α-tocopherol transfer protein is important for the normal development of placental labyrinthine trophoblasts in mice

α-Tocopherol transfer protein (α-TTP), a cytosolic protein that specifically binds α-tocopherol, is known as a product of the causative gene in patients with ataxia that is associated with vitamin E deficiency. Targeted disruption of the α-TTP gene revealed that α-tocopherol concentration in the circulation was regulated by α-TTP expression levels. Male α-TTP^-/- mice were fertile; however, placentas of pregnant α-TTP^-/- females were severely impaired with marked reduction of labyrinthine trophoblasts, and the embryos died at mid-gestation even when fertilized eggs of α-TTP^+/+ mice were transferred into α-TTP^-/- recipients. The use of excess α-tocopherol or a synthetic antioxidant (BO-653) dietary supplement by α-TTP^-/- females prevented placental failure and allowed full-term pregnancies. In α-TTP^+/+ animals, α-TTP gene expression was observed in the uterus, and its level transiently increased after implantation (4.5 days postcoitum). Our results suggest that oxidative stress in the labyrinth region of the placenta is protected by vitamin E during development and that in addition to the hepatic α-TTP, which governs plasma α-tocopherol level, the uterine α-TTP may also play an important role in supplying this vitamin.