Investigation of Developmental Toxicity and Teratogenicity of Antiemetics on Rat Embryos CulturedIn Vitro

Abstract

In this study, we aimed to investigate and compare the direct toxic and teratogenic effects of dimenhydrinate, metoclopramide and trimethobenzamide HCl, antiemetic drugs on embryonic growth and development in cultured rat embryos. Embryos were explanted on day 9.5 of gestation and cultured. Whole rat serum was used as a culture medium for the control group while different concentrations of dimenhydrinate (2.5-20 μg/ml), metoclopramide (10-50 μg/ml) and trimethobenzamide HCl (25-100 μg/ml) were added to serum for the experimental groups. Effects of antiemetics on embryonic developmental parameters were compared, and embryos were evaluated for the presence of any malformations. Also, the total DNA was extracted from the cells to determine the fragmentation of nuclear DNA of embryonic cells. Compared with the control embryos, the antiemetics significantly decreased all growth and developmental parameters dose dependently. There was no difference regarding the fragmentation of nuclear DNA of the all used agents and controls. Amongst the agents, trimethobenzamide HCl was found to have more toxic and teratogenic potential, and metoclopramide appears to be the least toxic antiemetic and therefore could be more safely used and might be preferred for the treatment of nausea and vomiting in pregnancy.

Effect of dimenhydrinate on neural tube development in early chick embryo model

“…Bu nedenle fetüslerde önemli yan etkilere ve malformasyonlara neden olabilir. Bazı deneysel çalışmalar, embriyonal dönemde dimenhidrinat kullanımının bazı organlarda teratojenik etkilere neden olabileceğini göstermiştir 22,[29][30][31][32] .…”

“…Embriyonun fleksiyonu, kalp gelişimi, nöral tüp gelişimi, kraniokaudal mesafe, somit sayısı gibi morfolojik parametreler değerlendirilmiştir. Çalışma sonucunda dimenhidrinatın en küçük dozdan itibaren önemli derecede teratojenik etkiye neden olduğu belirtilmiştir 32 . Czeizel ve arkadaşlarının yaptıkları çalışmada yarık dudaklı veya yarık damaklı doğan 1950 bebeğin annelerinde dimenhidrinat kullanımı değerlendirilmiştir.…”

Role of apoptosis in mediating diclofenac-induced teratogenesis

“…It was not only to verify the involvement of apoptosis in bringing these defects during major organogenesis in in vitro conditions but also whether it can be used as a reference end point marker for predicting teratogenicity well in advance. Rat whole-embryo Singh et al 5 culture method has emerged as a powerful test system for the detailed investigation of the normal embryogenesis regulations (Fazliogullari et al, 2012;Karabulut et al, 2008). Day 11 postimplantation rat embryos were cultured in rat serum with medium for 24 h with different DCF concentrations, that is, 3.75, 7.5 and 15 mg/ml, respectively.…”