RESUMO
Tamoxifen, a selective non-steroidal estrogen receptor modulator, is the standard adjuvant endocrine treatment for breast cancer. Since information on the risk of using tamoxifen during pregnancy is still scarce, this study evaluated whether the in utero and lactational treatment with this drug could compromise reproductive and behavioural parameters in male offspring. Pregnant Wistar rats were exposed to three doses of tamoxifen (0.12; 0.6; 3 µg/kg), by gavage, from gestational day 15 to lactational day 20. Tamoxifen exposure did not alter the anogenital distance in the male offspring; however, there was a significant increase in the body weight in the 0.12 µg/kg dose and a decrease in the 0.6 µg/kg dose. The male offspring treated with the highest dose exhibited a delay in the onset of puberty, evidenced by an increase in the age of preputial separation. Regarding sperm parameters, there was an increase in the sperm count in the cauda epididymis in the intermediate and highest dose groups, in addition to an increase in the number of static sperm and a decrease in the progressive sperm in the same groups. Moreover, an increase in the number of hyperplasia of the epithelial clear cells was observed in the epididymis. In conclusion, the present study demonstrated that maternal exposure to tamoxifen compromised the installation of puberty of the male offspring and the maturation of the epididymis, affecting sperm storage and motility in the adult life.
Assuntos
Comportamento Animal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Moduladores Seletivos de Receptor Estrogênico/toxicidade , Espermatozoides/efeitos dos fármacos , Tamoxifeno/toxicidade , Animais , Epididimo/efeitos dos fármacos , Epididimo/crescimento & desenvolvimento , Feminino , Hipotálamo/citologia , Lactação , Masculino , Troca Materno-Fetal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Gravidez , Ratos Wistar , Receptores Androgênicos/metabolismo , Maturidade Sexual/efeitos dos fármacos , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologiaRESUMO
Selective estrogen receptor modulators (SERMs) are a class of therapeutic chemicals which present tissue-specific estrogen receptor modulating activity. Neonatal exposure to SERMs has been reported to adversely affect central nervous system development, however, mechanism and involvement of hypothalamic kisspeptin neurone in this impairment remains undetermined. To clarify this uncertainty, neonates from female Donryu rats were subcutaneously injected with raloxifene (RLX) at 0.1, 1, and 10mg/kg or tamoxifen (TMX) at 10mg/kg on postnatal day 0, and then hypothalamic KiSS1 mRNA expression and gonadotropin levels were investigated during young adulthood and estrous cycling was monitored until middle age. Treatment with RLX or TMX at 10mg/kg significantly depressed luteinizing hormone surge levels and KiSS1 mRNA expression in the anteroventral periventricular nucleus (AVPV), the control center of estrous cyclicity. The 10mg/kg TMX group also showed decreased levels of follicle-stimulating hormone and KiSS1 mRNA expression in the arcuate nucleus (ARC). Early cessation of normal estrous cycling was observed in the 10mg/kg RLX group, while the estrous cycle in the 10mg/kg TMX group had ceased by the start of the analysis. The same dose of tamoxifen or raloxifene had either weak-estrogenic or anti-estrogenic activity on the uterus, respectively; however, treatment in adulthood with both SERMs did not affect KiSS1 mRNA expression in either the AVPV or ARC in the present study. These results indicate that neonatal exposure to SERMs could disrupt neuroendocrine development and postnatal reproductive function through the alteration of kisspeptin neurons.
Assuntos
Deficiências do Desenvolvimento/induzido quimicamente , Doenças do Sistema Endócrino/induzido quimicamente , Hipotálamo/patologia , Kisspeptinas/metabolismo , Neurônios/metabolismo , Moduladores Seletivos de Receptor Estrogênico/toxicidade , Fatores Etários , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Deficiências do Desenvolvimento/patologia , Modelos Animais de Doenças , Doenças do Sistema Endócrino/patologia , Estradiol/análogos & derivados , Estradiol/farmacologia , Ciclo Estral/efeitos dos fármacos , Feminino , Hormônios/metabolismo , Hipotálamo/efeitos dos fármacos , Kisspeptinas/genética , Neurônios/efeitos dos fármacos , Ovariectomia , Gravidez , Progesterona/farmacologia , Cloridrato de Raloxifeno/farmacologia , Ratos , Tamoxifeno/farmacologiaRESUMO
Genistein derivatives were synthesized from genistein through a facile sonochemical approach in high yields. The bioassay was performed on ovariectomized (OVX) rats in terms of bone mineral density (BMD) and the weight of bone ash (WBA) to lead to the discovery of eight novel genistein-based selective estrogen receptor modulators. Attention to the structure-activity relationship disclosed that the newly introduced 2-hydroxyethylthio scaffolds were essential for the anti-osteoporotic activity. Moreover, the anti-osteoporotic action of genistein, deprivable by methylation, could be restored and enhanced by subsequent sulfonation. The most promising compound was 4',5,7-tri[3-(2-hydroxyethylthio)propoxy]isoflavone, displaying 24% (or 8%) increment in BMD and 31% (or 11%) increase in WBA of the femora relative to those discerned with the OVX (or genistein) group. Acute toxicity test showed that none of the active compounds was acutely toxic.