Disrupted blastocoele formation reveals a critical developmental role for long-chain acyl-CoA dehydrogenase

Abstract

Long-chain acyl-CoA dehydrogenase (LCAD) deficiency has not been found in human patients. There has been an LCAD deficient (LCAD−/−) mouse model developed via gene targeting strategies that has gestational loss as a part of its phenotype. We tested the hypothesis that LCAD deficiency disrupts normal embryonic development and explains at least in part the gestational loss in the mouse and may suggest a mechanism to explain the lack of any human patients with this inherited enzyme deficiency. We cultured and evaluated embryos with three different genotypes: LCAD+/+, LCAD+/−, and LCAD−/−. We found a significantly increased rate of death ( P<0.012) in LCAD−/− embryos at the morula-to-blastocyst conversion indicating a deficient ability to complete the development of a blastocoele and formation of a blastocyst. Furthermore, we hypothesized that we could rescue LCAD−/− embryos in culture by supplying excess fatty acids of chain-lengths that could be readily oxidized by them despite their inherited enzyme deficiency. We were unable, however, to demonstrate any rescue by supplementing the culture medium with fatty acids of a wide-range of chain-lengths. Therefore, overall we demonstrated a severely deficient capacity for LCAD−/− embryos to develop past the morula stage with intermediate rates of development found in the LCAD+/− embryos as compared to the LCAD+/+ embryos. Furthermore, we were unable to rescue the LCAD−/− embryos with any fatty acid supplementation.