mRNA and protein were first detectable after metamorphosis when the gonads were well differentiated and remained present until the adult stage. In the testis, SOX9 expression was restricted to the nucleus of Sertoli-like cells, similarly to what has been observed in other vertebrates suggesting a conserved role in vertebrate testicular differentiation. In the ovary, in sharp contrast with what has been observed in all vertebrates examined so far, the SOX9 protein was localized in the cytoplasm of previtellogenic oocytes before being translocated into the nucleus of vitellogenic oocytes suggesting an unexpected role during oogenesis. These results suggest that the SOX9 gene may not be a sex-determining gene in X. tropicalis and may play different functions in testicular and ovarian differentiation. Developmental Dynamics 237:2996-3005, 2008. (c) 2008 Wiley-Liss, Inc

Temporal and spatial SOX9 expression patterns in the course of gonad development of the caudate amphibian Pleurodeles waltl

International audienceThe SOX family of transcription factors is thought to regulate gene expression in a wide variety of developmental processes. Namely, SOX9 expression is conserved in vertebrate sex determination or differentiation. Nevertheless, information about caudate amphibians is lacking. In this study, we provide data on Pleurodeles waltl, a species that displays a ZZ/ZW genetic mode of sex determination and a temperature-dependent mechanism of female-to-male sex reversal. Phylogenetic analysis of SOX9 P. waltl ortholog reveals that the deduced protein segregates from the group of anuran and could be more closely related to amniote than to anamniote. However, SOX9 lacks the PQA-rich domain present in amniotes. In larvae, SOX9 is expressed in both sexes in gonad-mesonephros complexes as soon as stage 42, before gonad differentiation. At stage 54(60d) at which testis differentiation is already in progress, analyses of isolated gonads reveal a male-enriched expression of SOX9, which was quantified by real-time PCR. At the end of metamorphosis (stage 56), SOX9 shows a nuclear localization only in the testis. In adults, SOX9 is still expressed in testes and ovaries. In the ovary, SOX9 is found in oocytes from stage I to stage VI but it is never detected in the nucleus. Our results suggest that in P. waltl, like in non mammalian vertebrates, SOX9 could play a role during the late phase of gonad differentiation rather than in sex determination. Its role in germ cells of the adult ovary has still to be elucidated

Hematopoietic prostaglandin D synthase (H-Pgds) is expressed in the early embryonic gonad and participates to the initial nuclear translocation of the SOX9 protein

In mammals, the Prostaglandin D(2) (PGD(2) ) signaling pathway is involved in male gonadal development, regulating Sox9 gene expression and SOX9 protein subcellular localization through lipocalin prostaglandin D synthase (L-Pgds) activity. Nevertheless, because L-Pgds is downstream of Sox9, its expression cannot explain the initial nuclear translocation of the SOX9 protein. Here, we show that another source of PGD(2) , hematopoietic-Pgds (H-Pgds) enzyme is expressed in somatic and germ cells of the embryonic gonad of both sexes, as early as embryonic day (E) 10.5, before the onset of L-Pgds expression. Inhibition of H-Pgds activity by the specific HQL-79 inhibitor leads to impaired nuclear translocation of SOX9 protein in E11.5 Sertoli cells. Furthermore, analysis of H-Pgds(-/-) male embryonic gonads confirms abnormal subcellular localization of SOX9 protein at the E11.5 early stage of mouse testicular differentiation suggesting a role for H-Pgds-produced PGD(2) in the initial nuclear translocation of SOX9