Tamoxifen exposure induces cleft palate in mice

Cleft palate is a common birth defect in mammals, which can be caused by genetic or environmental factors, or both. Decades have witnessed that many environmental exposures during gestation extremely increase the incidence of cleft palate. Tamoxifen (TAM), a widely-used drug in treating breast cancer, has been reported to be associated with craniofacial defects including micrognathia and cleft palate in humans. However, its exact effects on the developing palate remain unclear. Here we took advantage of a mouse model to explore how TAM affects palatal development at the molecular level. We showed that excess exposure of TAM in the early embryonic stages indeed leads to cleft palate in mice. RNA-sequencing results strongly suggest the involvement of mitogen-activated protein kinase (MAPK) signalling in TAM-induced cleft palate. Interestingly, in the anterior portion of the TAM-treated palatal shelf, phosphorylated (p)-AKT and p-ERK1/2 were activated but p-p38 was inhibited, while in the posterior palate, the p-AKT increased but the levels of p-p38 and p-JNK decreased. We conclude that excess TAM exposure causes cleft palate defects in mice by regulating MAPK pathways, which implicates the importance of tightly-regulated MAPK signalling in palatal development. This study provides a basis for further exploration of the molecular aetiology of cleft palate defects caused by environmental factors and, based on our results, we would give a serious warning regarding prescription of TAM and potential cleft palate defects in animal models involving the inducible Cre-LoxP system.