Adverse effects of retinoic acid on embryo development and the selective expression of retinoic acid receptors in mouse blastocysts

BACKGROUND: All-trans retinoic acid (RA), the oxidative metabolite of vitamin A, is essential for normal development. In addition, high levels of RA are teratogenic in many species. We have previously shown that excess RA results in immediate effects on the preimplantation embryo and on blastocyst development. This study was conducted to clarify the long-term survival of mouse blastocyst and the effect of RA on gene expression. METHODS AND RESULTS: Using an in vitro model, we identified the immediate adverse impact of RA on mouse blastocyst development. This involved an inhibition of cell proliferation and growth retardation. Using an in vivo model, we also identified the resorption of postimplanted blastocysts that had been treated with excess RA. Analysis of RA-mediated gene induction was also included. The retinoic acid receptors RAR alpha and RAR gamma were constitutively expressed in the blastocyst and the inner cell mass, whereas RAR beta was induced upon RA treatment. CONCLUSIONS: This is the first evidence to show the impacts of RA on mouse blastocysts in vitro and any carry-over effects in the uterus. There is a retardation of early postimplantation blastocyst development and then subsequent blastocyst death. Our findings also show that there is some degree of selective induction of retinoic acid receptors when excess RA is administered to the blastocysts.