Caffeine teratogenicity in rats: morphological characterization and hypothesized mechanisms

Caffeine consumption during pregnancy has been shown in the scientific literature to be associated with teratogenicity such as low birth weight, fetal malformations, and miscarriage. However, the morphological alterations of the offspring of dams exposed during pregnancy have not been consistently described, and the mechanisms why they occur remain elusive. Thus, we aimed to characterize the offspring malformations induced by moderate and high doses of caffeine during pregnancy. Dams were divided into three groups: control, moderate (0.3 g/L), and high dose (1.0 g/L) of caffeine, which was provided in the drinking water beginning on gestational day 1 and continuing throughout the entire gestation. At moderate doses, only one of the dams had stillborn pups, although no macroscopic malformations were observed. High doses of caffeine induced significantly more malformations (P<0.001) and early death (before P4). The malformations observed were related to fetal development and cardiovascular alterations, namely bruises, macrocephaly with short limbs, abnormal development (or absence) of head structures and limbs, labial malformations, hydrops fetalis, and poor placental formation. We discussed the proposed mechanisms by which caffeine might induce these phenotypes, which may involve down-regulation of adenosine A1 receptors, and increased mothers' catecholamines. Our findings further confirm the evidence of the teratogenic effects of high doses of caffeine administered during pregnancy. These findings support the recommendation to avoid caffeine exposure during pregnancy (AU)

Embriopatía por isotretinoína con microtia-anotia y cardiopatía: Presentación de un caso / Isotretinoin embryopathy with microtia-anotia and congenital heart disease: Case report

La isotretinoína es un retinoide derivado de la vitamina A utilizado para el tratamiento del acné noduloquístico y refractario, pero ha sido catalogado como un medicamento teratogénico. Se ha comunicado un espectro de defectos congénitos que incluyen malformaciones craneofaciales, defectos cardíacos y defectos en el sistema nervioso con la exposición prenatal a este medicamento. Se presenta el caso de una recién nacida con antecedente de exposición prenatal a isotretinoína con defectos congénitos craneofaciales que incluyen parálisis facial, anotia derecha y microtia izquierda, y cardiopatía compleja.

Isotretinoin is a retinoid that derivates from vitamin A. It is indicated for recalcitrant nodular acne treatment, but it has been classifed as teratogenic. A wide spectrum of birth defects including craniofacial, heart and nervous system malformations have been described associated to prenatal exposure to this drug. We report the case of a newborn with a history of prenatal exposure to isotretinoin with craniofacial defects, including facial paralysis, right anotia, left microtia and complex heart disease.

Morfometria das fibras colágeno cardíaco em ratos sadios e diabéticos suplementados com vitamina C / Morphometry of the collagen fibers in healthy and diabetic rats treated with vitamin C

The increase of heart collagen fibers in diabetics is a well known fact, but the consequences are not defined. The aim was to quantify the cardiac collagen fibers in normal and diabetic rats treated with vitamin C. We selected 32 Wistar rats, 16 diabetic animals induced endovenously with streptozootocin, and 16 healthy animals, half of them, diabetics and normals, were treated with vitamin C for 90 days. After the experimental proceeding, the hearts were removed and processed accordingly to conventional protocol for optical microscopy and specific staining for collagen. The results showed that the diabetic rats presented increase in the number of cardiac collagen fibers, but the ones treated with vitamin C showed little accumulation of fibers. It could be concluded that treatment with vitamin C is important for the prevention of heart failure in diabetic animals.

O aumento do conteúdo de fibras colágenas no coração de diabéticos é um fato bastante conhecido, suas conseqüências ainda são objeto de estudo e causam certa controvérsia, portanto este trabalho objetivou estudar a variação na quantidade das fibras de colágeno cardíacas em animais normais e diabéticos tratados pela vitamina C. Para isso foram selecionados 32 ratos Wistar, 16 diabéticos induzidos pela injeção endovenosa de estreptozootocina e 16 normais, sendo metade deles tratados com Vitamina C (diabéticos e normais) por um período de 90 dias. Após período experimental, os corações foram retirados e processados segundo protocolo convencional para microscopia óptica e coloração específica para colágeno. Os resultados mostram que animais diabéticos apresentam maior quantidade de fibras de colágeno cardíacas e que o tratamento com a vitamina C determinou um menor acúmulo na quantidade dessas fibras.

Recém nascido com cardiopatia congênita em decorrência do uso de isotretinoína materna / Maternal isotretinoin intake followed by congenital heart defects. Case report

Este trabalho apresenta um caso de um lactente do sexo feminino com 90 dias de vida, portador de interrupção do arco aórtico, defeito do septo ventricular e hipertensão pulmonar decorrentes do uso materno de Isotretinoína na segunda semana de gravidez. Foi submetido a cirurgia cardíaca para correção da cardiopatia, porém evoluiu para óbito no 5° pós-operatório, por hipertensão pulmonar

Fatal cardiac malformation in fetal valproate syndrome.

A neonate with a fatal cardiac malformation due to maternal valproate intake during pregnancy is presented.

Teratogenic effects of dilantin on thoraco-abdominal organs of developing chick embryos.

Congenital anomalies on some viscera like heart, liver and kidney have been investigated in chick embryos after a single injection of dilantin (3 mg/egg), a known antiepileptic drug, on 4th day of incubation. On 19th day of incubation, chick embryos were collected to observe the gross malformations and histological changes in heart, liver and kidney. On gross examination, visceroptosis (29%), thin anterior abdominal wall (28%), ectopia cordis (10%) and dextrocardia (1%) were observed. Histological examination of the kidney revealed glomerular degeneration in kidney while in liver, dilated central veins with degenerated hepatocytes were present. Longitudinal section of the heart showed thicker musculature specially of ventricles with a narrower lumen in comparison to that of the control. The results indicate teratogenicity of dilantin in developing chick embryos.

Cardiac laterality and ventricular looping in retinoic acid-treated rat embryos

To determine the ventricular looping pattern in relation to cardiac laterality, we studied rat embryos treated with retinoic acid (RA). A total of 243 Wistar rat embryos from an in vivo treated group (a single dose of 20-40 mg/kg all-trans RA administered to pregnant rats on day 6.5 to 9.5) and 29 control embryos were examined on day 13 of gestation. Twenty-nine embryos from the in-vitro treated group (treated by all-trans RA at 2 x 10(-7) M for 6 hr on day 9.0 or 9.5 during the entire embryo culture for 72 hr) and seven control embryos were examined on day 12 of gestation. Abnormalities in cardiac laterality and ventricular looping were found in the in-vivo groups treated on day 8.5 and 8.75 and in the in-vitro group on day 9.0. Among 25 animals with abnormal laterality, right isomerism was the most common feature (22 cases), while the type of ventricular looping varied. Cases with normal laterality had a low incidence of abnormal looping (1.4%). In rat embryos treated with all-trans RA, normal cardiac looping was expected when cardiac laterality was normal. But in cases with abnormal laterality, the type of abnormal ventricular looping was unexpected.

Visceral heterotaxy syndrome induced by retinoids in mouse embryo

Visceral heterotaxy syndrome causes abnormal arrangement of thoracoabdominal organs and severe complex cardiac anomalies by abnormal laterality. The purpose of the present study is to analyze the incidence and pattern of heterotaxy syndrome in etretinate and all-tran retinoic acid treated pregnant DDY mice. Pregnant DDY mice were intragastrically given a single dose of 15 mg/kg of etretinate at day 6, 7 of gestation, 30 mg/kg of etretinate at day 7 of gestation and 20 mg/kg of all-trans retinoic acid at day 7 of gestation. The incidence of visceral heterotaxy was highest in the etretinate 15 mg/kg treated group on day 7 of gestation (38.5%). The major cardiovascular anomalies in heterotaxy syndrome were common atrium, common atrioventricular valve, atrioventricular septal defect, transposition of great arteries, pulmonary atresia, pulmonary artery hypoplasia and aortic arch anomalies. Atrial situs of heterotaxy syndrome were right isomerism, solitus-like, inversus-like and left atrial aplasia, but right isomerism was observed most frequently. The results suggest that retinoic acid exerts a significant effect on the determination of atrial situs during the development of mouse embryo.