A 3Rs approach to assess drug toxicity on the mammalian embryo during early pregnancy in vitro using Gastruloids
Establishing a Gastruloid model
It is important for pregnant women, or women trying to conceive, to be aware of the risks posed by any medication they may have to take during pregnancy. This is especially important during the 1st trimester, when the embryo is at its most sensitive to developmental defects. The general advice given to women is not to take medication at all during their pregnancy & healthcare professionals are advised to prescribe only when the benefit to the mother outweighs the potential effects on the embryo. This demonstrates the need for adequate information on the effect of current & new drugs during pregnancy, especially when treating certain conditions (e.g. epilepsy, HIV) where withholding treatment might not be prudent. As pregnant women cannot be used to test whether drugs are harmful in pregnancy, we must rely on results from animals during pre-clinical testing, where millions of animals (a large proportion of which are rodents) are used & consequently the tests are highly expensive. Unfortunately, the accuracy of these Developmental & Reproductive Toxicity studies (DARTs) in predicting human developmental toxicity is still unknown & the absence of any effect in animal tests does not necessarily mean a drug is safe to take during pregnancy. Although there are validated in vitro alternatives, none of these provide an integrated approach to look at the early developing embryo.
We have developed a novel 3D tissue-culture protocol (Gastruloids) that uses small numbers of mouse embryonic stem cells (mESCs), grown in suspension. Over time, these gastruloids mimic many of the early developmental events seen during mouse development: symmetry-breaking, polarised gene expression, axis elongation & formation of 3 embryonic axes. Gastruloids are highly tractable, allowing precise experimental manipulation, difficult to do with embryos. This project aims to examine whether gastruloids will substitute mice during DARTs, directly targeting the area of drug development where animals are the predominant model for DARTs.