In vitro developmental toxicology assays: A review of the state of the science of rodent and zebrafish whole embryo culture and embryonic stem cell assays

Abstract

In vitro developmental model systems have been an important tool for advancing basic research in the embryology and teratology fields. The rat and zebrafish embryo models have had broad utility in both fields for many decades. Furthermore embryonic stem cells, applied as a basic research tool, have broad applications across the development fields and many other fields including cancer, regeneration and epigenetic research. These models have historically been applied in mechanistic studies but were also considered promising for evaluating teratogenic potential of test substances. In recent years, in vitro teratogenicity assays have become an area of interest for supporting the 3 Rs (reduction, refinement, and replacement of animal use). Generation of such assays also provides a means to facilitate early assessment of test agents at a higher throughput without excessive use of animals. In this review, the three models are described with an emphasis of how they are being developed and/or refined to support teratogenicity assessment as screening tools. An overview of the state of the science and future directions are described.

eNOS Deficiency Acts through Endothelin to Aggravate sFlt-1–Induced Pre-Eclampsia–Like Phenotype

“…The use of ET A R antagonists that cross the placenta is not recommended for treatment of pre-eclampsia because of their teratogenicity. 31,32 However, future studies may reveal targets downstream of ET receptor that could be harnessed for the treatment of pre-eclampsia.…”

A roadmap for the development of alternative (non-animal) methods for systemic toxicity testing

“…For this reason, an early focus in alternative method development was on tests for embryonic malformations (Augustine-Rauch et al, 2010). The most complete reflection of embryonic development apparently can be achieved with zebrafish embryos (Selderslaghs et al, 2011;Sukardi et al, 2011;Weigt et al, 2010Weigt et al, , 2011Yang et al, 2009), for example using dynamic cell imaging, or frog eggs (FETAX assay) (Hoke and Ankley, 2005), which has been evaluated more critically by IC-CVAM 1 .…”

Effects of Nitrite on Development of Embryos and Early Larval Stages of the Zebrafish (Danio rerio)

“…11 In addition, assays are being developed to screen environmental chemicals and drugs for possible embryotoxic and teratogenic effects. 12,13 For example, the teratogenic potential of 31 compounds was tested using a dechorionated embryo teratogenicity assay, and 87% of the compounds were successfully categorized as either teratogens or nonteratogens.…”