Hepatic toxicity caused by PLGA-microspheres containing usnic acid from the lichen C ladonia substellata (AHTI) during pregnancy in Wistar rats

ABSTRACT This study aimed to evaluate the teratogenic and hepatotoxic potential of the usnic acid encapsulated into PLGA-microspheres. In total, 12 female Wistar rats in pregnancy were randomly distributed in the control group (n= 6) that received 1.0 mL of physiological solution and treatment group (n= 6) that received 25 mg/kg of encapsulated usnic acid by oral administration. All females were euthanized at day 20 of pregnancy and their fetuses were removed and analyzed. During the pregnancy was observed a reduction in weight gain. There was no difference in serum transaminases levels analyzed as well as any difference in liver weight in both groups. The histomorphometric analysis of the liver from the treatment group revealed an increase in number of hepatocytes and a decrease in nuclear area of these cells. Moreover, no alteration was observed in cell area of hepatocytes or number of Kupffer cells. The fetuses had an increase in total number of hepatocytes and a reduction in the amount of megakaryocytes. These results show the hepatotoxic potential of usnic acid during pregnancy. However, its toxicity can be minimized by encapsulation in microspheres.

Prenatal and developmental toxicity study of meclizine and caffeine combination in female albino wistar rats.

Meclizine and caffeine combination is used for the treatment of morning sickness. Both compounds are teratogenic and caffeine is known to possess anti-fertility activity also. The present study was undertaken to evaluate the reproductive toxic effect of meclizine and caffeine combination. Three doses were taken for the study; low dose (LD; meclizine 3.7 mg/kg and caffeine 3 mg/kg) was selected from commercially available formulation, middle dose (MD; meclizine 37 mg/kg and caffeine 30 mg/kg) and high dose (HD; meclizine 370 mg/kg and caffeine 300 mg/kg). The mixture was administered 1-7 days and 8-14 days for fertility and embryotoxic studies respectively. Laparotomy was done on 10th day of gestation period. Number of implants and corpora lutea were counted, pre and post-implantation losses were determined. In embryo toxicity study fetuses were evaluated for external, skeletal and visceral examination. High dose was removed from both fertility and embryotoxicity studies due to its severe toxicity to the dam. Significant anti-fertility activity was observed at middle dose. Embryotoxicity study showed significant reduction in fetal body weight, body length and body mass index, dam body weight gain on gestation day 14. Absolute kidney weight in MD and absolute and relative spleen weight in both LD and MD were significantly reduced. There was no increase in external or internal congenital anomalies at both LD and MD. The, results suggest that prescription of meclizine and caffeine for morning sickness in early pregnancy should be reviewed carefully.

Effects of fluoxetine and imipramine in rat fetuses treated during a critical gestational period: a macro and microscopic study / Efeitos da fluoxetina e imipramina em fetos de ratas tratadas durante o período crítico da gestação: estudo macro e microscópico

OBJECTIVE: To evaluate morphological alterations in rat fetuses treated with fluoxetine and imipramine during the "critical" period of gestation. METHOD: Fifteen female rats were separated into three groups (n = 5) and treated with 10 mg/kg/day of test substances on the ninth, tenth and eleventh day of pregnancy: G1, fluoxetine; G2, imipramine hydrochloride; G3 (control), saline. On day 21, cesarean sections were performed to release the fetuses, whose bodies were weighed and macroscopically analyzed. The placenta was also weighed. The fetuses were then fixed and their encephala removed and weighed. Sections of the frontal lobe were taken for histological neuron counting. RESULTS: G1 and G2 showed the highest fetal body weight. Placental weight showed statistical differences (p < 0.01): G1 weighed more than G2 and G3. Otherwise, G2 exhibited the highest encephalon weight, statistically differing from G3 (control) and fluoxetine-treated G1 (p < 0.01). However, G1 did not statistically (p > 0.01) differ from the control group. G3 showed the highest number of neurons per area when compared to G1 and G2 (p < 0.01). CONCLUSION: The use of antidepressants in rats caused an increase in fetal weight and a decrease in the number of fetal frontal lobe neurons, thus suggesting that the use of antidepressants by pregnant women can induce depression in fetuses due to alterations in their neural development.

OBJETIVO: Avaliar as possíveis alterações ocorridas em nível macroscópico e microscópico de fetos de ratas submetidas ao tratamento com fluoxetina e imipramina durante o período "crítico" da gestação. MÉTODO: Quinze ratas, posteriormente ao acasalamento, foram divididas em três grupos experimentais (n = 5): G1, tratadas com 10mg/kg/dia de fluoxetina; G2, tratadas com 10mg/kg/dia de cloridrato de imipramina, e G3 (controle), tratadas com 10mg/kg/dia de solução fisiológica a 0,9 por cento, no 9º, 10º e 11º dias de prenhez das ratas. Posteriormente à cesária, no 21º dia de prenhez, analisou-se macroscopicamente o peso fetal e placentário. Os fetos foram fixados e houve a remoção do encéfalo para pesagem e preparação das lâminas do tecido neuronal para contagem de neurônios do lobo frontal. RESULTADOS: O G1 e G2 apresentaram maior peso fetal. O G1 apresentou maior peso placentário, diferindo do G2 e G3 (p < 0,01). De forma diferente, o G2 possuiu maior peso encefálico, diferindo do G3 e G1 (p < 0,01). G1 não diferiu estatisticamente do grupo controle (p > 0,01). O G3 exibiu maior número de neurônios, por área, do lobo frontal em relação a G1 e G2 (p < 0,01). CONCLUSÃO: A adoção dos antidepressivos causou, nos fetos, aumento de peso e redução da contagem de neurônios do lobo frontal, sugerindo que a indicação de antidepressivos às gestantes pode induzir a depressão nos fetos por alterações em seu neurodesenvolvimento.

Effects of Aspartame on Maternal-Fetal and Placental Weights, Length of Umbilical Cord and Fetal Liver: A Kariometric Experimental Study / Efectos del Aspartame sobre el Peso Materno-Fetal y Placentario, Largo del Cordón Umbilical e Hígado Fetal: Un Estudio Cartométrico Experimental

Aspartame is a synthetic sweetener consumed by more than half the adult population in 75 countries. Their metabolites can be toxic, principally to the liver and retina, and there are few studies on the use of aspartame in gestation. Twenty pregnant rats were weighed and allocated randomly (n=5 per group) to receive 14 mg/kg aspartame or water by oral-gastric drip. Treated Tl: aspartame diluted in water at room temperature; Treated T2: aspartame diluted in water heated to 40° C; control Cl: water at room temperature; and control C2: water heated to 40° C. Placentas were weighed, umbilical cords measured and 1000 nuclei of fetal hepatocytes (250 from each group) were analyzed morphometrically utilizing the technique of kariometry, with application of the Mann-Whitney U-Test. There were reductions in mean placental and maternal-fetal weights, in umbilical-cord length, and the majority of kariometric parameters of the hepatocytes in the group treated with aspartame diluted in distilled water at room temperature. Reduction of placental and maternal-fetal weights occurred, shortening of the umbilical cord, and decrease in kariometric parameters in fetal hepatocyte nuclei after administration of aspartame diluted in distilled water at 40°C temperature. The use of aspartame during gestation can be prejudicial to the fetus.

El aspartame es un endulzante sintético consumido por más de la mitad de la población adulta, en 75 países. Sus metabolitos pueden ser tóxicos, principalmente en el hígado y retina y hay algunos estudios sobre el aspartame en el embarazo. Veinte ratas preñadas fueron pesadas y distribuidas aleatoriamente (n=5 por grupo) y recibieron 14 mg/Kg de aspartame o agua por vía oral- gástrica. Tratamiento 1: aspartame diluido en agua a temperatura ambiente; Tratamiento T2: aspartame diluido en agua tibia a 40 °C; control Cl: agua a temperatura ambiente, y control C2: agua tibia a 40° C. Las placentas fueron pesadas, el cordón umbilical medido y 1000 núcleos de hepatocitos fetales (250 de cada grupo) se analizaron morfométricamente utilizando la técnica de canometría con aplicación del Test U de Mann-Whitney U-Test. En el grupo tratado con aspartame diluido en agua a temperatura ambiente, hubo reducción en los pesos promedios de la placenta y materno-fetal, largo del cordón umbilical y en la mayoría de los parámetros cartométricos de los hepatocitos. Lo mismo ocurrió en el grupo tratado con aspartame diluido en agua a 40 °C. El uso del aspartame durante las gestación puede ser perjudicial para el feto.

Protective effects of garlic juice against embryotoxicity of methylmercuric chloride administered to pregnant Fischer 344 rats

In order to investigate the beneficial effects of 0.5 or 1.0 g/kg Korean garlic juice against the embryotoxicity of 20 mg/kg methylmercury chloride (MMC, CH3HgCl), pregnant Fisher 344 rats were simultaneously orally administered on day 7 of gestation. On day 20 of gestation the dams were laparotomized under ether anesthesia, and the fetuses were removed and examined for toxicity of methylmercury. Garlic juice depressed the toxicity in terms of some parameters. In the case of simultaneous treatment with 0.1 g/kg garlic juice and MMC, rates of increase were 17.5% in maternal body weight, 13.2% and 41.9% in fetal and litters' weight respectively, and 37.0% in fetal survival rate. Decreasing rates were 10.0% in maternal death rate, and 6.9% and 31.3% in pre- and post-implantation loss respectively. Decreasing rates of mercury levels in dams were 67.2% in liver, 57.6% in brain, 47.2% in kidney, 42.1% in spleen and 40.9% in blood. As well, decreasing rates of mercury level in fetuses were 54.9% in all body burden, 55.9% in liver, 46.7% in kidney and 37% in brain, respectively. The number of fetal ossification centers were reduced by 23.8% to 58.0% following simultaneous treatment with 1.0 g/kg garlic juice. These findings indicated that garlic juice effectively inhibited the embryotoxicity of methylmercury in pregnant Fischer 344 rats.