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1.
Environ Health Perspect ; 123(3): 223-30, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25514601

RESUMO

BACKGROUND: Phthalate exposure induces germ cell effects in the fetal rat testis. Although experimental models have shown that the human fetal testis is insensitive to the steroidogenic effects of phthalates, the effects on germ cells have been less explored. OBJECTIVES: We sought to identify the effects of phthalate exposure on human fetal germ cells in a dynamic model and to establish whether the rat is an appropriate model for investigating such effects. METHODS: We used immunohistochemistry, immunofluorescence, and quantitative real-time polymerase chain reaction to examine Sertoli and germ cell markers on rat testes and human fetal testis xenografts after exposure to vehicle or di(n-butyl) phthalate (DBP). Our study included analysis of germ cell differentiation markers, proliferation markers, and cell adhesion proteins. RESULTS: In both rat and human fetal testes, DBP exposure induced similar germ cell effects, namely, germ cell loss (predominantly undifferentiated), induction of multinucleated gonocytes (MNGs), and aggregation of differentiated germ cells, although the latter occurred rarely in the human testes. The mechanism for germ cell aggregation and MNG induction appears to be loss of Sertoli cell-germ cell membrane adhesion, probably due to Sertoli cell microfilament redistribution. CONCLUSIONS: Our findings provide the first comparison of DBP effects on germ cell number, differentiation, and aggregation in human testis xenografts and in vivo in rats. We observed comparable effects on germ cells in both species, but the effects in the human were muted compared with those in the rat. Nevertheless, phthalate effects on germ cells have potential implications for the next generation, which merits further study. Our results indicate that the rat is a human-relevant model in which to explore the mechanisms for germ cell effects.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Dibutilftalato/toxicidade , Células Germinativas/efeitos dos fármacos , Substâncias Perigosas/toxicidade , Testículo/efeitos dos fármacos , Animais , Feto/efeitos dos fármacos , Humanos , Imuno-Histoquímica , Masculino , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Testículo/embriologia , Transplante Heterólogo
2.
Proc Natl Acad Sci U S A ; 111(18): E1924-32, 2014 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-24753613

RESUMO

Fetal growth plays a role in programming of adult cardiometabolic disorders, which in men, are associated with lowered testosterone levels. Fetal growth and fetal androgen exposure can also predetermine testosterone levels in men, although how is unknown, because the adult Leydig cells (ALCs) that produce testosterone do not differentiate until puberty. To explain this conundrum, we hypothesized that stem cells for ALCs must be present in the fetal testis and might be susceptible to programming by fetal androgen exposure during masculinization. To address this hypothesis, we used ALC ablation/regeneration to identify that, in rats, ALCs derive from stem/progenitor cells that express chicken ovalbumin upstream promoter transcription factor II. These stem cells are abundant in the fetal testis of humans and rodents, and lineage tracing in mice shows that they develop into ALCs. The stem cells also express androgen receptors (ARs). Reduction in fetal androgen action through AR KO in mice or dibutyl phthalate (DBP) -induced reduction in intratesticular testosterone in rats reduced ALC stem cell number by ∼40% at birth to adulthood and induced compensated ALC failure (low/normal testosterone and elevated luteinizing hormone). In DBP-exposed males, this failure was probably explained by reduced testicular steroidogenic acute regulatory protein expression, which is associated with increased histone methylation (H3K27me3) in the proximal promoter. Accordingly, ALCs and ALC stem cells immunoexpressed increased H3K27me3, a change that was also evident in ALC stem cells in fetal testes. These studies highlight how a key component of male reproductive development can fundamentally reprogram adult hormone production (through an epigenetic change), which might affect lifetime disease risk.


Assuntos
Células-Tronco Adultas/fisiologia , Androgênios/fisiologia , Desenvolvimento Fetal/fisiologia , Células Intersticiais do Testículo/fisiologia , Células-Tronco Adultas/efeitos dos fármacos , Animais , Callithrix , Linhagem da Célula/fisiologia , Dibutilftalato/toxicidade , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Células-Tronco Fetais/efeitos dos fármacos , Células-Tronco Fetais/fisiologia , Humanos , Técnicas In Vitro , Células Intersticiais do Testículo/efeitos dos fármacos , Hormônio Luteinizante/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Modelos Animais , Gravidez , Ratos , Ratos Transgênicos , Ratos Wistar , Receptores Androgênicos/deficiência , Receptores Androgênicos/genética , Receptores Androgênicos/fisiologia , Regeneração , Testículo/embriologia , Testículo/fisiologia , Testosterona/deficiência , Testosterona/fisiologia
3.
Asian J Androl ; 16(1): 31-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24369131

RESUMO

One of the major causes of defective sperm function is oxidative stress, which not only disrupts the integrity of sperm DNA but also limits the fertilizing potential of these cells as a result of collateral damage to proteins and lipids in the sperm plasma membrane. The origins of such oxidative stress appear to involve the sperm mitochondria, which have a tendency to generate high levels of superoxide anion as a prelude to entering the intrinsic apoptotic cascade. Unfortunately, these cells have very little capacity to respond to such an attack because they only possess the first enzyme in the base excision repair (BER) pathway, 8-oxoguanine glycosylase 1 (OGG1). The latter successfully creates an abasic site, but the spermatozoa cannot process the oxidative lesion further because they lack the downstream proteins (APE1, XRCC1) needed to complete the repair process. It is the responsibility of the oocyte to continue the BER pathway prior to initiation of S-phase of the first mitotic division. If a mistake is made by the oocyte at this stage of development, a mutation will be created that will be represented in every cell in the body. Such mechanisms may explain the increase in childhood cancers and other diseases observed in the offspring of males who have suffered oxidative stress in their germ line as a consequence of age, environmental or lifestyle factors. The high prevalence of oxidative DNA damage in the spermatozoa of male infertility patients may have implications for the health of children conceived in vitro and serves as a driver for current research into the origins of free radical generation in the germ line.


Assuntos
Dano ao DNA , Estresse Oxidativo , Saúde Reprodutiva , Envelhecimento , Animais , Cricetinae , DNA Glicosilases/metabolismo , Reparo do DNA , Humanos , Infertilidade Masculina/genética , Estilo de Vida , Peroxidação de Lipídeos , Masculino , Oócitos/fisiologia , Estresse Oxidativo/genética , Idade Paterna , Motilidade dos Espermatozoides/efeitos dos fármacos , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Espermatozoides/metabolismo
4.
Front Neurosci ; 7: 100, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23781169

RESUMO

Neonatal immune challenge by administration of lipopolysaccharide (LPS) produces enduring alterations in the development and activity of neuroendocrine, immune and other physiological systems. We have recently reported that neonatal exposure to an immune challenge by administration of LPS results in altered reproductive development in the female Wistar rat. Specifically, LPS-treated animals exhibited diminished ovarian reserve and altered reproductive lifespan. In the current study, we examined the cellular mechanisms that lead to the previously documented impaired ovulation and reduced follicular pool. Rats were administered intraperitoneally either 0.05 mg/kg of LPS (Salmonella Enteritidis) or an equivalent volume of non-pyrogenic saline on postnatal days (PNDs) 3 and 5, and ovaries were obtained on PND 7. Microarray analysis revealed a significant upregulation in transcript expression (2-fold change; p < 0.05) for a substantial number of genes in the ovaries of LPS-treated animals, implicated in immune cell signaling, inflammatory responses, reproductive system development and disease. Several canonical pathways involved in immune recognition were affected by LPS treatment, such as nuclear factor-κB (NF-κB) activation and LPS-stimulated mitogen-activated protein kinase (MAPK) signaling. Quantitative Real-time PCR analysis supported the microarray results. Protein expression analysis of several components of the MAPK signaling pathway revealed a significant upregulation in the expression of Toll-like receptor 4 (TLR4) in the neonatal ovary of LPS-treated animals. These results indicate that neonatal immune challenge by administration of LPS has a direct effect on the ovary during the sensitive period of follicular formation. Given the pivotal role of inflammatory processes in the regulation of reproductive health, our findings suggest that early life immune activation via TLR signaling may have significant implications for the programming of ovarian development and fertility.

5.
Endocrinology ; 151(6): 2868-75, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20392824

RESUMO

Androgens may be important regulators of Sertoli cell (SC) proliferation perinatally, with implications for the testicular dysgenesis syndrome (TDS) hypothesis. Fetal exposure of rats to 500 mg/kg . d di(n-butyl) phthalate (DBP) reduces fetal testosterone production and SC number at birth, but SC number recovers to normal by postnatal d (Pnd)25. It is unclear when and how SC proliferation is affected prenatally by DBP exposure or when and how postnatal compensation occurs. This study addressed these questions and investigated whether continued maternal exposure to DBP or to flutamide from Pnd1-Pnd15 could prevent SC number compensation, because this would have implications for how sperm counts might be lowered in TDS. DBP exposure attenuated SC proliferation by 7-18% throughout embryonic d (e)15.5-e21.5 (P < 0.05 at e21.5). After birth, SC proliferation increased significantly (>1.5-fold) between Pnd6 and Pnd10 in prenatally DBP-exposed animals, explaining the compensation. Continued maternal administration of DBP after birth attenuated (19% reduction) SC number compensation at Pnd25 and maternal administration of flutamide (100 mg/kg . d) to prenatally DBP-exposed animals was even more effective (42% reduction), suggesting the postnatal compensatory increase in SC proliferation after prenatal DBP exposure is androgen dependent. SC maturation (Pnd25) was unaffected, based on analysis of expression of key proteins, but lumen formation/expansion was attenuated in parallel with treatment-induced reduction in SC number. Our results provide further evidence that perinatal SC proliferation is androgen dependent and, importantly, show that similar exposure of mothers to antiandrogenic chemicals before birth and during lactation reduces final SC number, with implications for the origin of low sperm counts in TDS.


Assuntos
Dibutilftalato/farmacologia , Flutamida/farmacologia , Células de Sertoli/citologia , Células de Sertoli/efeitos dos fármacos , Animais , Feminino , Feto/efeitos dos fármacos , Feto/fisiologia , Imuno-Histoquímica , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Fatores de Transcrição SOX9/metabolismo , Células de Sertoli/metabolismo , Testículo/citologia , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testículo/fisiologia
6.
Endocrinology ; 149(10): 5280-7, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18566125

RESUMO

Fetal androgen action is an important determinant of Sertoli cell (SC) number at birth. Androgens "program" reproductive tract development in rats between embryonic d (e) 15.5 and e17.5 ("male programming window"), and this is reflected for life by anogenital distance (AGD). We investigated if androgen regulation of SC number/proliferation was also programmed by androgens in this window. Pregnant rats were treated in various fetal time windows with vehicle (control) or 500 mg/kg.d di(n-butyl) phthalate (DBP), which suppresses fetal intratesticular testosterone (ITT). ITT and SC number/proliferation index were determined at e17.5 or e21.5; AGD was also determined at e21.5. In controls, SC number increased 11-fold and ITT by 10-fold from e17.5-e21.5. In animals exposed daily to DBP from e13.5, SC number was reduced by approximately 50% at e21.5, but increased 6-fold, as did ITT, from e17.5-e21.5; DBP had no effect on ITT at e15.5, reduced ITT by 50% at e17.5, and by more than 75% at e19.5-21.5. DBP exposure just in the male programming window did not alter SC number at e17.5 or 21.5 but reduced AGD. DBP treatment beyond e19.5 caused major reductions in SC number/proliferation index and ITT at e21.5. Only DBP treatments that included the male programming window led to reduced AGD at e21.5, but SC number was clearly not programmed in this window. Nevertheless, testis weight correlated highly (P<0.001) with AGD at e21.5, and postnatal d 25 and 90 in animals exposed in utero to vehicle or DBP (e13.5-e21.5). Thus, AGD may predict adult testis size but probably not through a direct relationship with SC number.


Assuntos
Androgênios/metabolismo , Células de Sertoli/citologia , Testículo/citologia , Testículo/embriologia , Testosterona/metabolismo , Fatores Etários , Animais , Contagem de Células , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Dibutilftalato/farmacologia , Feminino , Imuno-Histoquímica , Masculino , Tamanho do Órgão , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Ratos , Ratos Wistar , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Maturidade Sexual/fisiologia , Testículo/metabolismo
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