RESUMEN
The increasing incidence of reproductive anomalies, described as testicular dysgenesis syndrome, is thought to be related to the exposure of the population to chemicals in the environment. Bisphenol A (BPA) and di(2-ethylhexyl)phthalate (DEHP), which have hormonal and antihormonal activity, have attracted public attention due to their presence in consumer products. The present study investigated the effects of BPA and DEHP on reproductive development. Timed-pregnant female rats were exposed to BPA and DEHP by gavage from gestational days 12 to 21. Results showed that prenatal exposures to test chemicals exerted variable effects on steroidogenic factor 1 and GATA binding protein 4 protein expression and increased (P < .05) sex-determining region Y-box 9 and antimüllerian hormone protein in the infantile rat testis compared with levels in the control unexposed animals. Pituitary LHß and FSHß subunit protein expression was increased (P < .05) in BPA- and DEHP-exposed prepubertal male rats but were decreased (P < .05) in adult animals relative to control. Exposure to both BPA and DEHP in utero inhibited (P < .05) global DNA hydroxymethylation in the adult testis in association with altered DNA methyltransferase protein expression. Together the present data suggest that altered developmental programming in the testes associated with chemical exposures are related to the disruption of sexual differentiation events and DNA methylation patterns. The chemical-induced effects impact the development of steroidogenic capacity in the adult testis.
Asunto(s)
Compuestos de Bencidrilo/farmacología , Dietilhexil Ftalato/farmacología , Contaminantes Ambientales/farmacología , Estrógenos no Esteroides/farmacología , Fenoles/farmacología , Plastificantes/farmacología , Diferenciación Sexual/efectos de los fármacos , Testículo/efectos de los fármacos , Animales , Hormona Antimülleriana/metabolismo , Metilación de ADN/efectos de los fármacos , Metilasas de Modificación del ADN/efectos de los fármacos , Metilasas de Modificación del ADN/metabolismo , Disruptores Endocrinos/farmacología , Femenino , Hormona Folículo Estimulante de Subunidad beta/efectos de los fármacos , Hormona Folículo Estimulante de Subunidad beta/metabolismo , Factor de Transcripción GATA4/efectos de los fármacos , Factor de Transcripción GATA4/metabolismo , Disgenesia Gonadal , Hormona Luteinizante de Subunidad beta/efectos de los fármacos , Hormona Luteinizante de Subunidad beta/metabolismo , Masculino , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Proteína de la Región Y Determinante del Sexo/efectos de los fármacos , Proteína de la Región Y Determinante del Sexo/metabolismo , Factor Esteroidogénico 1/efectos de los fármacos , Factor Esteroidogénico 1/metabolismo , Enfermedades Testiculares , Testículo/metabolismoRESUMEN
Ferredoxin 1 (FDX1; adrenodoxin) is an iron-sulfur protein that is involved in various metabolic processes, including steroid hormone synthesis in mammalian tissues. We investigated the transcriptional regulation of FDX1 in ovarian granulosa cells. Previously, we reported that the NR5A family, including steroidogenic factor-1 (SF-1) and liver receptor homolog-1 could induce differentiation of human mesenchymal stem cells (hMSCs) into steroidogenic cells. A ChIP assay showed that SF-1 could bind to the FDX1 promoter in differentiated hMSCs. Luciferase reporter assays showed that transcription of FDX1 was synergistically activated by the NR5A family and 8Br-cAMP treatment through two SF-1 binding sites and a CRE-like sequence in a human ovarian granulosa cell line, KGN. Knockdown of FDX1 attenuated progesterone production in KGN cells. These results indicate transcription of FDX1 is regulated by the NR5A family and cAMP signaling, and participates in steroid hormone production in ovarian granulosa cells.
Asunto(s)
Ferredoxinas/genética , Células de la Granulosa/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Factor Esteroidogénico 1/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Adrenodoxina/genética , Animales , Diferenciación Celular , Línea Celular Tumoral , AMP Cíclico/metabolismo , Proteínas de Unión al ADN/metabolismo , Femenino , Ferredoxinas/biosíntesis , Regulación de la Expresión Génica , Células HeLa , Humanos , Células Madre Mesenquimatosas/metabolismo , Progesterona/biosíntesis , Regiones Promotoras Genéticas , Unión Proteica , Interferencia de ARN , ARN Interferente Pequeño , Ratas , Ratas Wistar , Transducción de Señal , Factor Esteroidogénico 1/efectos de los fármacos , Transcripción GenéticaRESUMEN
The mechanisms by which TBT produces modulations of the endocrine systems are not fully described. In this study, juvenile salmon were force-fed diet containing TBT (0: solvent control, 0.1, 1 and 10 mg/kg fish) for 72 h. Subsequently, fish exposed to solvent control and 10 mg/kg TBT were exposed to waterborne concentration of the adenyl cyclase stimulator forskolin (200 µg/L) for 2 and 4 h. Tissue and blood were sampled from individual fish (n=6). Gene expression patterns of CYP11ß, steroidogenic factor-1 (SF-1), and glucocorticoid receptor (GlucR) were determined by qPCR. TBT generally decreased mRNA levels of CYP11ß, GlucR and SF-1, compared to the solvent control and these effects were differentially modulated by the presence of forskolin. This study suggests that TBT may exert broader endocrine disrupting effects through possible modulation of cAMP/PKA second messenger systems.
Asunto(s)
Colforsina/farmacología , Salmón/fisiología , Compuestos de Trialquiltina/toxicidad , Contaminantes Químicos del Agua/toxicidad , Animales , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Sistema Enzimático del Citocromo P-450/efectos de los fármacos , Sistema Enzimático del Citocromo P-450/metabolismo , Disruptores Endocrinos/toxicidad , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/metabolismo , Sistemas de Mensajero Secundario , Factor Esteroidogénico 1/efectos de los fármacos , Factor Esteroidogénico 1/metabolismoRESUMEN
Both fibroblast growth factor 2 (FGF2) and luteinizing hormone (LH) have been reported to regulate androgen production in Leydig cells in progenitor Leydig cells. The objective of the present study is to examine the regulation of androgen production in rat immature Leydig cells (ILCs). ILCs were isolated from 35-day-old rat testes and cultured in DMEM/F12 medium with LH (1 ng/ml) or FGF2 (10 ng/ml). 5alpha-Androstane-3alpha, 17beta-diol (3alpha-DIOL), the primary androgen in ILCs, and testosterone (T) were measured by Radioimmuno assay. The results showed the LH stimulated androgen production in ILCs, and FGF2 did not. However, FGF2 decreased the LH-stimulated androgen production. Real-time PCR and enzyme assay showed that FGF2 decreased levels of several steroidogenic enzymes, inhibited the expressions of steroidogenic acute regulatory (StAR) protein and steroidogenic factor 1 (Nr5a1) in LH-stimulated ILCs. FGF2-mediated inhibition of Nr5a1gene expression may be the mechanism through which FGF2 inhibits LH-stimulated androgen production.