RESUMO
The present study aimed to analyze the effect of multigenerational exposure to Mn at realistic doses on the functional quality of the male reproductive system of mice. Females and males (generation F0) were treated for 60 days with MnCl2, via gavage, at the doses of 0, 0.013, 0.13, and 1.3â¯mg/kg/day. Treatment of F0 dams continued throughout gestation and lactation periods. At the time of weaning, the offspring (F1 generation) was divided into: animals that were not exposed after weaning - parental exposure (PE); and those exposed via parental generation and directly (PDE) for additional 60 days, at the same dose of F0 generation. F0 and F1 males were euthanized for assessment of sperm parameters and redox changes in the reproductive system. There was a decrease in the sperm concentration of the F0 generation. In addition, the sperm parameters of F1 generation were drastically affected. The activity of antioxidant enzymes was significantly reduced in PE animals. It was possible to verify that the biochemical damages were higher in the PE individuals, as demonstrated by the integrated biomarker response index. Our results show that Mn, even at low doses, is able to promote a reduction in sperm quality over a generation.
Assuntos
Poluentes Ambientais/toxicidade , Genitália Masculina/efeitos dos fármacos , Manganês/toxicidade , Reprodução/efeitos dos fármacos , Animais , Biomarcadores/metabolismo , Catalase/metabolismo , Feminino , Glutationa Transferase/metabolismo , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Espermatozoides/fisiologia , Superóxido Dismutase/metabolismoRESUMO
We examined the anogenital distance (AGD) plasticity in rats through the manipulation of the androgen environment in utero and during puberty. Dams were treated from gestation days 13-20 with vehicle, flutamide (20mg/kg/day), di-(2-ethylhexyl) phthalate (DEHP, 750mg/kg/day), or testosterone (1.0mg/kg/day). After weaning, male pups were randomly assigned to one of four postnatal groups, which received the same treatments given prenatally. Sixteen treatment groups were established based on the combination of pre- and postnatal exposures. The postnatal treatments were conducted from postnatal days 23-53. In utero flutamide and DEHP exposure significantly shortened male AGD, although this effect was more pronounced in flutamide-exposed rats. Postnatal flutamide, DEHP, and testosterone induced slight but significant reductions in male AGD. Our study indicates that AGD is a stable anatomical landmark that reflects the androgen action in utero, although it can also be slightly responsive to changes in the androgen environment following pubertal exposure.
Assuntos
Antagonistas de Androgênios/toxicidade , Androgênios/fisiologia , Pênis/anormalidades , Efeitos Tardios da Exposição Pré-Natal , Testículo/anormalidades , Animais , Dietilexilftalato/toxicidade , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Flutamida/toxicidade , Masculino , Tamanho do Órgão/efeitos dos fármacos , Pênis/efeitos dos fármacos , Gravidez , Resultado da Gravidez , Ratos , Espermátides/efeitos dos fármacos , Espermátides/metabolismo , Testículo/efeitos dos fármacos , Testosterona/biossínteseRESUMO
This study evaluated the reproductive effects of fluoxetine exposure in utero and during lactation on pregnancy outcomes and the sexual development of offspring. Pregnant Wistar rats were treated daily with fluoxetine (0.4, 1.7 and 17 mg/kg/day) or distilled water by gavage from gestation day (GD) 7 to lactation day (LD) 21. A significant reduction in maternal body weight was observed during pregnancy and lactation in dams exposed to 17 mg/kg fluoxetine. Hormone analysis revealed an increase in progestagen and glucocorticoid metabolites on GD 15 and oestrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Oestrogen metabolites also were increased on LD 7 in dams treated with 0.4 mg/kg fluoxetine. Besides that, an increase in the weight of the adrenal glands and a reduction in uterine weight in dams exposed to highest dose of fluoxetine were observed. Finally, pup birthweight and the viability and weaning indices also were reduced in animals exposed to 17 mg/kg fluoxetine. Overall, maternal hormonal changes were only observed at the highest dose tested, which also induced maternal and foetal toxicity. No significant changes were seen in dams or offspring exposed to therapeutic-like doses.
Assuntos
Fluoxetina/administração & dosagem , Lactação , Resultado da Gravidez/veterinária , Desenvolvimento Sexual/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Peso Corporal , Relação Dose-Resposta a Droga , Estrogênios/metabolismo , Feminino , Fluoxetina/efeitos adversos , Masculino , Exposição Materna/efeitos adversos , Gravidez , Progestinas/metabolismo , Ratos , Ratos Wistar , Reprodução/efeitos dos fármacosRESUMO
Recent years have seen an increase in the use of antidepressant drugs, especially fluoxetine (FLX), in sensitive populations, such as pregnant and lactating women. Although some evidence suggests a possible endocrine action of FLX, no specific studies have been performed to investigate this hypothesis. In the present study, we investigated the possible (anti)androgenic and (anti)estrogenic actions of FLX using Hershberger, uterotrophic (0.4, 1.7, and 17mg/kg), and reporter gene (7.6-129µM) assays. In the Hershberger assay, no differences were observed in androgen-dependent organ weights. However, the uterotrophic and gene reporter assays indicated a possible estrogenic action of FLX. Uterine weight increased in the 1.7 and 17mg/kg/day groups in the 3-day uterotrophic assay in immature rats. Additionally, noncytotoxic concentrations of FLX induced estrogenic responses and increased the estrogenic response of estradiol in MCF-7 breast cancer cells transfected with luciferase.
Assuntos
Antidepressivos de Segunda Geração/toxicidade , Estrogênios não Esteroides/toxicidade , Fluoxetina/toxicidade , Receptores de Estrogênio/metabolismo , Útero/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Feminino , Genitália Masculina/anatomia & histologia , Genitália Masculina/efeitos dos fármacos , Humanos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Útero/patologiaRESUMO
AIM OF THE STUDY: Investigate the possible effects of Tribulus terrestris (TT) on endocrine sensitive organs in intact and castrated male rats as well as in a post-menopausal rat model using ovariectomized females. MATERIALS AND METHODS: Three different dose levels of TT (11, 42 and 110 mg/kg/day) were administered to castrated males for 7 days and to intact males and castrated females for 28 days. In addition to TT treatment, all experiments also included a group of rats treated with dehydroepiandrosterone (DHEA). In experiments using castrated males and females we also used testosterone and 17 alpha-ethynylestradiol, respectively, as positive controls for androgenicity and estrogenicity. RESULTS: Neither DHEA nor TT was able to stimulate androgen sensitive tissues like the prostate and seminal vesicle in both intact and castrated male rats. In addition, administration of TT to intact male rats for 28 days did not change serum testosterone levels as well as did not produce any quantitative change in the fecal excretion of androgenic metabolites. However, a slight increase in the number of homogenization-resistant spermatids was observed in rats treated with 11 mg/kg/day of TT extract. In ovariectomized females, TT did not produce any stimulatory effects in uterine and vaginal epithelia. CONCLUSIONS: Tribulus terrestris was not able to stimulate endocrine sensitive tissues such as the prostate, seminal vesicle, uterus and vagina in Wistar rats, indicating lack of androgenic and estrogenic activity in vivo. We also showed a positive effect of TT administration on rat sperm production, associated with unchanged levels of circulating androgens.
Assuntos
Androgênios/farmacologia , Extratos Vegetais/farmacologia , Espermátides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Tribulus/química , Androgênios/administração & dosagem , Androgênios/metabolismo , Animais , Castração , Contagem de Células , Relação Dose-Resposta a Droga , Epitélio/efeitos dos fármacos , Fezes/química , Feminino , Masculino , Medicina Tradicional , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Fitoterapia , Extratos Vegetais/administração & dosagem , Próstata/efeitos dos fármacos , Próstata/patologia , Ratos , Ratos Wistar , Glândulas Seminais/efeitos dos fármacos , Glândulas Seminais/patologia , Testículo/patologia , Testosterona/sangue , Testosterona/metabolismo , Útero/efeitos dos fármacos , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/patologiaRESUMO
This study was carried out to assess the influence of di(2-ethylhexyl)phthalate (DEHP) alone or associated with antioxidants on the male reproductive system in newborn rats, emphasizing the implications of oxidative stress and hormonal balance during prenatal and early postnatal periods. Wistar females were exposed by oral route to DEHP alone or associated with antioxidants from gestational day 7 to lactational day 2 according to the following treatment regimens: (C) vehicle control (canola oil + 1% Tween-80); (V) vitamin C (200 mg/kg) + canola oil; (R) resveratrol (10 mg/kg) + canola oil; (D) DEHP (500 mg/kg) + 1% Tween-80; (DV) DEHP (500 mg/kg) + vitamin C (200 mg/kg); and (DR) DEHP (500 mg/kg) + resveratrol (10 mg/kg). Two male pups per litter were randomly selected and necropsied on postnatal day 2. The brain and liver were removed and weighed and anogenital distance (AGD) was measured. Additionally, the testes were removed for assessment of intratesticular testosterone levels and histopathology; the liver was used to measure biomarkers of oxidative stress. Vitamin C and resveratrol alone did not affect the reproductive end points and did not induce oxidative stress. Exposure of dams to DEHP alone and associated with antioxidants resulted in hepatomegaly in offspring and significantly increased the incidence of multinucleated gonocytes in seminiferous cords. Testosterone and AGD presented a trend to decrease in DEHP-exposed groups. Catalase activity increased only in groups exposed to DEHP associated with antioxidants, although GST (gluthatione-S-transferase) activity decreased in all DEHP-exposed groups. The levels of hydroperoxides increased only in group exposed to DEHP associated with vitamin C. These results indicate that the association of DEHP with antioxidants was unable to ameliorate DEHP-induced reproductive changes, and the coadministration of DEHP and these antioxidants might even contribute to an overall increase in oxidative stress.
Assuntos
Antioxidantes/uso terapêutico , Ácido Ascórbico/uso terapêutico , Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Reprodução/efeitos dos fármacos , Estilbenos/uso terapêutico , Animais , Animais Recém-Nascidos , Antioxidantes/administração & dosagem , Ácido Ascórbico/administração & dosagem , Catalase/metabolismo , Relação Dose-Resposta a Droga , Feminino , Idade Gestacional , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/crescimento & desenvolvimento , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Wistar , Resveratrol , Estilbenos/administração & dosagem , Testículo/efeitos dos fármacos , Testículo/crescimento & desenvolvimento , Testículo/patologiaRESUMO
Phthalates are chemicals employed in several industrial products and there is a growing body of evidence demonstrating that they induce numerous adverse effects on the reproductive system. This study was carried out to assess possible alterations induced by the plasticizer di(2-ethylhexyl phthalate (DEHP) on cholesterol, testosterone, and thyroxine (total T4) levels, as well as to discuss the significance of these data in global changes observed in the reproductive tract of pubertal animals. Wistar rats aged 21 days received DEHP orally at 0, 250, 500, and 750 mg/kg/day for 30 days and were examined for different reproductive endpoints. At the end of the treatment, significant decreases in relative weight of testosterone-dependent organs, delayed preputial separation, and low serum testosterone were observed at the highest DEHP dose. The plot of the relationship between DEHP dose and serum cholesterol revealed a biphasic effect. The concentration of cholesterol in serum was significantly reduced at 250 mg/kg/day DEHP but returned to control values at 750 mg/kg/day. Cholesterol levels measured in testicular tissue increased with DEHP treatment. Serum T4 levels were not affected by DEHP at any dose, indicating the absence of a link between total thyroxin concentration and phthalate effects on cholesterol levels. Taken together these results indicate that effects observed in serum and testicular cholesterol levels may reflect distinct effects of DEHP on cholesterol synthesis and usage. These results confirm and extend previously reported findings showing that alterations in cholesterol balance may play a role in the suppression of steroidogenesis induced by DEHP in rats.
Assuntos
Colesterol/sangue , Colesterol/metabolismo , Dietilexilftalato/toxicidade , Poluentes Ambientais/toxicidade , Reprodução/efeitos dos fármacos , Testosterona/sangue , Tiroxina/sangue , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Masculino , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Wistar , Maturidade Sexual/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testículo/metabolismo , Testosterona/metabolismoRESUMO
The reproductive effects of the coadministration of di-2-(ethylhexyl) phthalate (DEHP) and di-butyl phthalate (DBP) were studied in both foetal and adult male rat offspring exposed in utero. Pregnant Wistar rats were treated by oral gavage from gestation day 13 to 21 with vehicle control, 150 mg DEHP/kg body weight (bw)/day, 100 mg DBP/kg bw/ or a combination of the two compounds (DEHP 150 + DBP 100 mg/kg bw/day). An additional group of dams received 500 mg DBP/kg bw/day. A significant decrease in foetal testicular testosterone levels was observed in animals exposed to 500 mg DBP/kg/day or the phthalate mixture. Similarly, histological analysis of the foetal testis revealed that the coadministration of DEHP and DBP was able to increase the diameter of seminiferous cords and induce gonocyte multinucleation at doses that individually had no significant effects on these variables. However, in the phthalate mixture group, no significant changes were observed in anogenital distance and nipple retention, variables that are used to indicate possible anti-androgenic effects. Also, the adult endpoints investigated, that included reproductive organ weights and the number of spermatids per testis, were unaffected by any treatment regimen. Overall, coadministration of DEHP and DBP in utero significantly reduced testicular testosterone levels and resulted in misshapen seminiferous cords and gonocyte multinucleation in rat foetal testis. Our results also confirm that these foetal endpoints seem to be the most sensitive markers of prenatal phthalate exposure.