Connexin 43 gene expression in male and female gonads of porcine offspring following in utero exposure to an anti-androgen, flutamide

Durlej, Małgorzata; Kopera, Ilona; Knapczyk-Stwora, Katarzyna; Hejmej, Anna; Duda, Małgorzata; Koziorowski, Marek; Słomczyńska, Maria; Bilińska, Barbara

doi:10.1016/j.acthis.2009.07.001

Cited by 39 publications

(36 citation statements)

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“…The administration of flutamide to pregnant rhesus monkeys induced androgen deficiency during the critical gestation window. Our previous studies on flutamide-treated pigs revealed that prenatal and neonatal changes in androgen actions resulted in altered expression of androgen-dependent genes in adulthood (Durlej et al 2011b(Durlej et al , 2012. To date most studies concerning the involvement of androgens in the process of fetal gonadal development were focused on examination of postnatal life.…”

Section: Discussionmentioning

confidence: 99%

“…Flutamide, a non-steroid antiandrogen, binds to and blocks androgen receptors (ARs) (Tevell et al 2006). As we showed previously flutamide applied in utero on critical days of gestation alters expression of androgendependent genes during postnatal life (Durlej et al 2011a(Durlej et al , 2011b. In light of our previously published results, which demonstrated the presence of AR in the fetal porcine ovaries (Burek et al 2007), we hypothesized that limited access to androgens may have an impact on the expression of some intraovarian factors responsible for fetal folliculogenesis.…”

Section: Introductionmentioning

confidence: 93%

“…The flutamide dose was based on the literature data (Williams et al 2001, Foster & Harris 2005 and results of our previous studies (Durlej et al 2011a(Durlej et al , 2011b; however time of antiandrogen administration was extended and frequency was increased. For each flutamide-exposed group a respective control group was used (nZ2 per each gestation period) and control animals were treated with corn oil in a manner similar to the flutamide-treated pigs.…”

Section: Experiments Design and Tissue Collectionmentioning

confidence: 99%

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Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

Knapczyk-Stwora

Grzesiak²,

Ciereszko³

et al. 2013

Reproduction

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Androgen deficiency during prenatal development may affect the expression of genes involved in the folliculogenesis regulation. In order to study the effect of antiandrogen on fetal ovarian development, pregnant gilts were injected with flutamide (for 7 days, 50 mg/kg body weight per day) or corn oil (control groups) starting on gestation days 43 (GD50), 83 (GD90), or 101 (GD108). The obtained fetal ovaries were fixed for histology and immunohistochemistry or frozen for real-time PCR. Morphological evaluation, TUNEL assay, and expression of selected factors (Ki-67, GATA binding transcription factor 4 (GATA4), E-Cadherin and tumor necrosis factor a (TNFa)) were performed. On GD90 and GD108, ovaries following flutamide administration showed a higher number of egg nests and lower number of follicles than those in respective control groups. An increased mRNA and protein expression of Ki-67 was observed in flutamide-treated groups compared with controls on GD50 and GD108 but decreased expression was found on GD90. In comparison to control groups a higher percentage of TUNEL-positive cells was shown after flutamide exposure on GD50 and GD90 and a lower percentage of apoptotic cells was observed on GD108. These data were consistent with changes in TNF (TNFa) mRNA expression, which increased on GD90 and decreased on GD108. E-cadherin mRNA and protein expression was upregulated on GD50 and downregulated on GD90 and GD108. In conclusion diminished androgen action in porcine fetal ovaries during mid-and late gestation leads to changes in the expression of genes crucial for follicle formation. Consequently, delayed folliculogenesis was observed on GD90 and GD108. It seems however that androgens exhibit diverse biological effects depending on the gestational period.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Experiments Design and Tissue Collectionmentioning

confidence: 99%

See 1 more Smart Citation

Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

Knapczyk-Stwora

Grzesiak²,

Ciereszko³

et al. 2013

Reproduction

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“…Flutamide was suspended in corn oil and delivered as subcutaneous injections daily for seven days at a dose of 50 mg/kg body weight. The flutamide dose was based on the results of our previous studies [19,20], however, the time of antiandrogen administration was extended and frequency was increased. For each flutamide-exposed group, a respective control group was used (n = 2, per each gestation period).…”

Section: Methodsmentioning

confidence: 99%

TGFβ (transforming growth factor β) superfamily members and their receptors in the fetal porcine ovaries: effect of prenatal flutamide treatment

Knapczyk-Stwora

Grzesiak

Duda

et al. 2015

Folia Histochem Cytobiol.

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Introduction. We have recently demonstrated that antiandrogen treatment during fetal life resulted in delayed folliculogenesis. The aim of the present study was to investigate the effect of androgen deficiency induced by flutamide on the expression of TGFb superfamily members and their receptors which are involved in follicle formation and its transition to the primary stage. Material and methods. Pregnant gilts were injected with flutamide (for seven days, 50 mg/day/kg b.w.) or corn oil (controls) starting at 43 (GD50), 83 (GD90) or 101 (GD108) gestational day. The expression in fetal ovaries of selected TGFb superfamily members (AMH, BMP4, GDF9), their receptors (AMHR-II, BMPR-IB, BMPR-II), and Smad1 and Smad3 proteins involved in signal transduction were investigated by real-time PCR and/or immunohistochemistry. Results. Flutamide treatment increased the expression of BMP4 mRNA on GD50 and GD108 and BMPR-IB mRNA on GD50. The expression of BMPR-II was decreased at mRNA level and lower immunostaining intensity was observed after flutamide administration only on GD50. GDF9 and AMHR-II mRNA expression levels were significantly downregulated in both GD90 and GD108 groups. However, AMHR-II was immunolocalized only on GD108 and less positively stained oocytes were found after flutamide treatment. AMH mRNA level was diminished in the GD90 group, while it was elevated in the GD108 group. Moreover, the higher amounts of positively stained oocytes for phosphorylated form of Smad1 were observed following flutamide administration on GD108. Conclusions. Experimentally-induced androgen deficiency during fetal development deregulates the expression level of some of TGFb superfamily members and their receptors which may affect primordial follicle assembly. Our findings further underline the role of androgens in the early stages of follicle development.

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“…The cryptorchid testes were located inguinally, and all of the rats with cryptorchidism had associated hypospadias [Ma et al 2011]. Several studies have addressed how in utero Flu-exposure could influence the development of male reproduction and spermatogenesis [Bozec et al 2004;Durlej et al 2011;Wilson et al 2008].…”

Section: Introductionmentioning

confidence: 99%

Connexin 43 expression in Sprague-Dawley rat seminiferous epithelium afterin uteroexposure to flutamide

Cai

Zhao

et al. 2014

Systems Biology in Reproductive Medicine

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This study explored the expression of connexin 43 (Cx43) in the testes of prepubertal SpragueDawley (SD) rats following in utero flutamide (Flu) exposure. Connexins constitute the major protein type in gap junctions. Connexin 43, the most prominent connexin family member expressed by testes, is localized at the base of seminiferous tubules in humans and rodents, and may be involved in fertility. Flutamide was injected subcutaneously into pregnant SD rats on gestational days 12-21 (25 mg/kg/day). Immunohistochemistry, Western blotting, and real-time PCR was used to investigate the distribution and the expression of Cx43 protein and mRNA in the testis on postnatal day 20 (PD20). Following Flu-exposure, Cx43 was observed between Sertoli cells in the seminiferous tubules. On PD20, no Cx43 protein was expressed by the spermatogonial cell layer of the seminiferous tubules in the controls, but was observed in the Flu-exposed group. Western blotting showed that Cx43 was expressed at significantly lower levels in Flu-exposed testes than controls on PD20 (p50.001). On PD20, levels of Cx43 mRNA in undescended Flu-exposed testes were significantly lower than in controls (p50.05) and descended Flu-exposed testes (p50.01). After Flu-exposure in the rat embryonic period, Cx43 mRNA and protein expression were downregulated, and its distribution in the seminiferous tubules was abnormal.

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Connexin 43 gene expression in male and female gonads of porcine offspring following in utero exposure to an anti-androgen, flutamide

Cited by 39 publications

References 58 publications

Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

Antiandrogen flutamide affects folliculogenesis during fetal development in pigs

TGFβ (transforming growth factor β) superfamily members and their receptors in the fetal porcine ovaries: effect of prenatal flutamide treatment

Connexin 43 expression in Sprague-Dawley rat seminiferous epithelium afterin uteroexposure to flutamide

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