RESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Chuanxiong (Chuanxiong Rhizoma, CR), the dried rhizome of Ligusticum chuanxiong Hort, has been used during pregnancy for more than 2000 years. However, the embryotoxicity of CR was not evaluated so far. The purpose of this study was to examine the safety and rational use of CR during pregnancy on mice and mouse embryonic stem cell (ES), and to explore the mechanism of embryotoxicity. AIM OF THE STUDY: This study was carried out to evaluate embryotoxicity of CR decoction in vivo and in vitro, and to explore the mechanism of embryotoxicity from the perspective of bone metabolism. MATERIALS AND METHODS: In animal experiments, pregnant mice were randomly assigned into 5 groups, i.e. mice were orally treated with CR decoction at dosages of 0 (distilled water, as negative controls), 2, 8, 32â¯g/kg/d (low, medium and high-dose group), and vitamin A (as positive controls), respectively. Maternal and embryo-fetal parameters were registered after cesarean section. The fetal skeletal development was further assessed with the alizarin red S and Hematoxylin-Eosin staining (H&E staining) and fluorescent imaging. Meanwhile, the mouse embryonic stem cell test model (EST model) was established to objectively evaluate the toxicity of CR on the embryo development. The median inhibitory proliferation values (IC50) for both the mouse embryonic stem cell D3 (ES) and mouse embryonic fibroblast 3T3 (3T3) were detected with MTT assays. After removal of inhibiting factor (LIF), mouse embryonic stem cells spontaneously differentiated into cardiomyocytes, the expression of specific myosin heavy chain gene (ß-MHC) contained in cardiomyocytes were detected by q-PCR quantitative analysis, and median inhibitory differentiation concentration (ID50) of ES was obtained. The development toxicity calculation formula was used to determine the embryotoxicity grade of CR decoction. finally, based on the successful induction of osteoblasts, the molecular mechanism of CR embryotoxicity was preliminarily studied based on BMP-Smads signal pathway. RESULTS: Compared with the negative control group, high, medium, and low doses of CR decoction had no significant effect on the maternal body weight and uterine weight (Pâ¯>â¯0.05), as well as on the maternal liver, heart, and kidneys. The observation results showed that high dose of CR decoction significantly increase the number of absorbed fetuses (Pâ¯<â¯0.05). The EST model was successfully established, the IC50 3T3, IC50 ES and ID50 ES of CR were 9.39â¯mg/mL, 18.78â¯mg/mL, and 10.20â¯mg/mL, respectively. CR was classified as weak embryonic development toxicity by the EST linear discriminant formula. Meanwhile, osteoblasts were successfully induced in vitro, the relative expression levels of BMP2, BMPR2, Smad1, and Smad5 were down-regulated in varying degrees after 3, 6, and 9 days of treatment with different concentration gradients of CR decoction. CONCLUSIONS: Combining in vivo and in vitro experiments, CR showed a potential embryotoxicity. The mechanism of embryotoxicity may be related to inhibiting the expression of key genes in the BMP-SMADs signaling pathway. In the clinical application, the normal dosage of CR is safe to a certain extent. However, when the dosage is too high (160â¯g/60â¯kg/d), there may be a risk of embryotoxicity.
Assuntos
Embrião de Mamíferos/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Ligusticum , Osteoblastos/efeitos dos fármacos , Extratos Vegetais/toxicidade , Animais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/metabolismo , Células Cultivadas , Embrião de Mamíferos/anormalidades , Feminino , Reabsorção do Feto/induzido quimicamente , Camundongos , Osteoblastos/metabolismo , Gravidez , Rizoma , Proteína Smad1/genética , Proteína Smad1/metabolismo , Proteína Smad5/genética , Proteína Smad5/metabolismo , Esterno/anormalidades , Esterno/efeitos dos fármacosRESUMO
In the semiarid region of Brazil, in areas with vegetation composed mainly of Poincianella pyramidalis, several cases of congenital malformation and reproductive losses were observed in goats and sheep from 2012 to 2014. To determine the teratogenic effect of P. pyramidalis, two groups of eight goats each were used. Goats from Group 1 received fresh P. pyramidalis, harvested daily, as the only roughage during the whole breeding and pregnancy period. Goats in Group 2 (control) received Cynodon dactylon (tifton) hay free choice. Ultrasound examination for pregnancy diagnosis was performed every 28 days. Four goats from Group 1 were pregnant on day 28 but not on day 56, suggesting embryonic death or abortion. Another goat from Group 1 died at day 70 of pregnancy, and the fetuses exhibited micrognathia. The other three goats bore six kids, three of which showed bone malformations in the limbs, spine, ribs, sternum, and head, including arthrogryposis, scoliosis and micrognathia. One kid also showed hypoplasia of the left pulmonary lobes. In the control group, all goats bore a total of 13 kids and none of them exhibited malformations. These results demonstrated that P. pyramidalis causes congenital malformations and other reproductive losses in goats.
Assuntos
Anormalidades Induzidas por Medicamentos/veterinária , Aborto Animal/induzido quimicamente , Caesalpinia/toxicidade , Reabsorção do Feto/veterinária , Doenças das Cabras/induzido quimicamente , Doenças das Cabras/etiologia , Intoxicação por Plantas/veterinária , Complicações na Gravidez/veterinária , Animais , Artrogripose/induzido quimicamente , Artrogripose/veterinária , Brasil , Cynodon , Feminino , Reabsorção do Feto/induzido quimicamente , Doenças das Cabras/fisiopatologia , Cabras , Micrognatismo/induzido quimicamente , Micrognatismo/veterinária , Componentes Aéreos da Planta/toxicidade , Intoxicação por Plantas/fisiopatologia , Gravidez , Complicações na Gravidez/fisiopatologia , Escoliose/induzido quimicamente , Escoliose/veterináriaRESUMO
Ginkgo extract, EGb 761 is known as a vasoregulatory variable for the conventional reproduction therapy. EGb 761 was orally administered in 0 (control), 3.7, 7.4, and 14.8 mg/kg bw/day for 28 days (thereafter mated with normal fertile male), from day 1 to day 7 of pregnancy or from the 10th to 18th day of pregnancy, respectively. Vaginal smears were performed daily. On 20th day of pregnancy, the females were killed by cervical dislocation and their kidneys, liver, brain, placenta, spleen and ovaries were removed and weighed. The ovaries were prepared for histological examinations, and then ovarian follicles were counted. Maternal toxicity, estrous cycle, reproductive hormones, ovarian follicle counts, resorption index, implantation index, fetal viability and fetuses, and placenta mean weights were evaluated. There was a dose-dependent ovarian toxic effect of EGb 761. Ovarian follicle counts, resorption index, implantation index, fetal viability were significantly reduced in 14.8 mg/kg bw/day dose. Treatment with 14.8 mg/kg bw/day EGb 761 induced disruption of estrous cycle and caused maternal toxicity, in addition to fetal toxicity. Therefore, the data obtained indicate that Ginkgo biloba extract at 14.8 mg/kg bw/day dose level exhibit toxic effect on reproductive cyclicity and could have anti-implantation and abotifacient properties in female mice.
Assuntos
Abortivos/farmacologia , Implantação do Embrião/efeitos dos fármacos , Ciclo Estral/efeitos dos fármacos , Ovário/efeitos dos fármacos , Extratos Vegetais/farmacologia , Vagina/efeitos dos fármacos , Administração Oral , Animais , Relação Dose-Resposta a Droga , Feminino , Desenvolvimento Fetal/efeitos dos fármacos , Reabsorção do Feto/induzido quimicamente , Viabilidade Fetal/efeitos dos fármacos , Ginkgo biloba , Masculino , Exposição Materna/efeitos adversos , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/patologia , Ovário/patologia , Placenta/efeitos dos fármacos , Placenta/patologia , Gravidez , Vagina/patologiaRESUMO
BACKGROUND: Psoralea corylifolia L. (PC) was commonly used to treat miscarriages clinically. The aim of this study was to examine its embryotoxicity in mice and embryonic stem cells (ESCs). METHODS: Quality control of PC extract including reference marker compounds, pesticide residues, and heavy metals was authenticated with HPLC, Gas chromatography-mass spectrometry (GC-MS), and inductively coupled plasma-mass spectrometry. Pregnant mice were randomly assigned into five groups and dosed with distilled water (G1), PC extract of 2 (G2), 4 (G3), or 8 g/kg/day (G4), and vitamin A (G5). Meanwhile, half maximal inhibitory concentration values for ESCs and 3T3 cells were identified in a cytotoxicity assay, and apoptosis in neuroepithelium was assessed by transmission electron microscopy. RESULTS: In the G4 group, a statistically significant decrease in the total fetus, live fetus, and gravid uterine weight, and increase in the resorbed fetus, postimplantation loss, and neuroepithelial apoptosis as well as maternal liver-weight were found (p < 0.05). CONCLUSIONS: PC extracts at 8 g/kg/day might cause fetal toxicity and maternal liver damage in mice, although it did not cause typical malformation and ESC's cytotoxicity in this experiment. Our data suggested that high dosage and long-term administration of PC preparations may not be safe for pregnant women.
Assuntos
Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Fetal/efeitos dos fármacos , Exposição Materna/efeitos adversos , Extratos Vegetais/toxicidade , Psoralea/química , Teratogênicos/toxicidade , Células 3T3/efeitos dos fármacos , Células 3T3/patologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Embrião não Mamífero/efeitos dos fármacos , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/patologia , Feminino , Reabsorção do Feto/induzido quimicamente , Peso Fetal/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Células Neuroepiteliais/efeitos dos fármacos , Células Neuroepiteliais/patologia , Células Neuroepiteliais/ultraestrutura , Tamanho do Órgão/efeitos dos fármacos , Extratos Vegetais/análise , Extratos Vegetais/classificação , Gravidez , Teratogênicos/classificação , Útero/efeitos dos fármacos , Útero/patologia , Vitamina A/toxicidadeRESUMO
BACKGROUND: Largehead Atractylodes Rhizome (LAR) is the most commonly used Chinese medicine to prevent early pregnancy loss due to threatened miscarriage. However, its safety profile during pregnancy is still not available. Here we aimed to identify the potential adverse effects of LAR on embryo-fetal development as well as prenatal and post-natal growth. METHODS: Pregnant mice, rats and rabbits were orally administered with LAR extracts in various doses (from 1×, 2×, 3× and up to 6× clinical doses) at different gestational periods (implantation, gastrulation, organogenesis, maturation and whole gestation). Maternal effects on weight loss, implantation failure and fetal resorption and perinatal effects on developmental delay, growth restriction and congenital malformations were studied. RESULTS: In mice, with early LAR exposure, a significant decrease in fetal growth parameters and a significant increase in post-implantation loss were identified. With late LAR exposure, significant increases in gestational duration as well as prenatal and post-natal mortality were found. At high clinical doses, congenital skeletal malformations were recorded. In rabbits, fetal resorption, hydrops fetalis and short ear anomaly were observed. No significant adverse effects were found in rats. CONCLUSIONS: Potential reproductive toxicity of LAR in pregnant animals was identified within the clinical dose. Caution should be taken in clinical applications of LAR during pregnancy.
Assuntos
Ameaça de Aborto/tratamento farmacológico , Atractylodes/toxicidade , Medicamentos de Ervas Chinesas/toxicidade , Fitoterapia/efeitos adversos , Anormalidades Induzidas por Medicamentos , Aborto Induzido , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Orelha/anormalidades , Implantação do Embrião/efeitos dos fármacos , Desenvolvimento Embrionário/efeitos dos fármacos , Feminino , Retardo do Crescimento Fetal/induzido quimicamente , Reabsorção do Feto/induzido quimicamente , Hidropisia Fetal/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Nível de Efeito Adverso não Observado , Gravidez , Resultado da Gravidez , Coelhos , Ratos , Ratos Sprague-Dawley , Rizoma , Crânio/anormalidadesRESUMO
The aims of this study was to evaluate the effects of oil-resin of Copaiba (Copaifera duckei Dwyer), aired in vaginal cream on the reproductive performance of female rats (Rattus norvegicus). To determine the components of the C. duckei oleoresin, gas chromatography coupled with mass spectrometry (CG-MS) was used, and considering the trans-caryophyllene sesquiterpene as a phytochemical marker in the oleoresin. Due to the extensive use of copaiba oleoresin in the suppository form for gynecological infections, an evaluation was carried out on the effects of copaiba oleoresin (Copaifera duckei Dwyer), delivered in a vaginal cream, on the reproductive performance of female Wistar rats. For this purpose, three groups (n=5-6/group) of female rats were treated as follows: 1--vaginal cream of copaiba oleoresin (28.6 mg/kg), 2--base vaginal cream and 3--control (physiological saline 0.9%), administered intravaginally, for 30 days before pregnancy, and from day zero to day 20 during pregnancy. Laparotomy was performed on the 21st day of pregnancy, followed by the determination of reproductive variables: number of live and dead fetuses, mass of the fetuses and placentas, number of implantations and resorptions, number of corpora lutea, pre- and post-implantation loss, and analyses of the fetuses with regard to external and internal anomalies and/or malformations (skeletal and visceral). The trans-caryophyllene present in the sample is suggested as a phytochemical marker and the results of this study demonstrate an absence of maternal toxicity and foetotoxicity embryofoetotoxicity at the dose administered, corresponding to ten times the recommended dose for use in humans. Accordingly, no significant statistical difference was observed between the treated and control groups, for the variables analyzed. Thus, it is concluded that the vaginal cream containing 2.5% copaiba oleoresin is safe during gestation, in female rats (Rattus norvegicus) of the Wistar strain.
Assuntos
Preparações de Plantas/administração & dosagem , Reprodução/efeitos dos fármacos , Anormalidades Induzidas por Medicamentos , Administração Intravaginal , Animais , Animais Recém-Nascidos/anormalidades , Cromatografia Gasosa , Avaliação Pré-Clínica de Medicamentos , Feminino , Reabsorção do Feto/induzido quimicamente , Peso Fetal/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Placenta/efeitos dos fármacos , Preparações de Plantas/química , Preparações de Plantas/toxicidade , Plantas Medicinais/química , Gravidez , Ratos , Ratos WistarRESUMO
Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus.
Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Consumo de Bebidas Alcoólicas/efeitos adversos , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Etanol/toxicidade , Ácido Fólico/farmacologia , Exposição Materna , Complexo Vitamínico B/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/metabolismo , Animais , Encéfalo/anormalidades , Encéfalo/metabolismo , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Feminino , Sangue Fetal/metabolismo , Reabsorção do Feto/induzido quimicamente , Reabsorção do Feto/prevenção & controle , Peso Fetal/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/metabolismo , Idade Gestacional , Cobaias , Hipocampo/anormalidades , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Complexo Vitamínico B/administração & dosagem , Complexo Vitamínico B/metabolismoRESUMO
Reproductive and developmental toxicities of zinc supplementation in F(0) rats and F(1) progeny were examined. Rats were treated by gavaging with zinc chloride (ZnCl(2)) at 0.0, 7.5, 15 and 30 mg/kg-d. ZnCl(2) treatment was associated with deficient energy imbalances, reduced number of live pups/litter, decreased live birth index, increased mortality and increased fetal resorption. Changes in serum clinical chemistry and hematologic parameters were sex-related. In F(0) females, ZnCl(2) was associated with increased liver/body weight ratios, reduced creatinine and reduced alkaline phosphatase concentrations. In F(0) males, ZnCl(2) significantly increased relative liver weight and elevated γ-GGT. In addition, at birth, F(1) males exhibited, a significant (p<0.05) increase in anogenital distance, whereas ZnCl(2) hastened the time of eye opening and incisor eruption in males and females. These results indicate that excess ZnCl(2) supplementation before and during pregnancy and during lactation could pose some health risk concerns to pregnant mothers and their offspring.
Assuntos
Cloretos/toxicidade , Reprodução/efeitos dos fármacos , Compostos de Zinco/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Cloretos/administração & dosagem , Suplementos Nutricionais/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Feminino , Morte Fetal/induzido quimicamente , Reabsorção do Feto/induzido quimicamente , Lactação , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Fígado/embriologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores de Risco , Fatores Sexuais , Compostos de Zinco/administração & dosagemRESUMO
Skeletal changes induced by treatment of pregnant rats with four potent teratogens, busulfan, acetazolamide, vitamin A palmitate, and ketoconazole, were evaluated using Alizarin Red S and Alcian Blue double-staining to investigate the relationship between drug-induced skeletal malformations and cartilaginous changes in the fetuses. Pregnant rats (N = 8/group) were treated once or twice between gestation days (GDs) 10 to 13 with busulfan at doses of 3, 10, or 30 mg/kg; acetazolamide at 200, 400, or 800 mg/kg; vitamin A palmitate at 100,000, 300,000, or 1,000,000 IU/kg; or ketoconazole at doses of 10, 30, or 100 mg/kg. Uterine evaluations and fetal external and skeletal examinations were conducted on GD 20. Marked skeletal abnormalities in ribs and hand/forelimb bones such as absent/ short/bent ribs, fused rib cartilage, absent/fused forepaw phalanx, and misshapen carpal bones were induced at the mid- and high-doses of busulfan and acetazolamide and at the high-dose of vitamin A palmitate and ketoconazole. Increased incidences of discontinuous rib cartilage (DRC) and fused carpal bone (FCB) were observed from the low- or mid-dose in the busulfan and acetazolamide groups, and incidences of FCB were increased from the mid-dose in the vitamin A palmitate and ketoconazole groups. Therefore, DRC and FCB were detected at lower doses than those at which ribs and hand/forelimb malformations were observed in the four potent teratogens.
Assuntos
Anormalidades Induzidas por Medicamentos/patologia , Ossos do Carpo/anormalidades , Cartilagem/anormalidades , Costelas/anormalidades , Teratogênicos/toxicidade , Acetazolamida/administração & dosagem , Acetazolamida/toxicidade , Animais , Bussulfano/administração & dosagem , Bussulfano/toxicidade , Diterpenos , Relação Dose-Resposta a Droga , Feminino , Morte Fetal/induzido quimicamente , Desenvolvimento Fetal/efeitos dos fármacos , Reabsorção do Feto/induzido quimicamente , Peso Fetal/efeitos dos fármacos , Feto/anormalidades , Cetoconazol/administração & dosagem , Cetoconazol/toxicidade , Gravidez , Distribuição Aleatória , Ratos , Ésteres de Retinil , Vitamina A/administração & dosagem , Vitamina A/análogos & derivados , Vitamina A/toxicidadeRESUMO
BACKGROUND: In order to justify clinical studies in women of child-bearing age with artemisone, a new artimisinin derivative, studies to assess fertility and early embryonic development in rats, developmental toxicity in rats and rabbits, and peri-post natal development in rats were performed. METHODS AND RESULTS: In the study on fertility and early embryonic development (dose levels 0-5-20-80 mg/kg bw/day), doses inducing clinical and organ toxicity were used. Only in severe toxicity conditions, a reduction of the number of estruses, a prolonged time to insemination, decreased numbers of corpora lutea, implantation sites, and viable fetuses were found. Two developmental toxicity studies were performed in rats (dose levels 0-1-2 mg/kg bw/day) and rabbits (dose levels 0-2.5-5.0-7.5 mg/kg bw/day). It was shown that rats were about 5 times more sensitive than rabbits. In rats, artemisone induced total litter loss (late resorptions) at 2 mg/kg body weight and above with an increased incidence of a common vascular variation and retarded ossification at this dose. In rabbits, maternal toxicity, abortion and a slightly increased incidence of cardiac ventricular septal defects was observed at 7.5 mg/kg body weight. In a pre- and postnatal developmental toxicity study in rats (dose levels 0-1-2-4 mg/kg bw/day), 4 mg/kg body weight artemisone induced clinical symptoms and affected postnatal survival, body weight gain in the F1 pups, and motor activity. CONCLUSIONS: In summary, artemisone was shown to be embryo- and fetotoxic and induced cardiac ventricular septal defects and retarded ossification in dosages where total litter loss and abortions were observed. However, no effect on reproductive and developmental parameters below severe toxic dosages could be observed.
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Antimaláricos/toxicidade , Artemisininas/toxicidade , Desenvolvimento Embrionário/efeitos dos fármacos , Fertilidade/efeitos dos fármacos , Reabsorção do Feto/induzido quimicamente , Crescimento e Desenvolvimento/efeitos dos fármacos , Comunicação Interventricular/induzido quimicamente , Infertilidade Feminina/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Animais , Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Hematopoese Extramedular/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Coelhos , Ratos , Ratos Wistar , Especificidade da Espécie , Baço/efeitos dos fármacos , Baço/embriologia , Esplenomegalia/induzido quimicamenteRESUMO
The effect of organophosphate insecticide dimethoate at three dosage levels (7, 15, and 28 mg/kg/day) on male reproduction in mice was studied. Dimethoate was given orally by gavage to male mice for 20 days before mating with untreated females. Signs of cholinergic effects were observed in the 15 and 28 mg/kg/day treated groups. Brain and skeletal muscle acetylcholinesterase activities were inhibited in both the middle and high dose groups. Dimethoate was associated with a decreased number of implantations and live fetuses, and an increased number of dead and early resorptions at 28 mg/kg/day treated group. The percent morphologically normal spermatozoa were unaffected in any of dose groups. However, sperm production and percent motile sperm were decreased in the 15 and 28 mg/kg/day treated groups compared to the control. Histological changes in testis were observed in the middle and high treated groups. The current study demonstrated the adverse effects of dimethoate on the reproductive performance of male mice and pregnancy outcomes following mating with untreated female mice at dose levels of 15 and 28 mg/kg/day. The No Observed Effect Level (NOEL) in the present study for reproductive performance was 7 mg/kg/day.
Assuntos
Inibidores da Colinesterase/toxicidade , Dimetoato/toxicidade , Inseticidas/toxicidade , Reprodução/efeitos dos fármacos , Testículo/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Administração Oral , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Relação Dose-Resposta a Droga , Implantação do Embrião/efeitos dos fármacos , Feminino , Morte Fetal/induzido quimicamente , Reabsorção do Feto/induzido quimicamente , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/enzimologia , Nível de Efeito Adverso não Observado , Contagem de Espermatozoides , Motilidade dos Espermatozoides/efeitos dos fármacos , Espermatozoides/citologia , Espermatozoides/efeitos dos fármacos , Testículo/patologiaRESUMO
Asparagus racemosus (AR) is a herb used as a rasayana in Ayurveda and is considered both general and female reproductive tonic. Methanolic extract of A. racemosus roots (ARM; 100 mg/kg/day for 60 days) showed teratological disorders in terms of increased resorption of fetuses, gross malformations e.g. swelling in legs and intrauterine growth retardation with a small placental size in Charles Foster rats. Pups born to mother exposed to ARM for full duration of gestation showed evidence of higher rate of resorption and therefore smaller litter size. The live pup showed significant decrease in body weight and length and delay of various developmental parameters when compared to respective control groups. AR therefore, should be used in pregnancy cautiously as its exposure during that period may cause damage to the offspring.
Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Asparagus/química , Desenvolvimento Fetal/efeitos dos fármacos , Ayurveda , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/embriologia , Animais , Peso Corporal/efeitos dos fármacos , Feminino , Reabsorção do Feto/induzido quimicamente , Tamanho da Ninhada de Vivíparos , Masculino , Extratos Vegetais/toxicidade , Raízes de Plantas/química , Gravidez , Ratos , Ratos EndogâmicosRESUMO
Based on previous in vitro studies that have illustrated prevention of ethanol-induced cell death by antioxidants, using an in vivo model, we have tested the anti-teratogenic potential of a potent synthetic superoxide dismutase plus catalase mimetic, EUK-134. The developing limb of C57BL/6J mice, which is sensitive to ethanol-induced reduction defects, served as the model system. On their ninth day of pregnancy, C57BL/6J mice were administered ethanol (two intraperitoneal doses of 2.9 g/kg given 4 h apart) alone or in combination with EUK-134 (two doses of 10 mg/kg). Pregnant control mice were similarly treated with either vehicle or EUK-134, alone. Within 15 h of the initial ethanol exposure, excessive apoptotic cell death was observed in the apical ectodermal ridge (AER) of the newly forming forelimb buds. Forelimb defects, including postaxial ectrodactyly, metacarpal, and ulnar deficiencies, occurred in 67.3% of the ethanol-exposed fetuses that were examined at 18 days of gestation. The right forelimbs were preferentially affected. No limb malformations were observed in control fetuses. Cell death in the AER of embryos concurrently exposed to ethanol and EUK-134 was notably reduced compared with that in embryos from ethanol-treated dams. Additionally, the antioxidant treatment reduced the incidence of forelimb malformations to 35.9%. This work illustrates that antioxidants can significantly improve the adverse developmental outcome that results from ethanol exposure in utero, diminishing the incidence and severity of major malformations that result from exposure to this important human teratogen.
Assuntos
Antioxidantes/uso terapêutico , Etanol/toxicidade , Transtornos do Espectro Alcoólico Fetal/tratamento farmacológico , Deformidades Congênitas dos Membros/prevenção & controle , Compostos Organometálicos/uso terapêutico , Salicilatos/uso terapêutico , Animais , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Catalase , Avaliação Pré-Clínica de Medicamentos , Feminino , Transtornos do Espectro Alcoólico Fetal/embriologia , Transtornos do Espectro Alcoólico Fetal/patologia , Reabsorção do Feto/induzido quimicamente , Reabsorção do Feto/prevenção & controle , Membro Anterior/anormalidades , Membro Anterior/efeitos dos fármacos , Deformidades Congênitas dos Membros/induzido quimicamente , Deformidades Congênitas dos Membros/embriologia , Troca Materno-Fetal , Metacarpo/anormalidades , Metacarpo/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Compostos Organometálicos/farmacologia , Estresse Oxidativo , Gravidez , Salicilatos/farmacologia , Superóxido Dismutase , Dedos do Pé/anormalidades , Dedos do Pé/embriologia , Ulna/anormalidades , Ulna/embriologiaRESUMO
Flubendazole was suspended in deionized water or olive oil and administered by gavage once daily to pregnant rats on Days 8-15 of pregnancy to examine if the embryolethal and teratogenic doses were affected by the vehicles used. Flubendazole in olive oil caused a statistically significant increase in embryolethality at doses of 7.83 mg/kg per day and higher, with complete resorption in all dams at 31.33 mg/kg per day. When flubendazole was suspended in deionized water, a significant increase in embryolethality occurred only at a maternal dose of 125.32 mg/kg per day. The proportion of litters with anomalous fetuses was significantly increased at doses of 31.33 mg/kg per day and above when flubendazole was administered in deionized water, but increased at doses at four times lower when flubendazole was administered as in olive oil. Administered as a single dose in olive oil on any one of Days 6-12 of pregnancy, a flubendazole dose of 31.33 mg/kg caused significant increases in embryolethality and decreased fetal body weights on Days 7-9, with an 82.7% incidence of embryolethality on Day 8, with complete resorption in 5 of the 8 dams. The critical periods for teratogenic effects were between Days 8 and 11 of pregnancy, with Day 9 being the most critical. Fetuses with gross, skeletal, or internal anomalies were seen in dams given a single dose of as low as 7.83 mg/kg.
Assuntos
Anormalidades Múltiplas/induzido quimicamente , Anti-Helmínticos/toxicidade , Mebendazol/análogos & derivados , Mebendazol/toxicidade , Veículos Farmacêuticos/administração & dosagem , Prenhez/efeitos dos fármacos , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/patologia , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Reabsorção do Feto/induzido quimicamente , Peso Fetal/efeitos dos fármacos , Idade Gestacional , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Troca Materno-Fetal , Mebendazol/administração & dosagem , Azeite de Oliva , Óleos de Plantas/administração & dosagem , Gravidez , Ratos , Ratos Sprague-Dawley , Água/administração & dosagem , Água/químicaRESUMO
BACKGROUND: Treatment of pregnant mice with 2-chloro-2'-deoxyadenosine (2CdA) on Day 8 of gestation induces microphthalmia through a mechanism linked to the p53 tumor suppressor pathway. The present study defines the response of Day 8 mouse embryos through time with respect to pharmacologic intervention with PK11195, a ligand of the mitochondrial peripheral benzodiazepine receptor (Bzrp). METHODS: Pregnant CD-1 mice dosed with 2CdA with or without PK11195 on gestation Day 8 provided fetuses for teratologic evaluation on Day 14 and Day 17; HPLC measured pyridine nucleotides (NADH/NAD+) at 1.5 hr, RT-PCR measured mitochondrial 16S rRNA abundance at 3.0 hr, and p53 protein induction was assessed with immunostaining at 4.5 hr postexposure. RESULTS: The mean incidences of malformed fetuses were significantly higher in the 7.5 mg/kg 2CdA treatment group (50.2% malformed) vs. the 2CdA + 4.0 mg/kg PK11195 co-treatment group (4.4% malformed). Malformed fetuses displayed a range of ocular defects that included microphthalmia and keratolenticular dysgenesis (Peters anomaly). No malformations were observed in the control or PK11195 alone groups. PK11195 also protected litters from increased resorption rates and fetal weight reduction. It did not rescue early effects on NADH balance (1.5 hr) or 16S rRNA expression (3.0 hr); however, the p53 response (4.5 hr) was downgraded in 2CdA + PK11195 embryos vs. 2CdA alone. By delaying the administration of PK11195 in 1.5 hr intervals it was determined that the window for protection closed between 4.5 to 6.0 hr after 2CdA. CONCLUSIONS: The capacity of PK11195 to suppress the pathogenesis of microphthalmia implies a critical role for mitochondrial peripheral benzodiazepine receptors in the p53-dependent mode of action of 2CdA on ocular development.
Assuntos
Didesoxiadenosina/análogos & derivados , Didesoxiadenosina/toxicidade , Anormalidades do Olho/induzido quimicamente , Isoquinolinas/uso terapêutico , Teratogênicos/toxicidade , Animais , Didesoxiadenosina/administração & dosagem , Didesoxiadenosina/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Anormalidades do Olho/prevenção & controle , Feminino , Proteínas Fetais/biossíntese , Proteínas Fetais/genética , Reabsorção do Feto/induzido quimicamente , Reabsorção do Feto/prevenção & controle , Feto/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Genes p53 , Idade Gestacional , Isoquinolinas/farmacologia , Camundongos , Microftalmia/induzido quimicamente , Microftalmia/prevenção & controle , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , NAD/metabolismo , Gravidez , RNA Ribossômico 16S/biossíntese , Receptores de GABA-A/efeitos dos fármacos , Proteína Supressora de Tumor p53/biossíntese , Proteína Supressora de Tumor p53/fisiologiaRESUMO
Rhazya stricta is a medicinal plant traditionally used in the treatment of diabetes mellitus, inflammation, and helminthiasis. Our objective was to determine if the plant extract has any effect on fetal development in the rat. A lyophilized extract of the plant was administered daily on three consecutive gestation days (GD) covering the period of preimplantation and organogenesis. The fetuses were examined on GD 20. Higher doses (5.0 or 8.0 g/kg) of R. stricta generally caused a reduction in maternal weight gain, compared to controls, whereas the lower doses (0.5 to 2.0 g/kg) did not. Treatment on GD 1, 2, 3, or 7, 8, 9 had no effect on the fetal weight. Treatment on later days GD 8, 9, 10, or 10, 11, 12, or 13, 14, 15 reduced both the number of live fetuses and their weight. Pronounced intrauterine growth retardation (IUGR) was observed in groups treated at later stages, particularly in the high dose groups. Extreme resorption characterized R. stricta treatment on GD 10, 11, and 12. Examination of the conceptus 24 h after R. stricta treatment indicated retarded placental development associated with hypovascularity, which possibly contributed to the IUGR and fetal death. The incidence of malformations such as micromelia, adactyly, maxillary-mandibular hypoplasia, protruding tongue, and edema, did not reach statistical significance. Except perhaps for a generalized growth retardation, no skeletal malformations were obvious. These observations are suggestive of potential fetal toxicity of R. stricta if taken during pregnancy.
Assuntos
Retardo do Crescimento Fetal/induzido quimicamente , Feto/efeitos dos fármacos , Plantas Medicinais , Teratogênicos/toxicidade , Animais , Peso Corporal , Cromatografia Líquida de Alta Pressão , Feminino , Reabsorção do Feto/induzido quimicamente , Tamanho do Órgão , Placenta/efeitos dos fármacos , Placenta/patologia , Extratos Vegetais/química , Extratos Vegetais/toxicidade , Gravidez , Ratos , Ratos WistarRESUMO
Boric acid (BA), an ingredient of many pharmaceutical, cosmetic, and pesticide products, was previously shown to induce reproductive and developmental toxicity in laboratory rodents. In this study, BA (0, 62.5, 125, or 250 mg/kg/day, po) was administered on Gestational Days (GD) 6-19 to New Zealand White rabbits (18-23 pregnant/group). Maternal body weight, food consumption, and clinical condition were monitored at regular intervals throughout gestation. At termination (GD 30), the numbers of uterine implantations, resorptions, dead fetuses, and live fetuses were determined. Fetuses were weighed, and live fetuses examined for external, visceral, and skeletal defects. Maternal food intake decreased during treatment at 250 mg/kg/day and increased at >/=125 mg/kg/day after treatment. Maternal body weight (GD 9-30), weight gain during treatment, gravid uterine weight, and number of ovarian corpora lutea decreased at 250 mg/kg/day. In contrast, maternal corrected gestational weight gain increased at >/=125 mg/kg/day. Maternal liver weight was not affected. Relative (but not absolute) maternal kidney weight increased at 250 mg/kg/day, and microscopic evaluation revealed no treatment-related renal pathology. At 250 mg/kg/day, prenatal mortality was increased (90% resorptions/litter vs 6% for controls), the proportion of pregnant females with no live fetuses was increased (73% vs 0%), and live litter size was reduced (2.3 fetuses/litter vs 8.8). As a result, there were only 14 live fetuses (6 live litters) available for evaluation in the high-dose group, compared to 153-175 live fetuses (18-23 live litters) in the other groups. The percentage malformed fetuses/litter was increased at 250 mg/kg/day, primarily due to cardiovascular defects in 72% of high-dose fetuses vs 3% of controls. The most prevalent cardiovascular malformation (interventricular septal defect) was observed in 57% of high-dose fetuses compared to 0.6% among controls. At 250 mg/kg/day, average fetal body weight/litter was 92% of the average control weight (not statistically significant). In summary, no definitive maternal or developmental toxicity was observed at 62.5 or 125 mg/kg/day BA. Mild maternal effects and severe developmental toxicity were observed at 250 mg/kg/day.
Assuntos
Anormalidades Induzidas por Medicamentos/patologia , Ácidos Bóricos/toxicidade , Prenhez/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Feminino , Morte Fetal/induzido quimicamente , Reabsorção do Feto/induzido quimicamente , Idade Gestacional , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , CoelhosRESUMO
Trichloroacetonitrile (TCAN) is a by-product of the chlorine disinfection of water containing natural organic material. When administered by gavage to pregnant Long-Evans rats in a medium-chain triglyceride vehicle, tricaprylin oil (Tricap), at a volume of 10 ml/kg, TCAN induced fetal cardiovascular anomalies at doses as low as 1 mg/kg/d (Smith et al., 1988). A slight but possibly biologically significant increase over the water control group in adverse pregnancy outcomes (resorptions, reduced fetal weight, and anomalies) was observed in the Tricap control group. This led us to reexamine the development effects of TCAN in a second vehicle, corn oil (CO). Five groups of approximately 20 pregnant female rats received TCAN in CO at 15, 35, 55, and 75 mg/kg/d, and in Tricap at 15 mg/kg/d (10 ml/kg dosing volume). Corn oil, Tricap, and water served as vehicle controls. Animals were treated by oral intubation on gestation d 6-18 (vaginal plug = d 0). Five out of 20 dams (75 mg/kg) died during treatment. Adjusted maternal weight gain was lower in females receiving 35 mg/kg TCAN or greater. The mean percent of nonlive implants per litter was elevated at 55 and 75 mg/kg TCAN (CO). The TCAN dose-response curve for fetal (but not maternal) effects was shifted to the right when CO was compared to Tricap. Fetal weight was reduced at 15 mg/kg TCAN (Tricap) and at > or = 55 mg/kg TCAN (CO). When TCAN was administered in CO, the mean frequency of soft-tissue malformations decreased with significantly fewer septal and great vessel cardiovascular defects observed. We hypothesize that the volatile haloacetonitrile, TCAN, may interact with the Tricap vehicle in such a way that effects on the developing cardiovascular system are potentiated. The lowest observed adverse effect level for TCAN (CO) was determined to be 35 kg/kg.
Assuntos
Acetonitrilas/toxicidade , Óleo de Milho , Desenvolvimento Embrionário e Fetal/efeitos dos fármacos , Acetonitrilas/administração & dosagem , Administração Oral , Animais , Caprilatos , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/embriologia , Relação Dose-Resposta a Droga , Excipientes , Feminino , Reabsorção do Feto/induzido quimicamente , Rim/efeitos dos fármacos , Tamanho da Ninhada de Vivíparos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Ratos , Baço/efeitos dos fármacos , Triglicerídeos , ÁguaRESUMO
58 Female Kun Ming mice of perinatal stage (from the 15th day of pregnacy to the 21th day after birth) were fed with Tripcholorolide (T4) isolated from multiglycosides of Tripterygium wilfordii (GTW) at a doze of 0.6 mg/kg for group 1 or 0.3 mg/kg for group 2 per day for 4 weeks. Lactation was decreased in some females and some F1 off spring died. The succinic dehydrogenase (SDH) activity of the mice liver were increased due to the destruction of its mitocondian. Liver cells degenerated and glycogen decreased. Distal tubules of kidney degenerated. Heart and spleen were normal. T4 was also fed to 10 female mice from the 5th to 17th day of pregnacy. However, neither the absorbed fetus nor dead fetus increased.
Assuntos
Diterpenos/toxicidade , Medicamentos de Ervas Chinesas/química , Embrião de Mamíferos/efeitos dos fármacos , Succinato Desidrogenase/metabolismo , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Diterpenos/isolamento & purificação , Feminino , Morte Fetal/induzido quimicamente , Reabsorção do Feto/induzido quimicamente , Imunossupressores/toxicidade , Túbulos Renais Distais/efeitos dos fármacos , Lactação/efeitos dos fármacos , Fígado/metabolismo , Glicogênio Hepático/metabolismo , Camundongos , Mitocôndrias Hepáticas/metabolismo , GravidezRESUMO
1,2-Dichloropropane (PDC) was evaluated for its potential to cause embryonal/fetal toxicity and teratogenicity in pregnant rats and rabbits. PDC was administered via oral gavage at dose levels of 0, 10, 30, or 125 mg/kg/day on Days 6 through 15 of gestation (rats) or 0, 15, 50, or 150 mg/kg/day on gestation Days 7 through 19 (rabbits). Fetuses were examined on Gestation Day 20 (rats) or Day 28 (rabbits). Maternal toxicity was observed in both rats and rabbits at the high dose levels. Rats given 125 mg/kg/day of PDC showed clinical signs of toxicity and decreased body weight and body weight gain. Rabbits given 150 mg/kg/day PDC showed changes in hematologic parameters and decreased body weight gain. Although maternal toxicity was apparent, no indication of teratogenicity was observed in rat or rabbit fetuses at any dose level. Significant increases in the incidence of delayed ossification of skull bones, considered secondary to decreased maternal body weight gain, were observed in rats given 125 mg/kg/day and in rabbits given 150 mg/kg/day. No maternal or developmental effects were observed in rats given 10 or 30 mg/kg/day or in rabbits given 15 or 50 mg/kg/day of PDC. Based on the results of these studies the maternal and developmental NOELs in rats and rabbits were 30 and 50 mg/kg/day, respectively.