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1.
Toxicol Appl Pharmacol ; 305: 242-249, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27151233

RESUMO

It is well established that the prototypical aryl hydrocarbon receptor (AHR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can both cause and protect against carcinogenesis in non-transgenic rodents. But because these animals almost never develop prostate cancer with old age or after carcinogen exposure, whether AHR activation can affect cancer of the prostate remained unknown. We used animals designed to develop this disease, Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, to investigate the potential role of AHR signaling in prostate cancer development. We previously reported that AHR itself has prostate tumor suppressive functions in TRAMP mice; i.e., TRAMP mice in which Ahr was knocked out developed neuroendocrine prostate carcinomas (NEPC) with much greater frequency than did those with both Ahr alleles. In the present study we investigated effects of AHR activation by three different xenobiotics. In utero and lactational TCDD exposure significantly increased NEPC tumor incidence in TRAMP males, while chronic TCDD treatment in adulthood had the opposite effect, a significant reduction in NEPC incidence. Chronic treatment of adult TRAMP mice with the low-toxicity selective AHR modulators indole-3-carbinol or 3,3'-diindolylmethane did not significantly protect against these tumors. Thus, we demonstrate, for the first time, that ligand-dependent activation of the AHR can alter prostate cancer incidence. The nature of the responses depended on the timing of AHR activation and ligand structures.


Assuntos
Anticarcinógenos , Carcinógenos , Dibenzodioxinas Policloradas , Efeitos Tardios da Exposição Pré-Natal , Animais , Anticarcinógenos/farmacologia , Anticarcinógenos/toxicidade , Carcinógenos/farmacologia , Carcinógenos/toxicidade , Carcinoma Neuroendócrino/tratamento farmacológico , Feminino , Lactação , Masculino , Camundongos , Camundongos Transgênicos , Dibenzodioxinas Policloradas/farmacologia , Dibenzodioxinas Policloradas/toxicidade , Gravidez , Neoplasias da Próstata/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/genética
2.
Toxicol Sci ; 150(2): 429-40, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26865671

RESUMO

Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1(+/-);Pten(fl/+) mice, which are genetically predisposed to prostate neoplasia, were exposedin uteroand during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 µg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 ß-estradiol (2.5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants.In uteroand lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life.


Assuntos
Envelhecimento/metabolismo , Poluentes Ambientais/toxicidade , Lactação , Sintomas do Trato Urinário Inferior/induzido quimicamente , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Animais Geneticamente Modificados , Poluentes Ambientais/farmacocinética , Etinilestradiol/farmacologia , Feminino , Predisposição Genética para Doença , Lactação/metabolismo , Sintomas do Trato Urinário Inferior/genética , Sintomas do Trato Urinário Inferior/metabolismo , Sintomas do Trato Urinário Inferior/patologia , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Dibenzodioxinas Policloradas/farmacocinética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/efeitos dos fármacos , Próstata/embriologia , Receptores de Hidrocarboneto Arílico/metabolismo , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/embriologia , Testosterona/farmacologia , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/embriologia
3.
Toxicol Sci ; 141(1): 176-87, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24928892

RESUMO

In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes ventral prostate agenesis in C57BL/6J mice by preventing ventral prostatic budding in the embryonic urogenital sinus (UGS). TCDD (5 µg/kg, po) administered to pregnant dams on embryonic day 15.5 (E15.5) activates the aryl hydrocarbon receptor in the UGS mesenchyme, disrupting the mesenchymally derived paracrine signaling that instructs epithelial prostatic budding. How TCDD alters the mesenchymal milieu is not well understood. We previously showed that TCDD disrupts some aspects of Wnt signaling in UGSs grown in vitro. Here we provide the first comprehensive, in vivo characterization of Wnt signaling in male E16.5 UGSs during normal development, and after in utero TCDD exposure. Vehicle- and TCDD-exposed UGSs were probed by in situ hybridization to assess relative abundance and localization of RNA from 46 genes that regulate Wnt signaling. TCDD altered the staining pattern of five genes, increasing staining for Wnt10a and Wnt16 and decreasing staining for Ror2, Rspo2, and Wif1. We also used immunohistochemistry to show, for the first time, activation of ß-catenin (CTNNB1) signaling in ventral basal epithelium of control UGSs at E16.5. This onset of CTNNB1 signaling occurred immediately prior to the initiation of ventral prostatic budding and is characterized by a pronounced increase in CTNNB1 nuclear localization and subsequent expression of the CTNNB1 signaling target gene, Lef1. In utero TCDD exposure prevented the onset of CTNNB1 signaling and LEF1 expression in the ventral basal epithelium, thereby elucidating a likely mechanism by which TCDD contributes to failed prostatic budding in the ventral UGS.


Assuntos
Poluentes Ambientais/toxicidade , Organogênese/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Próstata/efeitos dos fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Regulação para Baixo , Feminino , Idade Gestacional , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos Endogâmicos C57BL , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Próstata/embriologia , Próstata/metabolismo , Transdução de Sinais , Proteínas Wnt/genética , beta Catenina/genética
4.
Toxicol Sci ; 133(1): 42-53, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23429912

RESUMO

In mice, in utero exposure to 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) reduces the number of dorsolateral prostatic buds resulting in a smaller dorsolateral prostate and prevents formation of ventral buds culminating in ventral prostate agenesis. The genes and signaling pathways affected by TCDD that are responsible for disrupting prostate development are largely unknown. Here we show that treatment of urogenital sinus (UGS) organ cultures with known inhibitors of canonical Wnt signaling also inhibits prostatic bud formation. In support of the hypothesis that TCDD decreases canonical Wnt signaling, we identify inhibitory effects of TCDD on multiple components of the canonical Wnt signaling pathway in the UGS that temporally coincide with the inhibitory effect of TCDD on prostatic bud formation: (1) expression of R-spondins (Rspo2 and Rspo3) that promote canonical Wnt signaling is reduced; (2) expression of Lef1, Tcf1, and Wif1, established canonical Wnt target genes, is decreased; (3) expression of Lgr5, a RSPO receptor that activates canonical Wnt signaling, is reduced; and (4) expression of Dickkopfs (Dkks), inhibitors of canonical Wnt signaling, is not increased by TCDD. Thus, the TCDD-induced reduction in canonical Wnt signaling is associated with a decrease in activators (Rspo2 and Rspo3) rather than an increase in inhibitors (Dkk1 and Dkk2) of the pathway. This study focuses on determining whether treatment of TCDD-exposed UGS organ cultures with RSPO2 and/or RSPO3 is capable of rescuing the inhibitory effects of TCDD on canonical Wnt signaling and prostatic bud formation. We discovered that each RSPO alone or in combination partially rescues TCDD inhibition of both canonical Wnt signaling and prostatic bud formation.


Assuntos
Exposição Materna/efeitos adversos , Organogênese/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Próstata/embriologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Wnt/antagonistas & inibidores , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Idade Gestacional , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Organogênese/genética , Gravidez , Próstata/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Proteínas Wnt/genética
5.
Tex Med ; 108(2): e1, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22714802

RESUMO

This study was conducted to determine if a parent-oriented educational intervention reduces the use of emergency department (ED) services for the care of infants. Infants aged 7 days to 1 year and older children aged 2 to 10 years were tracked for 3 years in two separate primary care (PC) practices in Washington County, Texas, with the last year being the interventional study period. Also, infants aged 7 days to 1 year and older children aged 7 days to 5 years were tracked in a third PC practice in Burleson County, Texas. The study group consisted of all parents of patients aged 7 days to 1 year seen by the pediatric group in Washington County during the 1-year interventional period. Only parents of infants in the study group received a specific educational intervention booklet. Five separate control groups were followed in this study. The control groups received usual care with standardized patient information, but they did not receive the educational intervention booklet. Each group was evaluated by calculating its monthly ED utilization rate, which is the quotient derived from dividing the number of children from that particular group seen in the ED per month by the number of children from the same group seen in the PC clinic per month. A difference of proportions test was applied to test for statistical significance regarding ED utilization. Compared with parents in the control group, parents receiving the intervention booklet (the study group) showed significantly (P < .05) lower use of ED services for care of their infants. We found no change in ED utilization for children of parents receiving other standard educational information.


Assuntos
Serviço Hospitalar de Emergência , Pais , Humanos , Atenção Primária à Saúde , Texas
6.
Fam Med ; 43(2): 106-11, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21305425

RESUMO

BACKGROUND AND OBJECTIVES: A substantial proportion of emergency department (ED) visits by children are for non-urgent care. The objective of this research is to determine whether a parent-focused educational intervention can reduce non-urgent ED visits. METHODS: A regional hospital system (which includes a central hospital, four satellite hospitals, and two primary care clinics) provided monthly data retrospectively from January 2006 to October 2007 on ED visits by children. The same information was provided prospectively from November 2007 to April 2009. Starting in November 2007, a family medicine residency program affiliated with the same hospital network distributed a 6.7 grade reading level booklet on non-urgent care of children to the parents who brought their children to the outpatient clinic. The number of ED visits as a proportion of outpatient clinic visits at the residency program was calculated for each month and compared to historical and geographic trends. RESULTS: Long-term changes were observed only among the intervention group. There was a substantial and statistically significant reduction in ED use for non-urgent care of children. There was also a proportional reduction in ED charges for this group. CONCLUSION: An educational intervention among parents can substantially reduce non-urgent ED visits for their children.


Assuntos
Serviço Hospitalar de Emergência/estatística & dados numéricos , Medicina de Família e Comunidade/estatística & dados numéricos , Internato e Residência/estatística & dados numéricos , Relações Pais-Filho , Educação de Pacientes como Assunto/métodos , Criança , Proteção da Criança , Avaliação Educacional/métodos , Escolaridade , Humanos , Modelos Educacionais , Pacientes Ambulatoriais/estatística & dados numéricos , Educação de Pacientes como Assunto/estatística & dados numéricos , Pediatria/estatística & dados numéricos , Análise de Regressão , Estudos Retrospectivos , Texas , Fatores de Tempo
7.
Dev Dyn ; 239(2): 373-85, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19941349

RESUMO

The ventral urogenital sinus (UGS) of control male mice has two rows of 3-4 prostatic buds at birth, but how androgens regulate ventral bud (VB) number and patterning is unclear. VBs in both sexes appeared to be a mixture of prostatic and urethral buds. UGSs from Tfm male and antiandrogen (flutamide)-exposed mice had small VBs, suggesting that initiation of some VBs is androgen independent. Tfm male mice are widely considered completely androgen insensitive yet their UGSs were 5alpha-dihydrotestosterone (DHT)- responsive. VBs (6-8) were generally distributed bimodally on the left-right axis at both minimal and normal male androgen signaling. Yet control females and DHT-exposed Tfm males had 13-14 VBs, whose left-right distribution was fairly uniform. These results suggest that VB number and distribution respond biphasically as androgen signaling increases from minimal, and that androgens regulate bud specification. Complete VB agenesis by the selective budding inhibitor 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) required high androgen signaling.


Assuntos
Androgênios/metabolismo , Padronização Corporal , Feto/metabolismo , Próstata/embriologia , Receptores Androgênicos/metabolismo , Antagonistas de Androgênios , Síndrome de Resistência a Andrógenos/metabolismo , Animais , Animais Recém-Nascidos , Di-Hidrotestosterona , Feminino , Flutamida , Proteínas de Homeodomínio/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Técnicas de Cultura de Órgãos , Dibenzodioxinas Policloradas , Caracteres Sexuais , Transdução de Sinais , Teratogênicos , Terminologia como Assunto , Fatores de Transcrição/metabolismo , Uretra/embriologia
8.
Toxicol Sci ; 113(1): 198-206, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19805408

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) dorsalizes the pattern of prostatic buds developing from the urogenital sinus (UGS) of male fetal mice, causing some buds to form in inappropriate positions while blocking formation of others. This teratogenic TCDD action significantly reduces prostate main duct number and causes ventral prostate agenesis in exposed males. The purpose of this study was to determine whether inhibition of fibroblast growth factor 10 (FGF10) signaling is mechanistically linked to mouse prostatic budding impairment by TCDD. In utero TCDD exposure induced aryl hydrocarbon receptor-responsive cytochrome P450 1b1 messenger RNA (mRNA) in ventral UGS regions where Fgf10 and fibroblast growth factor receptor 2 (Fgfr2) mRNA were expressed and where budding was most severely inhibited by TCDD. However, TCDD exposure did not reduce Fgf10 or Fgfr2 mRNA abundance in the UGS or alter their distribution. Addition of FGF10 protein to UGS organ culture media increased the abundance of UGS basal epithelial cells immunopositive for phosphorylated extracellular signal-regulated kinase (ERK). FGF10 also increased the number of 5-bromo-2'-deoxyuridine (BrdU)-labeled UGS epithelial cells and increased the number of prostatic buds formed per UGS. Addition of TCDD to UGS organ culture media did not alter FGF10-induced ERK activation in UGS basal epithelium but prevented FGF10-induced BrdU incorporation and blocked FGF10-induced prostatic bud formation. These results identify basal urogenital sinus epithelium cells as the key site of FGF10 action during fetal prostate development and suggest that TCDD likely acts downstream of FGFR2 and ERK to restrict UGS epithelial cell proliferation and prevent prostatic bud formation.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Células Epiteliais/efeitos dos fármacos , Fator 10 de Crescimento de Fibroblastos/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Próstata/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP1B1 , Ativação Enzimática , Células Epiteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fator 10 de Crescimento de Fibroblastos/genética , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Idade Gestacional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos , Gravidez , Próstata/anormalidades , Próstata/metabolismo , RNA Mensageiro/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo
9.
Toxicol Appl Pharmacol ; 239(1): 80-6, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19523480

RESUMO

Estrogens play an important role in prostatic development, health, and disease. While estrogen signaling is essential for normal postnatal prostate development, little is known about its prenatal role in control animals. We tested the hypothesis that estrogen signaling is needed for normal male prostatic bud patterning. Budding patterns were examined by scanning electron microscopy of urogenital sinus epithelium from wild-type mice, mice lacking estrogen receptor (ER)alpha, ERbeta, or both, and wild-type mice exposed to the antiestrogen ICI 182,780. Budding phenotypes did not detectably differ among any of these groups, strongly suggesting that estrogen signaling is not needed to establish the prototypical prostatic budding pattern seen in control males. This finding contributes to our understanding of the effects of low-level estrogen exposure on early prostate development. In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can greatly alter the pattern in which prostatic buds form and reduce their number. For several reasons, including a prior observation that inhibitory effects of TCDD on prostatic budding in rats depend heavily on the sex of adjacent fetuses, we tested the hypothesis that estrogen signaling is needed for TCDD to disrupt prostatic budding. However, budding did not detectably differ among wild-type mice, or mice lacking ERalpha, ERbeta, or both, that were exposed prenatally to TCDD (5 microg/kg on embryonic day 13.5). Nor did ICI 182,780 detectably affect the response to TCDD. These results strongly suggest that estrogen signaling is not needed for TCDD to inhibit prostatic epithelial budding.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/fisiologia , Exposição Materna/efeitos adversos , Organogênese/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Próstata/efeitos dos fármacos , Animais , Receptor alfa de Estrogênio/biossíntese , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/biossíntese , Receptor beta de Estrogênio/genética , Estrogênios/biossíntese , Feminino , Idade Gestacional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Gravidez , Próstata/embriologia , Próstata/metabolismo , Transdução de Sinais/efeitos dos fármacos
10.
Biochem Pharmacol ; 77(7): 1151-60, 2009 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-19166822

RESUMO

The aryl hydrocarbon receptor (AhR) is a basic-helix-loop-helix transcription factor that binds halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, and endogenous compounds. We previously reported that AhR null (Ahr(-/-)) transgenic adenocarcinoma of the mouse prostate (TRAMP) mice on a C57BL/6J background develop prostate tumors with much greater frequency than AhR wild-type (Ahr(+/+)) TRAMP mice, suggesting that the AhR has tumor suppressor properties. Because AhR signaling pathway inactivation increased susceptibility to prostate tumorigenesis, we tested the hypothesis that a selective AhR modulator (SAhRM), 6-methyl-1,3,8-trichlorodibenzofuran (6-MCDF), can protect against prostate tumorigenesis. TRAMP mice on the standard C57BL/6JxFVB genetic background were fed 0, 10, or 40mg 6-MCDF/kg diet beginning at 8 weeks of age. Tumor incidence, pelvic lymph node metastasis, and serum vascular endothelial growth factor (VEGF) concentrations were determined at 140 days of age. Prostate tumor incidence and size were not significantly reduced in mice fed 6-MCDF. However, the frequency of pelvic lymph node metastasis was reduced fivefold in mice fed the 40mg 6-MCDF/kg diet. Serum VEGF concentrations were also reduced by 6-MCDF treatment, particularly in mice without prostate tumors, and 6-MCDF was shown to act directly on cultured prostates to inhibit VEGF secretion. Together, these results suggest that 6-MCDF inhibits metastasis, in part, by inhibiting prostatic VEGF production prior to tumor formation. This is the first report that 6-MCDF can confer protection against prostate cancer in vivo.


Assuntos
Benzofuranos/uso terapêutico , Neoplasias Pélvicas/prevenção & controle , Neoplasias Pélvicas/secundário , Neoplasias da Próstata/tratamento farmacológico , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Benzofuranos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Neoplasias Pélvicas/patologia , Neoplasias da Próstata/patologia
11.
Dev Biol ; 324(1): 10-7, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-18804104

RESUMO

The establishment of prostatic budding patterns occurs early in prostate development but mechanisms responsible for this event are poorly understood. We investigated the role of WNT5A in patterning prostatic buds as they emerge from the fetal mouse urogenital sinus (UGS). Wnt5a mRNA was expressed in UGS mesenchyme during budding and was focally up-regulated as buds emerged from the anterior, dorsolateral, and ventral UGS regions. We observed abnormal UGS morphology and prostatic bud patterns in Wnt5a null male fetuses, demonstrated that prostatic bud number was decreased by recombinant mouse WNT5A protein during wild type UGS morphogenesis in vitro, and showed that ventral prostate development was selectively impaired when these WNT5A-treated UGSs were grafted under under kidney capsules of immunodeficient mice and grown for 28 d. Moreover, a WNT5A inhibitory antibody, added to UGS organ culture media, rescued prostatic budding from inhibition by a ventral prostatic bud inhibitor, 2,3,8,7-tetrachlorodibenzo-p-dioxin, and restored ventral prostate morphogenesis when these tissues were grafted under immunodeficient mouse kidney capsules and grown for 28 d. These results suggest that WNT5A participates in prostatic bud patterning by restricting mouse ventral prostate development.


Assuntos
Próstata/embriologia , Proteínas Wnt/fisiologia , Animais , Padronização Corporal , Masculino , Camundongos , Camundongos Knockout , Organogênese , Próstata/metabolismo , Técnicas de Cultura de Tecidos , Proteína Wnt-5a
12.
Toxicol Sci ; 106(2): 488-96, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18779384

RESUMO

Prostate ductal development is initiated by androgen-dependent signals in fetal urogenital sinus (UGS) mesenchyme that stimulate prostatic bud formation in UGS epithelium. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 5 microg/kg maternal dose) inhibited ventral and dorsolateral but not anterior prostatic budding. We sought to determine which stage of budding, specification or initiation, was inhibited. Ventral prostatic bud formation was maximally inhibited when TCDD exposure spanned E15.5-16.5 and dorsolateral prostatic bud formation when it spanned E14.5-15.5. Because ventral and dorsolateral buds are specified at these times, TCDD impaired bud specification. We hypothesized that TCDD inhibited ventral bud specification by forming a continuous smooth muscle barrier between UGS mesenchyme and epithelium in the ventral prostatic UGS region, blocking mesenchymal-epithelial signaling, but no such barrier was found. We hypothesized that increased aryl hydrocarbon receptor (AHR) signaling in ventral and dorsolateral UGS increased their sensitivity to TCDD, but levels of AHR nuclear translocator (ARNT) protein, Ahr mRNA, and AHR-dependent gene expression were not higher than in anterior UGS where budding was unaffected. However, we identified overlapping expression of Ahr, ARNT, and AHR-induced transcripts in the periprostatic mesenchyme which intimately contacts UGS epithelium where buds are specified. This was considered the putative TCDD site of action in the UGS for inhibition of ventral and dorsolateral prostatic bud specification. Thus, hyperactivation of AHR signaling appears to disrupt dorsoventral patterning of the UGS, reprogramming where prostatic buds are specified, and prostate lobes are formed. Disrupted axial patterning provides a new paradigm for understanding how in utero TCDD exposure causes ventral prostate agenesis and may shed light on how TCDD impairs development of other organs.


Assuntos
Padronização Corporal/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Próstata/efeitos dos fármacos , Animais , Sequência de Bases , Primers do DNA , Relação Dose-Resposta a Droga , Feminino , Imuno-Histoquímica , Hibridização In Situ , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Gravidez , Próstata/embriologia
13.
Dev Dyn ; 237(5): 1321-33, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18393306

RESUMO

Formation of prostatic buds from the urogenital sinus (UGS) to initiate prostate development requires localized action of several morphogenetic factors. This report reveals all-trans-retinoic acid (RA) to be a powerful inducer of mouse prostatic budding that is associated with reciprocal changes in expression of two regulators of budding: sonic hedgehog (Shh) and bone morphogenetic protein 4 (Bmp4). Localization of retinoid signaling and expression of RA synthesis, metabolism, and receptor genes in the UGS on embryonic days 14.5-17.5 implicate RA in the mechanism of bud initiation. In UGS organ culture, RA increased prostatic budding, increased Shh expression, and decreased Bmp4. Prostatic budding was stimulated in the absence of RA by recombinant SHH, by blocking BMP4 signaling with NOGGIN, or by combined treatment with SHH and NOGGIN in UGS organ culture media. These observations suggest that reciprocal changes in hedgehog and BMP signaling by RA may regulate bud initiation.


Assuntos
Antineoplásicos/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Hedgehog/metabolismo , Morfogênese , Próstata/efeitos dos fármacos , Próstata/embriologia , Tretinoína/farmacologia , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Animais , Antineoplásicos/metabolismo , Proteína Morfogenética Óssea 4 , Proteínas Morfogenéticas Ósseas/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Regulação da Expressão Gênica , Proteínas Hedgehog/genética , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Próstata/anatomia & histologia , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Transdução de Sinais/fisiologia , Técnicas de Cultura de Tecidos , Tretinoína/metabolismo
14.
Toxicol Sci ; 104(1): 189-97, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18411234

RESUMO

The Hedgehog (Hh) signaling pathway is an essential regulator of embryonic development and appears to play important roles in postnatal repair and cancer progression and metastasis. The teratogenic Veratrum alkaloid cyclopamine is a potent Hh antagonist and is used experimentally both in vitro and in vivo to investigate the role of Hh signaling in diverse biological processes. Here, we set out to establish an administration regimen for cyclopamine-induced teratogenicity in the mouse. The dysmorphogenic concentration of cyclopamine was determined in vitro via mouse whole-embryo culture assays to be 2.0 microM. We administered cyclopamine to female C57BL/6J mice at varied doses by oral gavage, ip injection, or osmotic pump infusion and assessed toxicity and pharmacokinetic (PK) models. Bolus administration was limited by toxicity and rapid clearance. In vivo cyclopamine infusion at 160 mg/kg/day yielded a dam serum steady-state concentration of approximately 2 microM with a corresponding amniotic fluid concentration of approximately 1.5 microM. Gross facial defects were induced in 30% of cyclopamine-exposed litters, with affected embryos exhibiting cleft lip and palate. This is the first report describing the PKs and teratogenic potential of cyclopamine in the mouse and demonstrates that transient Hh signaling inhibition induces facial clefting anomalies in the mouse that mimic common human birth defects.


Assuntos
Fenda Labial/induzido quimicamente , Fissura Palatina/induzido quimicamente , Proteínas Hedgehog/antagonistas & inibidores , Teratogênicos/toxicidade , Alcaloides de Veratrum/toxicidade , Líquido Amniótico/química , Animais , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Embrião de Mamíferos/anormalidades , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Transdução de Sinais , Teratogênicos/farmacocinética , Alcaloides de Veratrum/administração & dosagem , Alcaloides de Veratrum/sangue , Alcaloides de Veratrum/farmacocinética
15.
Toxicol Sci ; 86(2): 387-95, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15888670

RESUMO

In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure inhibits ventral, dorsolateral, and anterior prostate development in C57BL/6 mice. To determine if prostatic abnormalities persist into senescence, mice born to dams given TCDD (5 mug/kg, po) or vehicle on gestation day 13 were examined at 100 and 510 days of age. Half the mice were castrated ten days prior to necropsy in order to assess androgen dependence, while the remaining mice were sham castrated. Effects of TCDD on the dorsolateral and anterior prostate of senescent sham-castrated mice were relatively subtle, whereas the ventral prostate was rudimentary or absent. Castration of vehicle-exposed mice caused far greater reductions in prostate lobe weights, epithelial cell height, and androgen-dependent gene expression (MP25 and probasin) in young mice than in senescent ones, while cell proliferation was decreased by castration in young mice and increased in senescence. Responses to castration were similar at 100 days of age in vehicle- and TCDD-exposed mice. At 510 days, however, TCDD-exposed mice were substantially more responsive to castration by most indices than vehicle-exposed mice. These results demonstrate that prostatic androgen dependence in mice declines substantially with age in several key ways, and that in utero and lactational TCDD exposure protects against this decline. Surprisingly, TCDD increased the incidence of cribriform structures in dorsolateral prostate ducts, from 2-3% in vehicle-exposed senescent mice to 16% in sham-castrated and to 7% in castrated senescent mice. Collectively, these results demonstrate that effects of in utero and lactational TCDD exposure on the prostate persist into senescence, and suggest that in utero and lactational TCDD exposure retards the aging process in the prostate. However, because cribriform structures are often considered to be associated with prostate carcinogenesis, these results also suggest that TCDD exposure early in development may increase susceptibility to prostate cancer.


Assuntos
Envelhecimento/fisiologia , Lactação , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Próstata/efeitos dos fármacos , Proteína de Ligação a Androgênios/genética , Proteína de Ligação a Androgênios/metabolismo , Animais , Castração , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Próstata/crescimento & desenvolvimento , Próstata/patologia , RNA Mensageiro/metabolismo , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/crescimento & desenvolvimento , Glândulas Seminais/patologia
16.
J Urol ; 172(1): 365-8, 2004 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15201812

RESUMO

PURPOSE: In utero and lactational 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure causes lobe specific inhibition of prostate development in C57BL/6 mice due primarily to region specific inhibition of prostatic epithelial bud formation by the urogenital sinus (UGS). This inhibition requires that the receptor for TCDD, the aryl hydrocarbon receptor (AhR), must be present. We tested the hypothesis that TCDD inhibits prostatic epithelial bud formation by acting directly on the UGS. MATERIALS AND METHODS: UGSs were removed from WT and AhR null mutant (AhRKO) male C57BL/6 mice on gestation day 14 and incubated in vitro with vehicle, 10-8 M testosterone or 10-8 M testosterone plus 10-9 M TCDD for 5 days. Budding was evaluated by a newly developed technique, namely scanning electron microscopy of UGS epithelium after removal of UGS mesenchyme. RESULTS: Few buds were present in UGSs of either genotype in the absence of testosterone, while many were observed when testosterone was present. TCDD prevented prostatic epithelial buds from forming in UGSs from WT mice but it had no effect on UGSs from AhRKO mice. CONCLUSIONS: TCDD can act directly on the UGS to cause AhR dependent inhibition of prostatic epithelial bud formation. Because this inhibition occurred at a TCDD concentration similar to the estimated concentration at which TCDD inhibits bud formation in vivo, it appears that TCDD inhibits prostatic budding primarily via direct effects on the UGS rather than indirectly through effects on other organs.


Assuntos
Dibenzodioxinas Policloradas/farmacologia , Próstata/anormalidades , Próstata/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Teratogênicos/farmacologia , Sistema Urogenital/efeitos dos fármacos , Animais , Meios de Cultura , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Hidrocarboneto Arílico/genética
17.
Toxicol Sci ; 79(2): 360-9, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15056816

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) inhibits the androgen-dependent processes by which the urogenital sinus (UGS) of fetal mice forms prostatic epithelial buds. This inhibition is mediated by aryl hydrocarbon receptors in UGS mesenchyme and causes prostate lobes to develop abnormally. Experiments were conducted to test the hypothesis that TCDD inhibits prostatic budding in C57BL/6J mice by inhibiting androgen signaling. In utero TCDD exposure sufficient to inhibit budding (5 microg/kg maternal dose on gestation day [GD] 13) had no effect on testicular testosterone content on GD 16 or 18. Nor did it inhibit the conversion of testosterone to 5alpha-dihydrotestosterone (DHT) by the UGS. Both hydroxyflutamide (OH-flutamide; a competitive androgen receptor antagonist) and TCDD inhibited prostatic epithelial budding by UGSs cultured in vitro with DHT. To determine if TCDD inhibits responsiveness to androgens, primary mesenchymal cells prepared from UGSs cultured for three days with DHT were transiently transfected with an androgen-responsive reporter plasmid (MMTV-luciferase). OH-flutamide prevented DHT from increasing luciferase activity in these cells but TCDD did not. The same results were obtained when the mesenchymal cells were isolated from UGSs cultured with both DHT and TCDD. The lack of effect of TCDD on androgen-dependent gene expression was not due to inability of transfected UGS mesenchymal cells to respond to TCDD, as shown by significant increases in luciferase activity after transfection with plasmids containing CYP1A1 and CYP1B1 promoters. Finally, while OH-flutamide prevented DHT from altering androgen receptor and 5alpha-reductase type II mRNA expression in UGS organ culture, TCDD had no such effects. Collectively, these results suggest that TCDD inhibits prostatic epithelial bud formation without impairing the androgen receptor signaling pathway.


Assuntos
Poluentes Ambientais/toxicidade , Exposição Materna , Dibenzodioxinas Policloradas/toxicidade , Próstata/efeitos dos fármacos , Sistema Urogenital/efeitos dos fármacos , Antagonistas de Androgênios/farmacologia , Animais , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Epitélio/efeitos dos fármacos , Feminino , Feto/efeitos dos fármacos , Flutamida/farmacologia , Regulação da Expressão Gênica no Desenvolvimento , Luciferases/metabolismo , Masculino , Mesoderma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Próstata/embriologia , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testículo/efeitos dos fármacos , Testículo/embriologia , Testículo/metabolismo , Testosterona/análise , Testosterona/metabolismo , Sistema Urogenital/ultraestrutura
18.
Toxicol Appl Pharmacol ; 196(1): 149-55, 2004 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-15050416

RESUMO

In utero exposure of male C57BL/6 mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) prevents prostatic epithelial buds from forming in the ventral region of the urogenital sinus (UGS) and reduces the number of buds that form in the dorsolateral region. This inhibition of budding is aryl hydrocarbon receptor (AHR) dependent and appears to be the primary cause of lobe-specific prostate abnormalities in TCDD-exposed mice. TCDD can inhibit prostatic epithelial bud formation by acting directly on the UGS in vitro, but whether it does so via AHR in UGS mesenchyme, epithelium, or both was unknown. To address this issue, UGS mesenchyme and epithelium from gestation day (GD) 15 wild-type C57BL/6J male mice were isolated, recombined, and cultured in vitro for 5 days with 10(-8) M 5alpha-dihydrotestosterone (DHT) and either 10(-9) M TCDD or vehicle. Prostatic epithelial buds were viewed by light microscopy after removal of mesenchyme. Effects depended greatly on which portions of the mesenchyme were used: TCDD had little if any effect when whole UGS epithelium (UGE) was recombined with ventral plus dorsolateral mesenchyme, tended to reduce bud numbers in recombinants made with UGE and dorsolateral mesenchyme, and severely reduced bud numbers in recombinants made with UGE and ventral mesenchyme (VM). [VM + UGE] recombinants prepared from wild-type and AHR knockout (Ahr(-/-)) mice were then cultured with DHT to determine the site of action of TCDD. AHR null mutation alone had no effect on budding. TCDD severely inhibited prostatic epithelial bud formation in recombinants that contained mesenchymal AHR, whereas bud formation was not inhibited by TCDD in recombinants lacking mesenchymal AHR, regardless of epithelial AHR status. These results demonstrate that UGS mesenchyme and not UGS epithelium is the site of action of TCDD. Therefore, the initial events responsible for abnormal UGS (and ultimately prostate) development occur within the UGS mesenchyme, and changes in gene expression in the UGS epithelium responsible for inhibited prostatic budding are secondary to the direct effects of TCDD on UGS mesenchyme.


Assuntos
Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Mesoderma/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Próstata/efeitos dos fármacos , Receptores de Hidrocarboneto Arílico/genética , Animais , Epitélio/efeitos dos fármacos , Epitélio/embriologia , Epitélio/metabolismo , Feminino , Masculino , Mesoderma/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Técnicas de Cultura de Órgãos , Próstata/embriologia , Próstata/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo
19.
Toxicol Sci ; 76(1): 171-81, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12944588

RESUMO

In utero 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure causes abnormal ventral, dorsolateral, and anterior prostate development in wild-type but not aryl hydrocarbon receptor (AhR) null mutant C57BL/6 mice. Experiments have now been conducted to test the hypothesis that TCDD causes an AhR-dependent inhibition of the earliest visible stage of prostate development, the formation of prostatic buds by urogenital sinus (UGS) epithelium. A novel method for viewing budding was developed that uses scanning electron microscopy of isolated UGS epithelium instead of three-dimensional reconstruction of serial histological sections of intact UGS. In the initial experiment, the time course for prostatic epithelial bud formation in vehicle- and TCDD-exposed wild-type C57BL/6J mice was determined. A single maternal dose of TCDD (5 mug/kg) on gestation day 13 delayed the appearance of dorsal, lateral, and anterior buds by about one day, reduced dorsolateral bud number, and prevented ventral buds from forming. No such effects were seen in TCDD-exposed AhR null mutant fetuses, while AhR null mutation, alone, had no detectable effect on budding. Treatment of wild-type dams with sufficient 5alpha-dihydrotestosterone (DHT) to masculinize female fetuses failed to protect against the inhibition of budding caused by TCDD. These results demonstrate that in utero TCDD exposure causes an AhR-dependent inhibition of prostatic epithelial bud formation commensurate with its inhibitory effects on ventral and dorsolateral prostate development, and that the inhibition of budding is not due to insufficient DHT. Inhibited bud formation appears to be the primary cause of abnormal prostate development in TCDD-exposed mice.


Assuntos
Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Epitélio/efeitos dos fármacos , Dibenzodioxinas Policloradas/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Próstata/efeitos dos fármacos , Teratogênicos/toxicidade , Animais , Di-Hidrotestosterona/farmacologia , Epitélio/embriologia , Epitélio/ultraestrutura , Feminino , Idade Gestacional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia Eletrônica de Varredura , Ductos Paramesonéfricos/efeitos dos fármacos , Ductos Paramesonéfricos/embriologia , Ductos Paramesonéfricos/ultraestrutura , Gravidez , Próstata/embriologia , Próstata/ultraestrutura , Receptores de Hidrocarboneto Arílico/genética , Uretra/efeitos dos fármacos , Uretra/embriologia , Uretra/ultraestrutura , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/embriologia , Ducto Deferente/ultraestrutura , Ductos Mesonéfricos/efeitos dos fármacos , Ductos Mesonéfricos/embriologia , Ductos Mesonéfricos/ultraestrutura
20.
Toxicol Sci ; 69(1): 202-9, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12215675

RESUMO

A single maternal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestation day (GD) 13 can greatly impair ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle development in wild-type C57BL/6 mice. The developmental stages at which these organs are most sensitive to TCDD exposure have now been investigated. Pregnant mice were dosed orally with 5 micro g TCDD/kg or vehicle on GD 13, and their pups were fostered at birth to dams of the same treatment or cross-fostered to dams of the opposite treatment. Additional males had in utero and lactational TCDD exposure following maternal dosing on GD 16. Organ weights and secretory protein, cytokeratin 8, and cyclophilin mRNA expression were determined at 35 days of age. Effects of TCDD on ventral prostate development were due primarily to in utero exposure; the critical window was between GD 13 and birth. Dorsolateral prostate development was inhibited about equally by in utero or lactational exposure, and vulnerability did not begin until GD 16. Anterior prostate development was also affected by both in utero and lactational TCDD exposure, particularly the former. Vulnerability began before GD 16 and continued into postnatal life. Seminal vesicle development was essentially unaffected by in utero or lactational exposure alone but was significantly inhibited by combined exposure, regardless of whether dams were dosed on GD 13 or 16. In summary, the time during which each organ was most vulnerable to TCDD exposure varied from one organ to another. These findings provide insights into the developmental processes that TCDD inhibits in each organ, and demonstrate that TCDD inhibits ventral prostate development before this organ first appears, presumably via effects on the urogenital sinus. The observation that in utero TCDD exposure (alone) inhibited development of each prostate lobe is significant because previous studies have shown that little TCDD is transmitted to mice before birth.


Assuntos
Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Próstata/crescimento & desenvolvimento , Glândulas Seminais/crescimento & desenvolvimento , Proteína de Ligação a Androgênios/biossíntese , Proteína de Ligação a Androgênios/genética , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Queratinas/biossíntese , Queratinas/genética , Lactação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Próstata/efeitos dos fármacos , Próstata/embriologia , Receptores de Hidrocarboneto Arílico/genética , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/embriologia
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