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1.
Environ Health Perspect ; 128(3): 37001, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32186404

RESUMO

BACKGROUND: Embryo implantation relies on precise hormonal regulation, associated gene expression changes, and appropriate female reproductive tract tissue architecture. Female mice exposed neonatally to the phytoestrogen genistein (GEN) at doses similar to those in infants consuming soy-based infant formulas are infertile due in part to uterine implantation defects. OBJECTIVES: Our goal was to determine the mechanisms by which neonatal GEN exposure causes implantation defects. METHODS: Female mice were exposed to GEN on postnatal days (PND)1-5 and uterine tissues collected on PND5, PND22-26, and during pregnancy. Analysis of tissue weights, morphology, and gene expression was performed using standard histology, confocal imaging with three-dimensional analysis, real-time reverse transcription polymerase chain reaction (real-time RT-PCR), and microarrays. The response of ovariectomized adults to 17ß-estradiol (E2) and artificial decidualization were measured. Leukemia inhibitory factor (LIF) injections were given intraperitoneally and implantation sites visualized. Gene expression patterns were compared with curated data sets to identify upstream regulators. RESULTS: GEN-exposed mice exhibited reduced uterine weight gain in response to E2 treatment or artificial decidualization compared with controls; however, expression of select hormone responsive genes remained similar between the two groups. Uteri from pregnant GEN-exposed mice were posteriorized and had reduced glandular epithelium. Implantation failure was not rescued by LIF administration. Microarray analysis of GEN-exposed uteri during early pregnancy revealed significant overlap with several conditional uterine knockout mouse models, including Foxa2, Wnt4, and Sox17. These models exhibit reduced endometrial glands, features of posteriorization and implantation failure. Expression of Foxa2, Wnt4, and Sox17, as well as genes important for neonatal uterine differentiation (Wnt7a, Hoxa10, and Msx2), were severely disrupted on PND5 in GEN-exposed mice. DISCUSSION: Our findings suggest that neonatal GEN exposure in mice disrupts expression of genes important for uterine development, causing posteriorization and diminished gland function during pregnancy that contribute to implantation failure. These findings could have implications for women who consumed soy-based formulas as infants. https://doi.org/10.1289/EHP6336.


Assuntos
Implantação do Embrião/efeitos dos fármacos , Genisteína/efeitos adversos , Fitoestrógenos/efeitos adversos , Útero/efeitos dos fármacos , Animais , Feminino , Camundongos , Gravidez , Útero/crescimento & desenvolvimento , Útero/fisiopatologia
2.
J Med Case Rep ; 13(1): 379, 2019 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-31864420

RESUMO

INTRODUCTION: Oophoritis, a complication of mumps, is said to affect only 5% of all postpubertal women. In this report, we present a case of a 31-year-old Iranian woman with amenorrhea and infertility due to an infantile uterus and atrophic ovaries associated with contracting mumps at a young age. She later successfully carried a healthy baby to term. CASE PRESENTATION: The patient was diagnosed with oophoritis when she was 8 years of age. She had no menses before treatment. The patient underwent a low-dose contraceptive treatment from age 19 until she was 31 years of age. During this period, the size of her uterus was constantly monitored, which revealed constant yet slow uterine growth. At age 31, Drospil (containing 3 mg of drospirenone and 0.03 mg ethinyl estradiol) treatment was initiated and administered for 3 months, which led to substantial uterine growth and menses. After her uterus had reached a mature size, the patient was referred to an assisted reproductive technology clinic. There she received a donor oocyte that was fertilized with the sperm of her husband. She had a successful low-risk pregnancy after the second embryo transfer. CONCLUSION: Low-dose contraceptive treatment containing progesterone, followed by Drospil, which includes both estradiol and progesterone, had a synergistic effect that led to the growth of the patient's uterus.


Assuntos
Androstenos/uso terapêutico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Caxumba/complicações , Ooforite/virologia , Progesterona/uso terapêutico , Anormalidades Urogenitais/virologia , Útero/anormalidades , Útero/efeitos dos fármacos , Adulto , Feminino , Humanos , Irã (Geográfico) , Caxumba/fisiopatologia , Ooforite/etiologia , Gravidez , Resultado da Gravidez , Técnicas de Reprodução Assistida , Anormalidades Urogenitais/etiologia , Útero/crescimento & desenvolvimento , Útero/virologia
3.
Nat Commun ; 10(1): 5378, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31772170

RESUMO

Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5+ stem/progenitor cells to uterine disorders.


Assuntos
Receptores Acoplados a Proteínas-G/metabolismo , Células-Tronco , Útero/crescimento & desenvolvimento , Proteínas Wnt/metabolismo , Animais , Linhagem da Célula , Endométrio/crescimento & desenvolvimento , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Camundongos Transgênicos , Ductos Paramesonéfricos/citologia , Organoides , Gravidez , Receptores Acoplados a Proteínas-G/genética , Células-Tronco/citologia , Células-Tronco/fisiologia , Proteínas Wnt/genética
4.
Int J Mol Med ; 44(6): 2145-2160, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638262

RESUMO

Endometriosis is associated with changes in long non­coding RNA (lncRNA) and mRNA expression, but the exact changes during the implantation window are unknown. Therefore, this study aimed to explore the lncRNA and mRNA expression profiles in the uterus of rats with endometriosis during the implantation window. A total of 35 non­pregnant female rats were randomized to the endometriosis (n=13), adipose tissue control (n=8) and blank control (n=14) groups. On the 5th day of pregnancy, the rats were sacrificed to obtain uterine tissues. lncRNA and mRNA were analyzed using gene chips. A total of five differentially expressed lncRNA and four mRNA were validated by reverse transcription­quantitative (RT­q)PCR. Immunohistochemistry and western blotting were used to determine the expression of the ADAM metallopeptidase with thrombospondin type 1 motif 7 (Adamts7), tumor protein p53 (Tp53), distal­less homeobox 3 (Dlx3) and pyrimidinergic receptor P2Y6 (P2ry6) proteins. There were 115 upregulated lncRNAs, 51 downregulated lncRNAs, 97 upregulated mRNAs and 85 downregulated mRNAs in the endometriosis group. RT­qPCR confirmed the trends for five lncRNAs and four mRNAs (Adamts7, Tp53, Dlx3 and P2ry6). The relative protein expression levels of Adamts7, P2ry6, Dlx3 and TP53 were significantly different in the endometriosis group (P<0.05 vs. controls). Bioinformatics predicted the co­expression relationship of the selected five lncRNA and four mRNA. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes predicted that Adamts7, P2ry6, Dlx3 and TP53 were involved in endometriosis­related inflammation and reproductive pathways. In conclusion, the changes in the expression of lncRNAs, mRNAs and proteins (Adamts7, P2ry6, Dlx3 and TP53) may possibly affect endometrial receptivity in rats with endometriosis during the implantation window, probably resulting in implantation failure of the embryo.


Assuntos
Proteína ADAMTS7/genética , Endometriose/genética , Proteínas de Homeodomínio/genética , Receptores Purinérgicos P2/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Animais , Implantação do Embrião/genética , Endometriose/patologia , Endométrio/crescimento & desenvolvimento , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Gravidez , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Ratos , Útero/crescimento & desenvolvimento , Útero/patologia
5.
J Agric Food Chem ; 67(36): 10207-10213, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31426637

RESUMO

Forchlorfenuron (FCF) is a synthetic plant cytokine-like growth regulator that is massively used in agriculture to increase fruit size and weight. There is an insufficiency of published data on the safety profile of FCF, especially as it is involved in ovarian function. In our study, a chronic toxicity study on FCF was conducted and designed by feeding at dosage levels of 0, 0.6, and 60 mg/kg body weight in Sprague-Dawley rats for 180 days. During the 180 day FCF administration, no biologically relevant changes were observed in the body weight, clinical signs, food consumption, organ weight, hematology, and clinical biochemistry of the tested animals. However, macroscopic and microscopic evaluations revealed the presence of severe hydrometra in the uterus and pathological changes in the ovaries. In addition, it was found that FCF inhibited the proliferation of granulosa cells (GCs) and H295R cells, as well as downregulated the expression of CYP17A1 and CYP19A1 in estradiol and progesterone production, resulting in decreased steroidogenesis in GCs and H295R cells. Taken together, our findings suggest that FCF has potential adverse effects on the ovaries and on steroidogenesis.


Assuntos
Hormônios Esteroides Gonadais/metabolismo , Compostos de Fenilureia/toxicidade , Reguladores de Crescimento de Planta/toxicidade , Piridinas/toxicidade , Administração Oral , Animais , Aromatase/genética , Aromatase/metabolismo , Peso Corporal/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Células da Granulosa/citologia , Células da Granulosa/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ovário/metabolismo , Ovário/patologia , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Ratos , Ratos Sprague-Dawley , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Útero/metabolismo , Útero/patologia
6.
Reprod Toxicol ; 88: 91-128, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31386883

RESUMO

There is a growing demand for wild type mice and mouse models of disease that may be more representative of human conditions but there is little information on neonatal and juvenile mouse anatomy. This project produces sound and comprehensive histology background data on the developing neonatal mouse at different time points from Day 0 until Day 28. The work describes optimal methods for tissue harvesting, fixation and processing from the neonatal and juvenile mice which can be used in routine toxicology studies. A review of the available literature revealed inconsistencies in the developmental milestones reported in the mouse. Although it is true that the sequence of events during the development is virtually the same in mice and rats, important developmental milestones in the mouse often happen earlier than in the rat, and these species should not be used interchangeably.


Assuntos
Animais Recém-Nascidos/crescimento & desenvolvimento , Camundongos Endogâmicos C57BL/crescimento & desenvolvimento , Fatores Etários , Animais , Animais Recém-Nascidos/anatomia & histologia , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Feminino , Vesícula Biliar/anatomia & histologia , Vesícula Biliar/crescimento & desenvolvimento , Trato Gastrointestinal/anatomia & histologia , Trato Gastrointestinal/crescimento & desenvolvimento , Intestino Grosso/anatomia & histologia , Intestino Grosso/crescimento & desenvolvimento , Intestino Delgado/anatomia & histologia , Intestino Delgado/crescimento & desenvolvimento , Rim/anatomia & histologia , Rim/crescimento & desenvolvimento , Fígado/anatomia & histologia , Fígado/crescimento & desenvolvimento , Pulmão/anatomia & histologia , Pulmão/crescimento & desenvolvimento , Masculino , Camundongos , Camundongos Endogâmicos C57BL/anatomia & histologia , Ovário/anatomia & histologia , Ovário/crescimento & desenvolvimento , Ratos , Estômago/anatomia & histologia , Estômago/crescimento & desenvolvimento , Testículo/anatomia & histologia , Testículo/crescimento & desenvolvimento , Toxicologia/normas , Útero/anatomia & histologia , Útero/crescimento & desenvolvimento
7.
Cell Mol Life Sci ; 76(24): 4813-4828, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31352535

RESUMO

Embryo implantation is one of the pivotal steps during mammalian pregnancy, since the quality of embryo implantation determines the outcome of ongoing pregnancy and fetal development. A large number of factors, including transcription factors, signalling transduction components, and lipids, have been shown to be indispensable for embryo implantation. Increasing evidence also suggests the important roles of epigenetic factors in this critical event. This review focuses on recent findings about the involvement of epigenetic regulators during embryo implantation.


Assuntos
Implantação do Embrião/genética , Epigênese Genética/genética , Fatores de Transcrição/genética , Útero/metabolismo , Animais , Blastocisto/metabolismo , Embrião de Mamíferos , Desenvolvimento Embrionário/genética , Feminino , Humanos , Gravidez , Transdução de Sinais/genética , Útero/crescimento & desenvolvimento
8.
Nat Commun ; 10(1): 3164, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320652

RESUMO

The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.


Assuntos
Células Endoteliais/classificação , Células da Granulosa/classificação , Miócitos de Músculo Liso/classificação , Folículo Ovariano/crescimento & desenvolvimento , Células Tecais/classificação , Adulto , Sequência de Bases , Feminino , Humanos , Folículo Ovariano/anatomia & histologia , Folículo Ovariano/citologia , Ovulação/fisiologia , Análise de Sequência de RNA , Útero/anatomia & histologia , Útero/citologia , Útero/crescimento & desenvolvimento
9.
Environ Toxicol ; 34(10): 1105-1113, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240815

RESUMO

The aim of the present study was to evaluate the effects of maternal exposure to triclosan (TCS) during pregnancy and lactation on the uterine morphology of rat offspring. For this, 32 Wistar rat dams were distributed into four dose groups (eight mothers per group), and gavage daily, throughout pregnancy and lactation, as follows: Group I-control (GI): corn oil; Group II (GII): TCS diluted in corn oil at a dose of 75 mg/kg/d; Group III (GIII): TCS diluted in corn oil at a dose of 150 mg/kg/d; Group IV (GIV): TCS diluted in corn oil at a dose of 300 mg/kg/d. A female pup of each mother was selected, and at 90 days the pups were euthanized for weighing and collection of the uterus for histomorphometric analysis. The results showed that the mean litter weight was minor in all the groups treated with TCS, when compared with control. The levels thyroid hormones thyroxine (T4) and triiodothyronine (T3) in TCS mother rats were reduced; however the levels of thyroid stimulating hormone (TSH) were increases. The offspring of all groups exposed to TCS presented deregulation of the estrous cycle, compared with control. Analysis of the uterine histological structure demonstrated that all layers of the uterus were affected by the administration of TCS, and the morphometric analysis showed increased uterine layers thickness in the treated groups. We concluded that maternal exposure to TCS during pregnancy and lactation causes intrauterine development restriction, deregulation of the oestrous cycle, and alters uterine tissue in rat offspring.


Assuntos
Anti-Infecciosos Locais/efeitos adversos , Retardo do Crescimento Fetal/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Triclosan/efeitos adversos , Útero/crescimento & desenvolvimento , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Lactação/efeitos dos fármacos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Wistar , Hormônios Tireóideos/metabolismo , Útero/efeitos dos fármacos , Útero/fisiologia
10.
J Assist Reprod Genet ; 36(6): 1211-1223, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093867

RESUMO

PURPOSE: The main purpose of this investigation was to determine an efficient whole-organ decellularization protocol of a human-sized uterus and evaluate the in vivo properties of the bioscaffold. METHODS: Twenty-four ovine uteri were included in this investigation and were decellularized by three different protocols (n 6). We performed histopathological and immunohistochemical evaluations, 4,6-diamidino-2-phenylindole (DAPI) staining, DNA quantification, MTT assay, scanning electron microscopy, biomechanical studies, and CT angiography to characterize the scaffolds. The optimized protocol was determined, and patches were grafted into the uterine horns of eight female Wistar rats. The grafts were extracted after 10 days; the opposite horns were harvested to be evaluated as controls. RESULTS: Protocol III (perfusion with 0.25% and 0.5% SDS solution and preservation in 10% formalin) was determined as the optimized method with efficient removal of the cellular components while preserving the extracellular matrix. Also, the bioscaffolds demonstrated native-like biomechanical, structural, and vascular properties. Histological and immunohistochemical evaluations of the harvested grafts confirmed the biocompatibility and recellularization potential of bioscaffolds. Also, the grafts demonstrated higher positive reaction for CD31 and Ki67 markers compared with the control samples which indicated eminent angiogenesis properties and proliferative capacity of the implanted tissues. CONCLUSIONS: This investigation introduces an optimized protocol for whole-organ decellularization of the human-sized uterus with native-like characteristics and a prominent potential for regeneration and angiogenesis which could be employed in in vitro and in vivo studies. To the best of our knowledge, this is the first study to report biomechanical properties and angiographic evaluations of a large animal uterine scaffold.


Assuntos
Perfusão/métodos , Engenharia Tecidual , Anormalidades Urogenitais/diagnóstico por imagem , Útero/anormalidades , Útero/diagnóstico por imagem , Animais , Matriz Extracelular/metabolismo , Feminino , Humanos , Microscopia Eletrônica de Varredura , Modelos Animais , Ratos , Ovinos , Tecidos Suporte , Anormalidades Urogenitais/fisiopatologia , Útero/crescimento & desenvolvimento , Útero/fisiopatologia
11.
J Pediatr Adolesc Gynecol ; 32(5): 530-534, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31145987

RESUMO

STUDY OBJECTIVE: To evaluate the efficacy of long-term estrogen replacement therapy (ERT) in uterine development and bone mineral density (BMD) of Turner syndrome (TS) women with premature ovarian insufficiency (POI). DESIGN AND SETTING: Retrospective study. PARTICIPANTS AND INTERVENTIONS: Thirty-seven TS women grouped according to ovarian function status: TS women with POI (n = 32), aged 11-26 years, and those with intact ovarian function (IOF; n = 5), aged 13-17 years. TS women with POI underwent ERT. MAIN OUTCOME MEASURES: Changes in uterine length, anterior-posterior (AP) fundal diameter of the uterus, and BMD were assessed. Statistical methods included Mann-Whitney U test and paired t test. RESULTS: In TS women with POI, uterine length, AP fundal diameter, and BMD significantly increased after ERT (P < .001). TS women with POI were subdivided into classic (n = 11) and variant (n = 21) types, and there were no significant differences in uterine development and BMD according to types of chromosome. After receiving ERT, AP fundal diameter was significantly longer in classic TS women (P = .034) compared with those with variant type. CONCLUSION: Long-term ERT increased uterine length (before: 4.4 cm; after: 7.2 cm) and AP fundal diameter (before: 0.9 cm; after: 2.4 cm), and improved BMD in TS women with POI. After ERT, in TS women with POI, uterine length, BMD at lumbar 2-4 and femoral neck were similar to those of TS women with IOF. Therefore, TS women with POI can catch up to those with IOF by receiving ERT.


Assuntos
Terapia de Reposição de Estrogênios/métodos , Estrogênios/uso terapêutico , Insuficiência Ovariana Primária/tratamento farmacológico , Síndrome de Turner/tratamento farmacológico , Adolescente , Adulto , Densidade Óssea/efeitos dos fármacos , Estudos de Casos e Controles , Criança , Estrogênios/farmacologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Adulto Jovem
12.
Reprod Toxicol ; 86: 56-61, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940504

RESUMO

In female mice, the Müllerian duct develops into the oviduct, uterus and vagina. The fate of epithelia is determined by factors secreted from the mesenchyme. Retinoic acid (RA) and its receptors are present in the mesenchyme of cranial Müllerian duct. RA induces Müllerian duct to uterine epithelial differentiation whereas inhibition of RA receptors induces vaginal epithelial differentiation. Thus, RA signaling in the Müllerian duct is required to promote differentiation of the mesenchyme into the future uterus. Perinatal estrogen exposure induces various abnormalities in Müllerian duct-derived organs. These include a cranial shift of the border among oviduct, uterus and vagina as well as precancerous lesions suppressed by co-treatment with RA and estrogen. Since RA synthesis enzymes and receptors are expressed both in the epithelium and stroma after birth, RA signaling may act in the epithelia to maintain adult epithelial homeostasis and to prevent irreversible lesions induced by perinatal estrogen exposure.


Assuntos
Ductos Paramesonéfricos/crescimento & desenvolvimento , Tretinoína/fisiologia , Útero/crescimento & desenvolvimento , Animais , Estrogênios/metabolismo , Feminino , Humanos , Transdução de Sinais
13.
Mol Cell Endocrinol ; 491: 110435, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029737

RESUMO

Proper myometrial adaptation during gestation is crucial for embryo implantation, pregnancy maintenance and parturition. Previously, we reported that neonatal exposure to endosulfan alters uterine development and induces implantation failures. The present work investigates the effects of endosulfan exposure on myometrial differentiation at the pre-implantation period, and myometrial activation during labor. Newborn female rats were s.c. injected with corn oil (vehicle) or 600 µg/kg/day of endosulfan (Endo600) on postnatal days (PND) 1, 3, 5 and 7. On PND90, the rats were mated to evaluate: i) the myometrial differentiation on gestational day 5 (GD5, pre-implantation period), by assessment myometrial histomorphology, smooth muscle cells (SMCs) proliferation, and expression of proteins involved in myometrial adaptation for embryo implantation (steroid receptors, Wnt7a and Hoxa10); ii) the timing of parturition and myometrial activation during labor by determining the uterine expression of contraction-associated genes (oxytocin receptor, OTXR; prostaglandin F2α receptor, PTGFR and connexin-43, Cx-43). Endosulfan decreased the thickness of both myometrial layers, with a concomitant decrease in the collagen remodeling. Blood vessels relative area in the interstitial connective tissue between muscle layers was also decreased. Endo600 group showed lower myometrial proliferation in association with a downregulation of Wnt7a and Hoxa10. Although in all females labor occurred on GD23, the exposure to endosulfan altered the timing of parturition, by inducing advancement in the initiation of labor. This alteration was associated with an increased uterine expression of OTXR, PTGFR and Cx-43. In conclusion, neonatal exposure to endosulfan produced long-term effects affecting myometrial adaptation during early pregnancy and labor. These alterations could be associated with the aberrant effects of endosulfan on the implantation process and the timing of parturition.


Assuntos
Adaptação Fisiológica/efeitos dos fármacos , Endossulfano/administração & dosagem , Inseticidas/administração & dosagem , Trabalho de Parto/efeitos dos fármacos , Miométrio/efeitos dos fármacos , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Diferenciação Celular , Feminino , Trabalho de Parto/metabolismo , Miométrio/crescimento & desenvolvimento , Miométrio/metabolismo , Gravidez , Ratos , Ratos Wistar , Contração Uterina/metabolismo , Útero/crescimento & desenvolvimento , Útero/metabolismo
14.
J Anim Sci ; 97(4): 1874-1890, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30895321

RESUMO

Tall fescue [Lolium arundinaceum (Scheyreb.) Darbysh] is the primary cool season forage grass in the Southeastern United States. Most tall fescue contains an endophytic fungus (Epichloë coenophiala) that produces ergot alkaloids and upon ingestion induces fescue toxicosis. The objective of this study was to assess how exposure to endophyte-infected (E+; 1.77 mg hd-1 d-1 ergovaline and ergovalinine) or endophyte-free (E-; 0 mg hd-1 d-1 ergovaline and ergovalinine) tall fescue seed fed during 2 stages of gestation (MID, days 35-85/LATE, days 86-133) alters placental development. Thirty-six, fescue naïve Suffolk ewes were randomly assigned to 1 of 4 fescue treatments: E-/E-, E-/E+, E+/E-, or E+/E+. Ewes were individually fed the same amount of E+ or E- seed mixed into total mixed ration during MID and LATE gestation. Terminal surgeries were conducted on day 133 of gestation. Ewes fed E+ fescue seed had elevated (P < 0.001) ergot alkaloid excretion and reduced (P < 0.001) prolactin levels during the periods when fed E+ seed. Ewes switched on day 86 from E- to E+ seed had a 4% reduction (P = 0.005) in DMI during LATE gestation, which translated to a 2% reduction (P = 0.07) in DMI overall. Average daily gain was also reduced (P = 0.049) by 64% for E-/E+ ewes during LATE gestation and tended to be reduced (P = 0.06) by 33% overall. Ewes fed E+ seed during LATE gestation exhibited a 14% and 23% reduction in uterine (P = 0.03) and placentome (P = 0.004) weights, respectively. Caruncle weights were also reduced by 28% (P = 0.003) for E-/E+ ewes compared with E-/E- and E+/E-. Ewes fed E+ seed during both MID and LATE gestation exhibited a 32% reduction in cotyledon (P = 0.01) weights, whereas ewes fed E+ seed only during MID gestation (E+/E-) had improved (P = 0.01) cotyledon weights. The percentage of type A placentomes tended to be greater (P = 0.08) for E+/E+ ewes compared with other treatments. Other placentome types (B, C, or D) did not differ (P > 0.05). Total fetal weight per ewe was reduced (P = 0.01) for ewes fed E+ seed during LATE gestation compared with E-; however, feeding E+ seed during MID gestation did not alter (P = 0.70) total fetal weight per ewe. These results suggest that exposure to ergot alkaloids during LATE (days 86-133) gestation has the greatest impact on placental development by reducing uterine and placentome weights. This, in turn, reduced total fetal weight per ewe by 15% in ewes fed E+ seed during LATE gestation (E-/E+ and E+/E+).


Assuntos
Epichloe/química , Alcaloides de Claviceps/toxicidade , Festuca/química , Ovinos/fisiologia , Ração Animal , Animais , Endófitos , Epichloe/fisiologia , Ergotaminas/toxicidade , Feminino , Festuca/microbiologia , Placentação/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ovinos/crescimento & desenvolvimento , Sudeste dos Estados Unidos , Útero/crescimento & desenvolvimento , Útero/fisiologia
15.
J Reprod Dev ; 65(1): 7-17, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30333376

RESUMO

Soy-based formula contains high concentrations of the isoflavone genistein. Genistein possesses estrogenic and tyrosine kinase inhibitory activity and interferes with cellular proliferation and development. To date, the acute and chronic effects of genistein on ovarian and uterine development have not been fully elucidated. In this study, mice at postnatal day 1 were subcutaneously injected with 100 mg/kg genistein for 10 consecutive days, and then their ovaries and uteri were collected on days 10, 21, and 90. Histological evaluation was performed after hematoxylin and eosin staining. The proliferating activity was indicated by the proliferating indicator protein Ki67. Results showed that the subcutaneous injection of genistein to neonatal mice induced the formation of multi-oocyte follicles and delayed the primordial follicle assembly in the ovaries. Genistein significantly enlarged the cross-sectional area of the uterine cavity and wall and disrupted the regularity between the uterine stroma and myometrium. Genistein exposure inhibited proliferative activity because fewer Ki67-positive nuclei were detected in ovarian and uterine cell populations than in the control. Furthermore, most ovaries from adult mice given neonatal genistein were without corpora lutea, and there appeared to be cystic follicles and hypertrophy of the theca, and cortical and medullary layers. Considering the high concentration of isoflavone in soy-based infant formulas and livestock feed, we suggest that the use of isoflavone-rich diets in humans and livestock receive closer examination.


Assuntos
Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Genisteína/toxicidade , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Animais , Feminino , Genisteína/administração & dosagem , Genisteína/análise , Antígeno Ki-67/análise , Camundongos , Ovário/citologia , Alimentos de Soja/análise , Útero/citologia
16.
Hum Reprod ; 34(1): 137-147, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476149

RESUMO

STUDY QUESTION: Does the phenotype of women with normosmic congenital hypogonadotrophic hypogonadism (nCHH) and pituitary resistance to GnRH caused by biallelic mutations in the GnRH receptor (GNRHR) (nCHH/bi-GNRHR) differ from that of women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Women with nCHH/bi-GNRHR have variable pubertal development but nearly all have primary amenorrhea and an exaggerated LH response to GnRH stimulation, similar to that seen in women with PCOS. WHAT IS KNOWN ALREADY: Women with nCHH/bi-GNRHR are very rare and their phenotype at diagnosis is not always adequately documented. The results of gonadotrophin stimulation by acute GnRH challenge test and ovarian features have not been directly compared between these patients and women with PCOS. STUDY DESIGN, SIZE, DURATION: We describe the phenotypic spectrum at nCHH/bi-GNRHR diagnosis in a series of 12 women. Their reproductive characteristics and acute responses to GnRH were compared to those of 70 women with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients and controls (healthy female volunteers aged over 18 years) were enrolled in a single French referral centre. Evaluation included clinical and hormonal studies, pelvic ultrasonography and GnRH challenge test. We also functionally characterized two missense GNRHR mutations found in two new consanguineous families. MAIN RESULTS AND THE ROLE OF CHANCE: Breast development was highly variable at nCHH/bi-GNRHR diagnosis, but only one patient had undeveloped breasts. Primary amenorrhea was present in all but two cases. In untreated nCHH/bi-GNRHR patients, uterine height (UH) correlated (P = 0.01) with the circulating estradiol level and was shorter than in 23 nulliparous post-pubertal age-matched controls (P < 0.0001) and than in 15 teenagers with PCOS under 20-years-old (P < 0.0001) in which PCOS was revealed by primary amenorrhea or primary-secondary amenorrhea. Unexpectedly, the stimulated LH peak response in nCHH/bi-GNRHR patients was variable, and often normal or exaggerated. Interestingly, the LH peak response was similar to that seen in the PCOS patients, but the latter women had significantly larger mean ovarian volume (P < 0.001) and uterine length (P < 0.001) and higher mean estradiol (P < 0.001), anti-Müllerian hormone (AMH) (P = 0.02) and inhibin-B (P < 0.001) levels. In the two new consaguineous families, the affected nCHH/bi-GNRHR women carried the T269M or Y290F GNRHR missense mutation in the homozygous state. In vitro analysis of GnRHR showed complete or partial loss-of-function of the T269M and Y290F mutants compared to their wildtype counterpart. LIMITATIONS, REASONS FOR CAUTION: The number of nCHH/bi-GNRHR patients reported here is small. As this disorder is very rare, an international study would be necessary to recruit a larger cohort and consolidate the phenotypic spectrum observed here. WIDER IMPLICATIONS OF THE FINDINGS: In teenagers and young women with primary amenorrhea, significant breast and uterine development does not rule out CHH caused by biallelic GNRHR mutations. In rare patients with PCOS presenting with primary amenorrhea and a mild phenotype, the similar exaggerated pituitary LH responses to GnRH in PCOS and nCHH/bi-GNRHR patients could lead to diagnostic errors. This challenge test should therefore not be recommended. As indicated by consensus and guidelines, careful analysis of clinical presentation and measurements of testosterone circulating levels remain the basis of PCOS diagnosis. Also, analysis of ovarian volume, UH and of inhibin-B, AMH, estradiol and androgen circulating levels could help to distinguish between mild PCOS and nCHH/bi-GNRHR. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the French National Research Agency (ANR) grant ANR-09-GENO-017 KALGENOPATH, France; and by the Italian Ministry of Education, University and Research (MIUR) grant PRIN 2012227FLF_004, Italy. The authors declare no conflict of interest.


Assuntos
Amenorreia/fisiopatologia , Hipogonadismo/fisiopatologia , Fenótipo , Síndrome do Ovário Policístico/fisiopatologia , Receptores LHRH/genética , Adolescente , Adulto , Amenorreia/etiologia , Mama/crescimento & desenvolvimento , Diagnóstico Diferencial , Feminino , Humanos , Hipogonadismo/complicações , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Mutação , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/diagnóstico , Reprodução/fisiologia , Útero/crescimento & desenvolvimento , Adulto Jovem
17.
Annu Rev Anim Biosci ; 7: 125-147, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30183326

RESUMO

All mammalian uteri contain glands that synthesize or transport and secrete substances into the uterine lumen. Uterine gland development, or adenogenesis, is uniquely a postnatal event in sheep and pigs and involves differentiation of glandular epithelium from luminal epithelium, followed by invagination and coiling morphogenesis throughout the stroma. Intrinsic transcription factors and extrinsic factors from the ovary and pituitary as well as the mammary gland (lactocrine) regulate uterine adenogenesis. Recurrent pregnancy loss is observed in the ovine uterine gland knockout sheep, providing unequivocal evidence that glands and their products are essential for fertility. Uterine gland hyperplasia and hypertrophy during pregnancy are controlled by sequential actions of hormones from the ovary and/or pituitary as well as the placenta. Gland-derived histotroph is transported by placental areolae for fetal growth. Increased knowledge of uterine gland biology is expected to improve pregnancy outcomes, as well as the health and productivity of mothers and their offspring.


Assuntos
Fertilidade/fisiologia , Ovinos/fisiologia , Suínos/fisiologia , Animais , Animais Domésticos , Diferenciação Celular , Endométrio/crescimento & desenvolvimento , Endométrio/fisiologia , Epitélio/fisiologia , Feminino , Hormônios/metabolismo , Glândulas Mamárias Animais/metabolismo , Morfogênese/fisiologia , Ovário/fisiologia , Hipófise/metabolismo , Placenta/fisiologia , Gravidez , Ovinos/crescimento & desenvolvimento , Suínos/crescimento & desenvolvimento , Útero/crescimento & desenvolvimento , Útero/fisiologia
19.
Differentiation ; 103: 46-65, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30236463

RESUMO

Development of the human female reproductive tract is reviewed from the ambisexual stage to advanced development of the uterine tube, uterine corpus, uterine cervix and vagina at 22 weeks. Historically this topic has been under-represented in the literature, and for the most part is based upon hematoxylin and eosin stained sections. Recent immunohistochemical studies for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium and its known pelvic derivatives) shed light on an age-old debate on the derivation of vaginal epithelium supporting the idea that human vaginal epithelium derives solely from urogenital sinus epithelium. Aside for the vagina, most of the female reproductive tract is derived from the Müllerian ducts, which fuse in the midline to form the uterovaginal canal, the precursor of uterine corpus and uterine cervix an important player in vaginal development as well. Epithelial and mesenchymal differentiation markers are described during human female reproductive tract development (keratins, homeobox proteins (HOXA11 and ISL1), steroid receptors (estrogen receptor alpha and progesterone receptor), transcription factors and signaling molecules (TP63 and RUNX1), which are expressed in a temporally and spatially dynamic fashion. The utility of xenografts and epithelial-mesenchymal tissue recombination studies are reviewed.


Assuntos
Genitália Feminina/crescimento & desenvolvimento , Ductos Paramesonéfricos/crescimento & desenvolvimento , Útero/crescimento & desenvolvimento , Vagina/crescimento & desenvolvimento , Feminino , Genitália Feminina/metabolismo , Proteínas de Homeodomínio/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Receptores de Progesterona/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
20.
Elife ; 72018 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-30226466

RESUMO

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women's health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin.


Assuntos
Loci Gênicos , Predisposição Genética para Doença , Instabilidade Genômica , Leiomioma/genética , Neoplasias Uterinas/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Morfogênese , Medição de Risco , Útero/crescimento & desenvolvimento
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