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1.
Differentiation ; 103: 100-119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30287094

RESUMO

We have studied the ontogeny of the developing human male and female urogenital tracts from 9 weeks (indifferent stage) to 16 weeks (advanced sex differentiation) of gestation by immunohistochemistry on mid-sagittal sections. Sixteen human fetal pelvises were serial sectioned in the sagittal plane and stained with antibodies to epithelial, muscle, nerve, proliferation and hormone receptor markers. Key findings are: (1) The corpus cavernosum in males and females extends into the glans penis and clitoris, respectively, during the ambisexual stage (9 weeks) and thus appears to be an androgen-independent event. (2) The entire human male (and female) urethra is endodermal in origin based on the presence of FOXA1, KRT 7, uroplakin, and the absence of KRT10 staining. The endoderm of the urethra interfaces with ectodermal epidermis at the site of the urethral meatus. (3) The surface epithelium of the verumontanum is endodermal in origin (FOXA1-positive) with a possible contribution of Pax2-positive epithelial cells implying additional input from the Wolffian duct epithelium. (4) Prostatic ducts arise from the endodermal (FOXA1-positive) urogenital sinus epithelium near the verumontanum. (5) Immunohistochemical staining of mid-sagittal and para-sagittal sections revealed the external anal sphincter, levator ani, bulbospongiosus muscle and the anatomic relationships between these developing skeletal muscles and organs of the male and female reproductive tracts. Future studies of normal human developmental anatomy will lay the foundation for understanding congenital anomalies of the lower urogenital tract.


Assuntos
Desenvolvimento Fetal/genética , Imuno-Histoquímica , Uretra/crescimento & desenvolvimento , Sistema Urogenital/crescimento & desenvolvimento , Clitóris/crescimento & desenvolvimento , Clitóris/metabolismo , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Genitália Feminina/crescimento & desenvolvimento , Fator 3-alfa Nuclear de Hepatócito/genética , Humanos , Queratina-10/genética , Masculino , Fator de Transcrição PAX2/genética , Pênis/crescimento & desenvolvimento , Pênis/metabolismo , Uretra/metabolismo , Sistema Urogenital/metabolismo , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
2.
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
3.
Biol Reprod ; 99(4): 718-726, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767686

RESUMO

The mouse vagina consists of stratified squamous epithelium and stroma and is regulated by ovarian hormones. Vaginal epithelial cells do not stratify, but rather form a monolayer and show an inconsistent responsiveness to ovarian hormones when cultured on plastic dish or matrix. To address the discrepancy between in vivo and in vitro observations, three-dimensional (3D) co-culture models are developed with clonal vaginal epithelial and stromal cell lines; stromal cells are embedded in collagen gel and epithelial cells are seeded on the gel. In the 3D models, epithelial cells express Transformation related protein 63 (Trp63) and begin to stratify when they are co-cultured with two out of three stromal cell lines, but not with the other stromal cell line. Stroma may consist of various types of cells with distinct functions.


Assuntos
Vagina/anatomia & histologia , Vagina/crescimento & desenvolvimento , Animais , Membrana Basal/metabolismo , Linhagem Celular , Células Clonais/citologia , Células Clonais/metabolismo , Técnicas de Cocultura , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Epitélio/efeitos dos fármacos , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Estradiol/farmacologia , Feminino , Camundongos , Camundongos Knockout , Modelos Anatômicos , Fosfoproteínas/deficiência , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Estromais/citologia , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Transativadores/deficiência , Transativadores/genética , Transativadores/metabolismo , Vagina/metabolismo
4.
Biol Reprod ; 99(4): 727-734, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29762632

RESUMO

Stratification of the vaginal epithelium is regulated by stromal factors. To analyze the mechanisms of stratification in vitro, 3 dimensional (3D) co-culture models were established with clonal cell lines. In the models, stromal cells were embedded in collagen gel and epithelial cells were seeded on the gel. In the 3D co-culture, stromal SV-6c4a1b cells induced epithelial stratification but stromal MV-1e6g1a cells did not, suggesting that SV-6c4a1b cells secrete molecules to induce stratification. Microarray analyses of these stromal cell lines identified chordin-like 1 (Chrd1) and WNT1 inducible signaling pathway protein 2 (Wisp2) as candidate genes inducing stratification. Chrdl1 variant1 and variant2 mRNAs were expressed not only in stromal SV-6c4a1b and MV-1e6g1a cells but also in epithelial SV-4b6b cells. Wisp2-overexpressing MV-1e6g1a cells, secreting WISP2 as much as SV-6c4a1b cells, induced stratification of epithelial cells. In addition, Wisp2-knockdowned SV-6c4a1b cells were unable to induce epithelial stratification. These results suggest that WISP2 is one of the stromal factors inducing stratification of the mouse vaginal epithelium.


Assuntos
Vagina/anatomia & histologia , Vagina/crescimento & desenvolvimento , Animais , Células Clonais/citologia , Células Clonais/metabolismo , Técnicas de Cocultura , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Epitélio/anatomia & histologia , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Estradiol/farmacologia , Proteínas do Olho/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Variação Genética , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Proteínas do Tecido Nervoso/genética , Progesterona/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Células Estromais/citologia , Células Estromais/metabolismo , Vagina/metabolismo
5.
Differentiation ; 97: 54-72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29053991

RESUMO

Human female reproductive tract development rests mostly upon hematoxilyn and eosin stained sections despite recent advances on molecular mechanisms in mouse studies. We report application of immunohistochemical methods to explore the ontogeny of epithelial and mesenchymal differentiation markers (keratins, homobox proteins, steroid receptors), transcription factors and signaling molecules (TP63 and RUNX1) during human female reproductive tract development. Keratins 6, 7, 8, 10, 14 and 19 (KRT6, KRT7, KRT8, KRT10, KRT14, KRT19) were expressed in a temporally and spatially dynamic fashion. The undifferentiated Müllerian duct and uterovaginal canal, lined by simple columnar epithelia, expressed KRT7, KRT8 and KRT19. Glandular derivatives of the Müllerian duct (uterine tube, uterine corpus and endocervix) maintained expression of these keratins, while tissues that undergo stratified squamous differentiation (exocervix and vagina) expressed KRT6, KRT14 and KRT10 during development in an age-dependent fashion. TP63 and RUNX1 were expressed prior to KRT14, as these two transcription factors are known to be upstream from KRT14 in developing Müllerian epithelium. In the vagina, KRT10, a marker of terminal differentiation, appeared after endogenous estrogens transformed the epithelium to a thick glycogenated squamous epithelium. Uroplakin, a protein unique to urothelium, was expressed only in the bladder, urethra and vaginal introitus, but not in the female reproductive tract itself. Mesenchymal differentiation was examined through immunostaining for HOXA11 (expressed in uterine mesenchyme) and ISL1 (expressed in vaginal mesenchyme). A detailed ontogeny of estrogen receptor alpha (ESR1), progesterone receptor (PGR) and the androgen receptor (AR) provides the mechanistic underpinning for the teratogenicity of estrogens, progestins and androgens on female reproductive tract development. Immunohistochemical analysis of differentiation markers and signaling molecules advance our understanding of normal development of the human female reproductive tract. These observations demonstrate remarkable similarities in mouse and human female reproductive tract development, but also highlight some key differences.


Assuntos
Genitália Feminina/crescimento & desenvolvimento , Proteínas de Homeodomínio/genética , Queratinas/genética , Receptores de Esteroides/genética , Reprodução/genética , Animais , Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Receptor alfa de Estrogênio/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Genitália Feminina/metabolismo , Humanos , Camundongos , Ductos Paramesonéfricos/crescimento & desenvolvimento , Ductos Paramesonéfricos/metabolismo , Receptores Androgênicos/genética , Receptores de Progesterona , Útero/crescimento & desenvolvimento , Útero/metabolismo , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
6.
Differentiation ; 97: 9-22, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28918284

RESUMO

We present a detailed review of the embryonic and fetal development of the human female reproductive tract utilizing specimens from the 5th through the 22nd gestational week. Hematoxylin and eosin (H&E) as well as immunohistochemical stains were used to study the development of the human uterine tube, endometrium, myometrium, uterine cervix and vagina. Our study revisits and updates the classical reports of Koff (1933) and Bulmer (1957) and presents new data on development of human vaginal epithelium. Koff proposed that the upper 4/5ths of the vagina is derived from Müllerian epithelium and the lower 1/5th derived from urogenital sinus epithelium, while Bulmer proposed that vaginal epithelium derives solely from urogenital sinus epithelium. These conclusions were based entirely upon H&E stained sections. A central player in human vaginal epithelial development is the solid vaginal plate, which arises from the uterovaginal canal (fused Müllerian ducts) cranially and squamous epithelium of urogenital sinus caudally. Since Müllerian and urogenital sinus epithelium cannot be unequivocally identified in H&E stained sections, we used immunostaining for PAX2 (reactive with Müllerian epithelium) and FOXA1 (reactive with urogenital sinus epithelium). By this technique, the PAX2/FOXA1 boundary was located at the extreme caudal aspect of the vaginal plate at 12 weeks. During the ensuing weeks, the PAX2/FOXA1 boundary progressively extended cranially such that by 21 weeks the entire vaginal epithelium was FOXA1-reactive and PAX2-negative. This observation supports Bulmer's proposal that human vaginal epithelium derives solely from urogenital sinus epithelium. Clearly, the development of the human vagina is far more complex than previously envisioned and appears to be distinctly different in many respects from mouse vaginal development.


Assuntos
Fator 3-alfa Nuclear de Hepatócito/genética , Ductos Paramesonéfricos/crescimento & desenvolvimento , Fator de Transcrição PAX2/genética , Vagina/crescimento & desenvolvimento , Animais , Desenvolvimento Embrionário/genética , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Ductos Paramesonéfricos/metabolismo , Reprodução/genética , Vagina/metabolismo
7.
Reprod Domest Anim ; 52(5): 756-762, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28432701

RESUMO

In the last decades, selection for improved prolificacy has resulted in higher litter sizes and has thereby increased the proportion of low birthweight (LW) piglets. It is well documented that LW piglets have lower growth performance, muscle accretion and poor carcass quality. However, little is known about the relations of birthweight with subsequent reproductive performance in gilts. This study investigated the effects of birthweight on reproductive tract and ovarian follicle development in 150-day-old gilts. Twenty eight female pigs of different birthweight ranges (high-HW: 1.8-2.2 kg; low-LW: 0.8-1.2 kg) from higher parity commercial sows were reared until 150 days of age, and their body weights were recorded at weaning, end of nursery and end of the grower-finisher phase. The animals were killed and their reproductive tracts collected for biometrical and histomorphometrical analysis. LW gilts showed significantly lower body weights and growth rates during all phases of production compared to their HW counterparts (p < .01). Most biometrical measurements of the reproductive tract were similar between the experimental groups, except vaginal length and the gonadossomatic index (relative ovarian weight), which were affected by birthweight class (p < .05). LW females also showed fewer medium size (3-5 mm; p < .01) ovarian follicles, pre-antral follicles (p < .07) and more atretic follicles per ovarian cortex area (p < .05). Therefore, besides the effects on post-natal growth performance, birthweight affects vaginal length and the follicular dynamics process, which may impair the reproductive performance of replacement gilts.


Assuntos
Peso ao Nascer/fisiologia , Genitália Feminina/crescimento & desenvolvimento , Folículo Ovariano/crescimento & desenvolvimento , Sus scrofa/fisiologia , Animais , Peso Corporal/fisiologia , Feminino , Tamanho do Órgão/fisiologia , Folículo Ovariano/fisiologia , Vagina/crescimento & desenvolvimento
8.
Sci Rep ; 7: 44591, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28294161

RESUMO

Gel-forming mucins are macromolecules produced by goblet cells and responsible for the mucus gel formation. Changes in goblet cell density and in gel-forming mucin production have emerged as sensitive indicators for mucosal diseases. A Muc5b-GFP tagged reporter mouse was used to assess Muc5b production in mouse tissues by immunofluorescence microscopy and fluorescent activity using stereromicroscopy and probe-based confocal laser endomicroscopy. Muc5b production was followed longitudinally by recording the fluorescent activity in vagina and in embryonic lung explants under stimulation by interleukin 13. We show that the GFP is easily visualized in the mouse adult ear, nose, trachea, gallbladder, and cervix. Live Muc5b is also easily monitored in the nasal cavity, trachea and vagina where its production varies during the estrus cycle with a peak at the proestrus phase and in pregnant mice. Explant culture of reporter mouse embryonic whole lung shows that interleukin 13 stimulates Muc5b production. The transgenic Muc5b-GFP mouse is unique and suitable to study the mechanisms that regulate Muc5b production/secretion and mucous cell differentiation by live imaging and can be applied to test drug efficacy in mucosal disease models.


Assuntos
Imagem Molecular , Mucina-5B/genética , Muco/metabolismo , Animais , Feminino , Células Caliciformes/metabolismo , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Transgênicos , Mucina-5B/biossíntese , Mucina-5B/metabolismo , Cavidade Nasal/química , Cavidade Nasal/metabolismo , Técnicas de Cultura de Órgãos , Traqueia/metabolismo , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
9.
Toxicol Pathol ; 45(1): 206-215, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27753638

RESUMO

Evaluation of the female reproductive system in a general toxicity setting can be challenging for the toxicologic pathologist due to the cyclic nature of the estrous and menstrual cycles, timing of puberty and reproductive senescence, and species differences. Age in particular can have a significant impact on the histologic appearance of the female reproductive system and create challenges when trying to distinguish test article-related findings from normal developmental or senescent changes. This review describes the key physiologic and histologic features of immaturity, the transition through puberty, sexual maturity, and reproductive senescence in the female reproductive system, with an emphasis on practical applications for the toxicologic pathologist, and includes recommendations for distinguishing and documenting these developmental periods. Rats and cynomolgus monkeys are used as examples throughout with correlations to clinically observed end points to better aid the toxicologic pathologist in understanding how age may impact study interpretation.


Assuntos
Envelhecimento/patologia , Ovário/patologia , Maturidade Sexual/efeitos dos fármacos , Útero/patologia , Vagina/patologia , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Humanos , Macaca fascicularis , Ciclo Menstrual/efeitos dos fármacos , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ratos , Especificidade da Espécie , Testes de Toxicidade/métodos , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Vagina/efeitos dos fármacos , Vagina/crescimento & desenvolvimento
10.
Sci Rep ; 6: 26924, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27229740

RESUMO

Panax ginseng (GS) and Veratrum nigrum (VN) are representative of incompatible pairs in "eighteen antagonistic medicaments" that have been recorded in the Chinese medicinal literature for over 2,000 years. However, evidence linking interference effects with combination use is scare. Based on the estrogen-like effect of GS described in our previous studies, we undertake a characterization of the interaction on estrogenic activity of GS and VN using in vivo models of immature and ovariectomized (OVX) mice and in vitro studies with MCF-7 cells for further mechanism. VN decreased the estrogenic efficacy of GS on promoting the development of the uterus and vagina in immature mice, and reversing the atrophy of reproductive tissues in OVX mice. VN interfered with the estrogenic efficacy of GS by decreasing the increase of the serum estradiol and the up-regulation of ERα and ERß expressions by treatment with GS. And VN antagonized the estrogenic efficacy of GS on promoting the viability of MCF-7 cells and up-regulation of protein and gene expressions of ERs. In conclusion, this study provided evidence that GS and VN decreased effects on estrogenic activity, which might be related to regulation of estrogen secretion and ERs.


Assuntos
Estradiol/sangue , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Panax/química , Extratos Vegetais/farmacologia , Veratrum/química , Animais , Antagonismo de Drogas , Medicamentos de Ervas Chinesas , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Feminino , Hormônio Foliculoestimulante/sangue , Hormônio Foliculoestimulante/genética , Regulação da Expressão Gênica , Humanos , Hormônio Luteinizante/sangue , Hormônio Luteinizante/genética , Células MCF-7 , Medicina Tradicional Chinesa , Camundongos , Ovariectomia , Maturidade Sexual/fisiologia , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Útero/metabolismo , Vagina/efeitos dos fármacos , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
11.
J Toxicol Environ Health A ; 79(6): 266-73, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27074097

RESUMO

Fipronil, a phenylpyrazole insecticide, is used in agriculture, veterinary medicine, and public health. Because this insecticide is considered a potential endocrine disruptor, the aim of this study was to examine the influence of perinatal exposure to fipronil on neonatal female reproductive system development. Pregnant rats were exposed (via gavage) daily to fipronil (0.03, 0.3, or 3 mg/kg) from gestational day 15 to day 7 after birth, and effects on the reproductive functions assessed on postnatal day (PND) 22. No signs of maternal toxicity were observed during daily treatment with fipronil. Perinatal exposure to the highest dose of fipronil (3 mg/kg) delayed the age of vaginal opening (VO) and first estrus without markedly affecting the anogenital distance (AGD). Further, exposure to 0.3 mg/kg fipronil produced a significantly shorter estrus cycle and reduced number of cycles during the period of evaluation. However, the other reproductive parameters analyzed, including fertility, hormone levels, sexual behavior, and histology of ovaries and uterus, displayed no marked alterations. In this experimental model, fipronil interfered with development of neonatal female reproductive system as evidenced by delay in VO and estrus cycle alterations without apparent significant effects on fertility. Further studies are needed to identify the mechanisms of action associated with the observed female reproductive system changes.


Assuntos
Inseticidas/toxicidade , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Pirazóis/toxicidade , Desenvolvimento Sexual/efeitos dos fármacos , Animais , Estro/efeitos dos fármacos , Feminino , Fertilidade/efeitos dos fármacos , Hormônios Esteroides Gonadais/sangue , Lactação , Masculino , Ovário/anatomia & histologia , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Gravidez , Ratos , Ratos Wistar , Comportamento Sexual Animal/efeitos dos fármacos , Útero/anatomia & histologia , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Vagina/crescimento & desenvolvimento
12.
Gynecol Endocrinol ; 32(9): 752-755, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27019210

RESUMO

The neonatal and/or prepubertal androgen milieu affects sexual maturation and reproductive function in adulthood. However, the effects of chronic dehydroepiandrosterone (DHEA) treatment on reproductive functions have not been fully elucidated. Therefore, the reproductive phenotypes and parameters of rats that had been subjected to chronic DHEA treatment were evaluated in this study. The chronic DHEA-treated (from postnatal day 23-12 weeks of age) rats exhibited earlier vaginal opening, indicating that DHEA treatment promotes sexual maturation. In addition, the estrus phase lasted longer in the DHEA-treated rats, suggesting that their estrous cycles had been disrupted. As the DHEA-treated rats' serum luteinizing hormone levels and hypothalamic Kiss1 mRNA expression levels were decreased and their uterine weight was increased, DHEA and/or estrogen might directly affect reproductive phenotypes. While DHEA treatment caused changes in body weight and body composition in chronic testosterone-treated models in previous studies, no such changes were seen in the present study.


Assuntos
Desidroepiandrosterona/farmacologia , Ciclo Estral/efeitos dos fármacos , Hormônios Esteroides Gonadais/farmacologia , Kisspeptinas/efeitos dos fármacos , Hormônio Luteinizante/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Desidroepiandrosterona/administração & dosagem , Feminino , Hormônios Esteroides Gonadais/administração & dosagem , Hipotálamo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Vagina/crescimento & desenvolvimento
13.
Toxins (Basel) ; 7(11): 4668-83, 2015 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-26569305

RESUMO

Growing evidence has revealed the deleterious influence of environmental and food contaminants on puberty onset and development in both animals and children, provoking an increasing health concern. T-2 toxin, a naturally-produced Type A trichothecene mycotoxin which is frequently found in cereal grains and products intended for human and animal consumption, has been shown to impair the reproduction and development in animals. Nevertheless, whether this trichothecene mycotoxin can disturb the onset of puberty in females remains unclear. To clarify this point, infantile female rats were given a daily intragastric administration of vehicle or 187.5 µg/kg body weight of T-2 toxin for five consecutive days from postnatal day 15 to 19, and the effects on puberty onset were evaluated in the present study. The results revealed that the days of vaginal opening, first dioestrus, and first estrus in regular estrous cycle were delayed following prepubertal exposure to T-2 toxin. The relative weights of reproductive organs uterus, ovaries, and vagina, and the incidence of corpora lutea were all diminished in T-2 toxin-treated rats. Serum levels of gonadotropins luteinizing hormone, follicle-stimulating hormone, and estradiol were also reduced by T-2 toxin treatment. The mRNA expressions of hypothalamic gonadotropin-releasing hormone (GnRH) and pituitary GnRH receptor displayed significant reductions following exposure to T-2 toxin, which were consistent with the changes of serum gonadotropins, delayed reproductive organ development, and delayed vaginal opening. In conclusion, the present study reveals that prepubertal exposure to T-2 toxin delays the onset of puberty in immature female rats, probably by the mechanism of disturbance of hypothalamic-pituitary-gonadal (HPG) axis function. Considering the vulnerability of developmental children to food contaminants and the relative high level of dietary intake of T-2 toxin in children, we think the findings of the present study provide valuable information for the health risk assessment in children.


Assuntos
Maturidade Sexual/efeitos dos fármacos , Toxina T-2/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Corpo Lúteo/efeitos dos fármacos , Diestro/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Estro/efeitos dos fármacos , Feminino , Hormônio Liberador de Gonadotropina/sangue , Intubação Gastrointestinal , Tamanho do Órgão , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Ratos , Ratos Sprague-Dawley , Receptores LHRH/biossíntese , Receptores LHRH/efeitos dos fármacos , Toxina T-2/administração & dosagem , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Vagina/efeitos dos fármacos , Vagina/crescimento & desenvolvimento
14.
J Tradit Chin Med ; 35(4): 460-7, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26427118

RESUMO

OBJECTIVE: To evaluate the estrogenic efficacy of Renshen (Radix Ginseng) (GS) on reproductive target tissues in immature mice. METHODS: One hundred and ten female immature Kunming (KM) mice, 21-day-old, were randomly assigned to eleven groups, 10 for each; one served as control group treated with 0.154 mg/kg estradiol valerate (EV, n = 10), the rest were treated respectively with GS intragastrically at a daily dose of 0.5, 1.0, 1.5, 3.0, 6.0, 12.0, 18.0, 24.0 and 30.0 g/kg (n = 10 in per group) for 7 days. The estrous cycle, uterine weight, hormone levels in circulation and histomorphology changes of uterus and vagina were scrupulously examined. The estrogen receptor (ER) α and ERß expressions in the uterus and vagina were detected by immunohistochemistry and western blotting. RESULTS: Treatment with GS at the dose of 12.0, 18.0 and 24.0 g/kg resulted significant estrogenic activity in the mice, as indicated by advanced and prolonged estrous stage and increased uterine weight (all P < 0.05). GS treatment substantially promoted development of reproductive tisue by thickening the uterine endometrium and increasing vaginal epithelial layers. In addition, treatment with GS induced significant up-regulation of ERα and ERß expressions in reproductive tissues, and ERα up-regulation was stronger than that of ERß. GS could raise levels of circulating estrogen, simultaneously decrease levels of luteinizing hormone and follicle-stimulating hormone (all P < 0.001) compared with the control group. CONCLUSION: Our findings suggest that GS had estrogenic effect on reproductive tissues in immature mice by stimulating biosynthesis of estrogen in circulation and up-regulating ERs.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Estrogênios/metabolismo , Panax/química , Útero/efeitos dos fármacos , Vagina/efeitos dos fármacos , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Humanos , Ciclo Menstrual/efeitos dos fármacos , Camundongos , Reprodução/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Útero/fisiologia , Vagina/crescimento & desenvolvimento , Vagina/fisiologia
15.
Sex Dev ; 9(4): 216-28, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26406875

RESUMO

The mammalian prostate is a compact structure in humans but multi-lobed in mice. In humans and mice, FOXA1 and SOX9 play pivotal roles in prostate morphogenesis, but few other species have been examined. We examined FOXA1 and SOX9 in the marsupial tammar wallaby, Macropus eugenii, which has a segmented prostate more similar to human than to mouse. In males, prostatic budding in the urogenital epithelium (UGE) was initiated by day 24 postpartum (pp), but in the female the UGE remained smooth and had begun forming the marsupial vaginal structures. FOXA1 was upregulated in the male urogenital sinus (UGS) by day 51 pp, whilst in the female UGS FOXA1 remained basal. FOXA1 was localised in the UGE in both sexes between day 20 and 80 pp. SOX9 was upregulated in the male UGS at day 21-30 pp and remained high until day 51-60 pp. SOX9 protein was localised in the distal tips of prostatic buds which were highly proliferative. The persistent upregulation of the transcription factors SOX9 and FOXA1 after the initial peak and fall of androgen levels suggest that in the tammar, as in other mammals, these factors are required to sustain prostate differentiation, development and proliferation as androgen levels return to basal levels.


Assuntos
Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/genética , Macropodidae/metabolismo , Próstata/crescimento & desenvolvimento , Fatores de Transcrição SOX9/genética , Sistema Urogenital/crescimento & desenvolvimento , Envelhecimento , Animais , Feminino , Fator 3-alfa Nuclear de Hepatócito/análise , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Reação em Cadeia da Polimerase/veterinária , Antígeno Nuclear de Célula em Proliferação/análise , Próstata/metabolismo , Fatores de Transcrição SOX9/análise , Caracteres Sexuais , Sistema Urogenital/química , Sistema Urogenital/metabolismo , Vagina/crescimento & desenvolvimento
16.
Biol Reprod ; 93(2): 32, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26134866

RESUMO

Neonatal exposure to estrogens is known to cause delayed effects, a late-occurring adverse effect on adult female reproductive functions, such as early onset of age-matched abnormal estrous cycling. However, the critical period in which neonates are sensitive to delayed effects inducible by exogenous estrogen exposure has not been clearly identified. To clarify this window, we examined the intensity and timing of delayed effects using rats exposed to ethynylestradiol (EE) at various postnatal ages. After subcutaneous administration of a single dose of EE (20 µg/kg, which induces delayed effects) on Postnatal Day (PND) 0, 5, 10, or 14 in Wistar rats, hypothalamic and hormonal alterations in young adults and long-term estrous cycling status were investigated as indicators of delayed effects. In young adults, peak luteinizing hormone concentrations at the time of the luteinizing hormone surge showed a decreasing trend, and KiSS1 mRNA expression of the anterior hypothalamus and number of KiSS1-positive cells in the anteroventral periventricular nucleus were significantly decreased in the PND 0, 5, and 10 groups. The reduction in KiSS1 mRNA and KiSS1-postive cells was inversely correlated with age at time of exposure. These groups also exhibited early onset of abnormal estrous cycling, starting from 17 wk of age in the PND0 group and 19 wk of age in the PND5 and 10 groups. These indicators were not apparent in the PND14 group. Our results suggest that PND0-PND10 is the critical window of susceptibility for delayed effects, and PND14 is presumed to be the provisional endpoint of the window.


Assuntos
Etinilestradiol/toxicidade , Envelhecimento , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Etinilestradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo Anterior/metabolismo , Kisspeptinas/biossíntese , Kisspeptinas/genética , Hormônio Luteinizante/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Wistar , Diferenciação Sexual/efeitos dos fármacos , Vagina/efeitos dos fármacos , Vagina/crescimento & desenvolvimento , Doenças Vaginais/induzido quimicamente , Doenças Vaginais/patologia
17.
Clin Obstet Gynecol ; 58(3): 442-52, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26083130

RESUMO

The appearance of the female external genitalia is key for understanding and diagnosing many diseases that women of all ages encounter. Alas, the normal appearance of the vulva is an elusive concept, scarcely represented in textbooks, and the growing number of vulvar cosmetic surgery calls for a review of the normal appearance of the vulva and its diversity. In this paper I will review vulvar embryology, anatomy, the current literature discussing vulvar appearance, and describe meticulous vulvar examination, including the diagnostic tools.


Assuntos
Exame Ginecológico , Vagina/anatomia & histologia , Vulva/anatomia & histologia , Biópsia , Feminino , Humanos , Microscopia , Testes do Emplastro , Vagina/crescimento & desenvolvimento , Vagina/fisiologia , Esfregaço Vaginal , Vulva/crescimento & desenvolvimento , Vulva/fisiologia
18.
Can J Physiol Pharmacol ; 93(8): 603-14, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26061900

RESUMO

Bacterial toxins are widespread in the environment as well as in the digestive system of humans and animals. Toxin from Gram-negative bacteria (endotoxin or lipopolysaccharide; LPS) has a life-long programming effect on reproduction in rats, but the mediators have not been well-documented, so we investigated the effects of LPS on the timing of puberty in female rats. Because the levels of nitric oxide (NO) and interleukin 1ß (IL-1ß) increase following injection of LPS, we injected neonates (post-natal day (pnd) 7) with LPS, with or without NO or IL-1ß inhibitors. Half of the prepubescent (pnd 30) animals received an additional LPS injection. Vaginal opening, number of ovarian follicles, and serum anti-LPS antibodies were determined. A single LPS injection was sufficient to reduce the primordial follicle pool, but puberty was delayed when rats received 2 LPS injections (at pnd 7 and 30). NO or IL-1ß inhibitors improved both of these parameters, suggesting that the early detrimental effects of LPS on puberty and primordial follicle pool are mediated by NO and IL-1ß.


Assuntos
Caspase 1/metabolismo , Lipopolissacarídeos/toxicidade , Óxido Nítrico/metabolismo , Folículo Ovariano/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Vagina/efeitos dos fármacos , Fatores Etários , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Animais Recém-Nascidos , Inibidores de Caspase/farmacologia , Feminino , Interleucina-1beta/sangue , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/sangue , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Folículo Ovariano/metabolismo , Quinolinas/farmacologia , Ratos Wistar , Fatores Sexuais , Transdução de Sinais/efeitos dos fármacos , Vagina/crescimento & desenvolvimento , Vagina/metabolismo
19.
Reprod Toxicol ; 57: 1-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25962730

RESUMO

Nitrotriazolone (3-nitro-1,2,4-triazol-5-one; NTO) is an insensitive munition that has demonstrated effects on reproductive organs in adult male rats. NTO was administered to male (0, 250, and 500milligrams per kilogram per day (mg/kg-day)) and female (0, 500, and 1000mg/kg-day) Sprague-Dawley rats (15/sex/group) via oral gavage from weaning through post-natal day 53/54 and 42/43, respectively. Age and body mass at vaginal opening (VO) and preputial separation (PPS), as well as all measures of estrous cyclicity were not affected by treatment with NTO. Males treated with NTO exhibited reductions in testis mass associated with tubular degeneration/atrophy. Less pronounced reductions in accessory sex organ masses were also observed in the 500mg/kg-day group. Treatment with NTO did not affect thyroid hormone or testosterone levels. These findings suggest that NTO is not acting as an estrogen or thyroid active compound, but may indicate effects on steroidogenesis and/or direct testicular toxicity.


Assuntos
Genitália Masculina/efeitos dos fármacos , Nitrocompostos/toxicidade , Triazóis/toxicidade , Animais , Ciclo Estral/efeitos dos fármacos , Feminino , Genitália Masculina/crescimento & desenvolvimento , Genitália Masculina/patologia , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Reprodução , Caracteres Sexuais , Maturidade Sexual/efeitos dos fármacos , Testosterona/sangue , Hormônios Tireóideos/sangue , Vagina/efeitos dos fármacos , Vagina/crescimento & desenvolvimento
20.
Drug Deliv Transl Res ; 5(3): 279-94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25874971

RESUMO

Gels are one of the soft material platforms being evaluated to deliver topically acting anti-HIV drugs (microbicides) to the vaginal environment. For each drug, its loaded concentration, gel properties and applied volume, and frequency of dosing can be designed to optimize PK and, thence, PD. These factors also impact user sensory perceptions and acceptability. Deterministic compartmental modeling of vaginal deployment and drug delivery achieved by test gels can help delineate how multiple parameters characterizing drug, vehicle, vaginal environment, and dosing govern details of PK and PD and also gel leakage from the canal. Such microbicide delivery is a transport process combining convection, e.g., from gel spreading along the vaginal canal, with drug diffusion in multiple compartments, including gel, mucosal epithelium, and stroma. The present work builds upon prior models of gel coating flows and drug diffusion (without convection) in the vaginal environment. It combines and extends these initial approaches in several key ways, including: (1) linking convective drug transport due to gel spreading with drug diffusion and (2) accounting for natural variations in dimensions of the canal and the site of gel placement therein. Results are obtained for a leading microbicide drug, tenofovir, delivered by three prototype microbicide gels, with a range of rheological properties. The model includes phosphorylation of tenofovir to tenofovir diphosphate (which manifests reverse transcriptase activity in host cells), the stromal concentration distributions of which are related to reference prophylactic values against HIV. This yields a computed summary measure related to gel protection ("percent protected"). Analyses illustrate tradeoffs amongst gel properties, drug loading, volume and site of placement, and vaginal dimensions, in the time and space history of gel distribution and tenofovir transport to sites of its anti-HIV action and concentrations and potential prophylactic actions of tenofovir diphosphate therein.


Assuntos
Adenina/análogos & derivados , Fármacos Anti-HIV/administração & dosagem , Modelos Biológicos , Membrana Mucosa/metabolismo , Organofosfonatos/administração & dosagem , Veículos Farmacêuticos/química , Vagina/metabolismo , Absorção Vaginal , Adenina/administração & dosagem , Adenina/análise , Adenina/química , Adenina/farmacocinética , Algoritmos , Fármacos Anti-HIV/análise , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Biotransformação , Biologia Computacional , Convecção , Difusão , Composição de Medicamentos , Feminino , Géis , Humanos , Membrana Mucosa/crescimento & desenvolvimento , Organofosfonatos/análise , Organofosfonatos/química , Organofosfonatos/farmacocinética , Fosforilação , Tenofovir , Distribuição Tecidual , Vagina/crescimento & desenvolvimento , Cremes, Espumas e Géis Vaginais/administração & dosagem , Cremes, Espumas e Géis Vaginais/análise , Cremes, Espumas e Géis Vaginais/química , Cremes, Espumas e Géis Vaginais/farmacocinética , Viscosidade
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