[show abstract][hide abstract] ABSTRACT: The present 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 estrogen and progestagen metabolites on LD 7 in dams treated with 17 mg/kg fluoxetine. Estrogen 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 was observed. Finally, pup birth weight 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.
[show abstract][hide abstract] ABSTRACT: Artemisinins combination therapy (ACT) is the first choice therapy for falciparum malaria. Data on the safety of ACTs in pregnancy are limited and controversial and the use is not recommended on the first trimester. To evaluate the effects of isolated and combined artesunate (AS)/mefloquine (MQ) on embryo rats, pregnant rats were treated orally with AS (15 and 40 mg/kg body weight (bwt)/day), MQ (30 and 80 mg/kg bwt/day) and AS/MQ (15/30 and 40/80 mg/kg bwt/day) on days 9-11 post coitum (pc). The dams were euthanized on day 12 pc and gestational and embryos histological parameters were evaluated. Embryolethality and histopathological anomalies were significant when AS was given alone or combined with MQ. Combination of AS and MQ did not enhance their toxicity compared to their separate administrations; on the other side, there was a reduction in the toxic effects of the AS when combined with MQ. Isolated MQ did not induce developmental toxicity.
Human & Experimental Toxicology 02/2013; · 1.31 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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 17 mg/kg), and reporter gene (7.6–129 μM) 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 17 mg/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.
[show abstract][hide abstract] ABSTRACT: Antimalarial drug combinations containing artemisinins (ACTs) have become first choice therapies for P. falciparum malaria. Data on safety of ACTs in pregnancy are limited and no previous study has been conducted on the developmental toxicity of artesunate-mefloquine combinations on the first trimester of gestation. To evaluate the developmental toxicity of an artesunate/mefloquine combination, pregnant rats were treated orally with artesunate (15 and 40mg/kg bwt/day), mefloquine (30 and 80mg/kg bwt/day) and artesunate/mefloquine (15/30 and 40/80mg/kg bwt/day) on gestation days 9-11. Dams were C-sectioned on day 20, and their uteri and fetuses removed and examined for soft tissue and skeleton abnormalities. Artesunate increased embryolethality and the incidence of limb long bone malformations on the absence of overt maternal toxicity. Mefloquine (80mg/kg bwt/day) was maternally toxic and enhanced fetal variations. Combination of artesunate and mefloquine did not enhance their toxicity compared to the toxicity observed after its separate administration. Embryotoxicity of artesunate was apparently attenuated when it is co-administered with mefloquine.
[show abstract][hide abstract] ABSTRACT: The use of medicinal plants for the treatment of diseases usually comes from the belief that they present low toxicity due their natural origin. However, it is necessary a toxicological and pharmacological evaluation for these plants. Tropaeolum majus is a medicinal plant used in popular medicine to treat several diseases, including cardiovascular disorders, urinary tract infections and asthma. Even though several studies proved its therapeutic effects, there are few toxicological studies with this species.
The present study was carried out to evaluate the subchronic toxicity of the hydroethanolic extract obtained from leaves of T. majus (HETM) in Wistar rats.
Male and female Wistar rats received three doses of HETM (75, 375 and 750 mg/kg) for 28 days. After the treatments biochemical, hematological and histopathological parameters were analyzed.
No significant alterations in the animal's body weight gain, relative organs weight, serum biochemical analysis, hematological or histopathological analyses of liver, kidneys and spleen were observed.
These results demonstrate the absence of subchronic toxicity due to oral treatment with HETM for 28 days in Wistar rats. However, other toxicological studies are necessary to evaluate the total safety of this plant.
Journal of ethnopharmacology 05/2012; 142(2):481-7. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
[show abstract][hide abstract] ABSTRACT: Tropaeolum majus L. (Tropaeolaceae) is a medicinal herb popularly used in Brazil for treatment of inflammatory and cardiovascular diseases. Despite some published data on its efficacy, there are still few toxicological data describing the safety of this plant. The aim of this study was to evaluate the (anti)estrogenic and (anti)androgenic activity of the hydroethanolic extract obtained from Tropaeolum majus L. (HETM), as well as its possible effects on uterine contractility.
Three experimental protocols were performed, (a) uterotrophic assay, (b) Hershberger assay and (c) an ex vivo test to investigate the effects of maternal administration of HETM on uterine contractility at the end of pregnancy. In all protocols three doses of the HETM were administered to Wistar rats: 3, 30 and 300mg/kg.
In vivo tests for detection of (anti)androgenic and (anti)estrogenic activities did not show any significant alterations. Similarly, no alterations were observed on uterine contractility induced by oxytocin and arachidonic acid.
HETM was unable to produce (anti)estrogenic or (anti)androgenic activities in the short-term in vivo screening assays performed. In addition, there was no evidence that HETM can affect uterine contractility following gestational exposure of rats.
Journal of ethnopharmacology 03/2012; 141(1):418-23. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: Snake venoms present different action mechanisms because of their complex composition, represented mainly by toxins and enzymes. This work aimed to investigate the effects of the Crotalus durissus terrificus(Cdt) venom in the liver. Wistar rats were inoculated intraperitoneally with saline (control) or Cdt venom. After 3, 4, or 6 h, the following parameters were analyzed: (a) hepatic function, (b) oxidative stress parameters, and (c) the metabolism of alanine in the isolated perfused liver. Plasma activities of alanine aminotransferase and aspartate aminotransferase and hepatic glutathione S-transferase and catalase presented significant elevation in rats inoculated with 300 μg ⋅ kg(-1) Cdt venom. Liver lipoperoxidation was enormously increased by venom doses of 100, 200, and 300 μg ⋅kg(-1) , whereas glutathione S-transferase was not changed. Perfused livers from rats inoculated with 1500 μg ⋅kg(-1) venom showed increased production of lactate, pyruvate, and ammonia when alanine was the metabolic substrate. These results demonstrate that the Cdt venom can produce several changes in hepatocytes. The causes of the changes are possibly related to the disequilibrium in the redox homeostasis but also to specific needs of the poisoned organism, for example, an increased supply of lactate and pyruvate in response to an increased activity of the Cori cycle.
Journal of Biochemical and Molecular Toxicology 05/2011; 25(3):195-203. · 1.60 Impact Factor
[show abstract][hide abstract] ABSTRACT: The in vivo and in vitro effects of the pesticide endosulfan on the cholinesterase (ChE) activity were investigated in rats. ChE activity decreased in dams and in male pups within 65 days corresponding to 35% and 32% of inhibition respectively in the higher endosulfan dose (1.5 mg/kg). In vitro, the enzyme activity was found to be inhibited in a concentration dependent manner. The results suggest that endosulfan is able to inhibit the ChE activity and to cross the placental barrier and/or to be eliminated through milk affecting the enzyme activity in male rat pups.
Bulletin of Environmental Contamination and Toxicology 02/2011; 86(4):368-72. · 1.11 Impact Factor
[show abstract][hide abstract] ABSTRACT: Different products of plant Morinda citrifolia L. (noni) have been marketed and used around the world based on properties described by Polynesian people that use them for more than 2000 years. Marketing of these products is based on their presumptive phytotherapic properties. However there is little scientific evidence about their safety, especially when used during pregnancy.
Evaluate the possible developmental toxicity of the noni fruit aqueous extract and commercial product of TAHITIAN NONI juice in rats exposed during pregnancy.
Pregnant Wistar rats were exposed by gavage to 7, 30 and 300 mg/kg bw (body weight) of noni aqueous extract or to 0.4, 2 and 20 mL/kg bw (body weight) of noni juice between day 7 and day 15 of pregnancy. Caesarean sections were performed on day 20 of pregnancy and reproductive parameters were evaluated. Implantations sites and postimplantation losses were recorded. Fetuses were weighted and examined for externally visible anomalies. After, the fetuses were cleared with KOH and the bones stained with alizarin red. Skeletal alterations of the skull, vertebral column, ribs, forelimbs, hindlimbs, sternum, sings of delayed ossification and variations were examined in accordance with pre-defined criteria and identified using harmonized and internationally accepted nomenclature recommended by the International Federation of Teratology Societies.
Exposure with extract and juice of Morinda citrifolia did not induce maternal toxicity at the tested doses, but induced delayed ossification in fetuses.
The exposure of pregnant rats to aqueous extract or juice Morinda citrifolia during organogenesis period may induce adverse effects on the normal development of fetuses. These findings indicate the need for further studies with noni derivates preceding their use in pregnant women.
Journal of ethnopharmacology 03/2010; 128(1):85-91. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
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.
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.
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.
Journal of ethnopharmacology 09/2009; 127(1):165-70. · 2.32 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Archives of Environmental Contamination and Toxicology 09/2009; 57(4):785-93. · 2.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
Archives of Environmental Contamination and Toxicology 04/2009; 57(4):777-84. · 2.01 Impact Factor
[show abstract][hide abstract] ABSTRACT: 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.
International Journal of Andrology 01/2009; 32(6):704-12. · 3.57 Impact Factor
[show abstract][hide abstract] ABSTRACT: Morinda citrifolia Linn (syn. Noni) is a plant widely used as food and medicine worldwide but there are no toxicological tests about this plant focused on reproduction.
To investigate possible endocrine activity and toxic effect on the reproductive system of Wistar rats by exposure of aqueous extract of the Morinda citrifolia.
Two experimental protocols in vivo were developed, (a) uterotrophic assay and (b) in utero and lactational assay, and one test in vitro to investigate the effect on the contractility of pregnant uteri isolated from rats (doses of the extract: 7.5, 75 and 750 mg/kg).
The uterotrophic assay indicates presence of in vivo antiestrogenic activity of extract at doses of 7.5 and 750 mg/kg. The in utero and lactation exposure showed that the treatment with extract at the dose of 7.5mg/kg induced a reduction of 50% in parturition index and an increase of 74% in postimplantation losses index. The in vitro test showed that uteri from rats treated with 7.5mg/kg of the extract presented a 50% reduction on contraction induced by arachidonic acid.
The exposure of aqueous extract of Morinda citrifolia in Wistar rats induced reproductive toxicity in nonlinear dose-response.
Journal of Ethnopharmacology 11/2008; 121(2):229-33. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Artemisinin compounds are important for treating multidrug-resistant malaria; however, the possible resorption and abnormalities observed in animal reproduction studies may contraindicate artemisinin use during the first trimester. To evaluate whether artemisinin interferes with developmental outcomes at different periods of pregnancy, Wistar rats were treated by gavage with increasing doses of 7, 35 and 70 mg/kg/day from gestational day [GD] 7 to 13 or 14 to 20. Viable embryos and post-implantation losses, and progestagens and testosterone levels, were monitored in the former treatment group and pregnancy and outcomes data, post-implantation losses and male and female developmental endpoints of the offspring were evaluated in the latter treatment group. Results indicate toxicity for both periods of treatment, with lower sensitivity at later stages of pregnancy. The results showed that dosing with 35 or 75 mg/kg of artemisinin caused high percentages of post-implantation losses that correlated with a trend to lower maternal progestagens and a significant maternal testosterone decrease. These findings demonstrate that oral administration of artemisinin can adversely effect post-implantation development and pregnancy in the rat.
[show abstract][hide abstract] ABSTRACT: Glyphosate is the active ingredient and polyoxyethyleneamine is the surfactant present in the herbicide Roundup formulation commercialized in Brazil. The aim of this study was to assess the reproductive effects of glyphosate-Roundup on male and female offspring of Wistar rats exposed during pregnancy and lactation. Dams were treated orally with water or 50, 150 or 450 mg/kg glyphosate during pregnancy (21-23 days) and lactation (21 days). These doses do not correspond to human exposure levels. The results showed that glyphosate-Roundup did not induce maternal toxicity but induced adverse reproductive effects on male offspring rats: a decrease in sperm number per epididymis tail and in daily sperm production during adulthood, an increase in the percentage of abnormal sperms and a dose-related decrease in the serum testosterone level at puberty, and signs of individual spermatid degeneration during both periods. There was only a vaginal canal-opening delay in the exposed female offspring. These findings suggest that in utero and lactational exposure to glyphosate-Roundup may induce significant adverse effects on the reproductive system of male Wistar rats at puberty and during adulthood.
Archive für Toxikologie 10/2007; 81(9):665-73. · 5.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mikania laevigata (Asteraceae) is a native plant from South America and popularly used as antispasmodic and to treat respiratory diseases. Coumarin is the major chemical substance found in this plant, which have been shown to have antifertility activity in female rats. This study evaluates the toxicity of the exposure to the Mikania laevigata syrup using coumarin as chemical marker on reproductive endpoints in male Wistar rats. Endpoints including reproductive organs weight, sperm and spermatids numbers and sperm morphology were evaluated. Animals were treated daily with Mikania laevigata syrup (3.5; 7.0 and 14.0mg/kg of coumarin) during 90 days by oral gavage. No alterations were observed in body and organ weights, sperm and spermatids numbers as well as sperm morphology of the male rats after the exposure to the Mikania laevigata syrup. Results therefore suggest absence of male reproductive toxicity of the Mikania laevigata syrup at tested doses.
Journal of Ethnopharmacology 05/2007; 111(1):29-32. · 2.76 Impact Factor
[show abstract][hide abstract] ABSTRACT: Phthalates are chemicals used in many industrial products (plastic toys, shampoos, soaps), and are suspected of inducing adverse effects on the male reproductive system. In the present study, we evaluated the effects of the plasticizer di-(2-ethylhexyl)-phthalate (DEHP) on the reproductive function and sexual behavior of male offspring rats, exposed in utero and during lactation (0, 20, 100 and 500 mg/kg per day by gavage). The effects produced clearly demonstrate the ability of DEHP to disrupt the androgen-regulated development of the male reproductive tract. Absolute and relative weights of androgen-dependent tissue organs (ventral prostate and seminal vesicle) were significantly reduced at the highest dose level tested (500 mg/kg per day). Impairment of male sexual behavior (500 mg/kg per day) was also observed. Moreover, the reduction in daily sperm production and epididymal sperm counts observed after administration of the highest dose suggests an impairment of the spermatogenic processes. Most of the adverse effects reported here were observed both during puberty and during adulthood, indicating permanent effects of in utero and lactational DEHP exposure.
Human & Experimental Toxicology 07/2006; 25(6):297-303. · 1.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: Data from in vitro studies suggest that the pesticides deltamethrin (D) and endosulfan (E) exert estrogen-like effects. There is concern that interaction between weakly estrogenic compounds can increase their estrogenic potency. The aim of the present study was to determine estrogenic activity in an animal model and the possible female reproductive adverse effects of these pesticides combined. Wistar rats received daily (po), from day 6 of pregnancy to day 21 of lactation, deltamethrin and endosulfan concomitantly: D: 2.0 mg/kg+E: 1.5 mg/kg, or D: 3.0 mg/kg+E: 2.0 mg/kg, or D: 4.0 mg/kg+E: 3.0mg/kg. Some offspring also were exposed directly after weaning. Maternal and reproductive outcome data were assessed. An uterotrophic assay to screen in vivo estrogenic activity of D+E was also performed. A group of female offspring was analyzed for vaginal opening (VO), first estrus, estrous cycle regularity, and weights of the uterus and ovaries. No signs of maternal toxicity were detected. Results from the uterotrophic assay indicate absence of in vivo estrogenic activity of D+E. No significant variations in reproductive endpoints of females were observed. These results suggest that administration of D+E does not pose a reproductive hazard to female rats exposed during critical periods of development, indicating that the combination does not exert estrogen-like effects in vivo or is not delivered to target organs.