Evaluation of the maternal and developmental toxicity of 6-methylmercaptopurine riboside in rats.

Thiopurine prodrugs (azathioprine, AZA, and 6-mercaptopurine, 6MP) are embryotoxic to rodents and rabbits. Little is known about the developmental toxicity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine drug metabolite that is thought to mediate its liver toxicity. A limb bud assay found that 6MMPr impairs the in vitro morphogenetic differentiation of mouse limb extremities, being more potent than 6MP in the assay. This study evaluated the embryotoxicity of 6MMPr (0, 7.5, 15, 30 mg/kg bw sc) in rats after single-dose exposure in mid organogenesis (GD10). One group of pregnant rats was similarly treated with 6MP (15 mg/kg bw sc). After C-section (GD21), fetuses were weighed, and examined for external abnormalities. One third of each litter was examined for soft-tissue abnormalities while the remaining fetuses were cleared and stained for skeleton evaluation. 6MMPr caused a dose-dependent maternal weight loss followed by recovery before term pregnancy. Except for a nonsignificant increase in embryolethality and slight reduction in fetal weight at 30 mg/kg bw, no indication of embryotoxicity was noted at this dose or at lower doses of 6MMPr. In contrast, 6MP led to nearly 98 % of post-implantation losses in the presence of slight-to-mild maternal toxicity. These results are consistent with the notion that maternal treatment with 6MMPr affects embryo development, causing a nonsignificant increase in embryolethality and a slight reduction in fetal weight at 30 mg/kg bw. However, there was no increase in abnormalities at this dose, which was severely toxic to the dams, as reflected in the maternal weight gain data.

Evaluation of the developmental toxicity of solvents, metals, drugs, and industrial chemicals using a freshwater snail (Biomphalaria glabrata) assay.

A freshwater snail assay was employed to assess the embryotoxicity of solvents including acetone, methanol, ethanol, isopropanol, dimethyl-sulfoxide, glycerin, metals/metalloids including mercuric chloride (HgCl2), cadmium chloride (CdCl2,), antimony salts Sb+3 and Sb+5, drugs including colchicine, hydroxyurea, cyclophosphamide, an industrial chemical sodium azide (SA), an anionic surfactant dodecyl sodium sulfate-(DSS), H2O2 and sodium chloride (NaCl). The assay consists of exposing Biomphalaria glabrata egg masses (EM) to the substances for 96-hr and following up embryo/snail development for lethality, abnormal morphology (teratogenicity), and day of hatching up to day 10 or 14 after spawning. Based upon concentration-response relationships, LC50%s (embryolethality), EC50%s (teratogenicity) and IC50%s (hatching retardation) and 95%CIs were determined for tested chemicals. The LOECs indicated that HgCl2 (37 nM) and CdCl2 (140 nM) are potent embryotoxic agents in snails. Teratogenic indices (TI = LC50/EC50) for almost all tested chemicals were lower than or close to unity suggesting that these compounds were not teratogenic in this assay. The snail assay may be adequately performed in a cost-effective standardized protocol which enables testing a number of environmental chemicals over a broad concentration range. The snail assay needs to undergo further validation to be recognized for an internationally harmonized hazard identification in ecotoxicity risk assessment.

Maternal and fetal outcome of pregnancy in Swiss mice infected with Plasmodium berghei ANKAGFP.

Malaria in pregnant women is associated with risk of maternal and perinatal morbidity and mortality, and there are few antimalarial drugs considered safe to treat them, so it is necessary to develop safer antimalarial medicines. The goal of this study was to develop an animal model for human malaria during pregnancy by characterizing the maternal and fetal outcomes in malaria infected Swiss mice. For that, in the present study, we evaluated the outcome of pregnancy in Swiss mice infected with Plasmodium berghei ANKAGFP. We observed a reduction of fetal body weight and signs of skeletal ossification retardation in the offspring of mice infected on GD 12. The group of mice infected with malaria presented premature deliveries and histopathology changes consistent with placental malaria. Our study suggests that Swiss Webster mice infected with P. berghei ANKAGFP on GD 12 might be a valuable model to investigate the safety and the efficacy of new antimalarial drugs indicated to pregnant women.

Delayed ossification in Wistar rats induced by Morinda citrifolia L. exposure during pregnancy.

UNLABELLED: 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. AIM OF THE STUDY: Evaluate the possible developmental toxicity of the noni fruit aqueous extract and commercial product of TAHITIAN NONI juice in rats exposed during pregnancy. MATERIALS AND METHODS: 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. RESULTS: Exposure with extract and juice of Morinda citrifolia did not induce maternal toxicity at the tested doses, but induced delayed ossification in fetuses. CONCLUSION: 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.