The influence of the intrauterine environment on human placental development.

Development of the human placenta is modulated heavily by the intrauterine environment. During the first trimester, development takes place in a low oxygen environment supported by histiotrophic nutrition from the endometrial glands. Consequently, the rate of growth of the chorionic sac is almost invariable across this period, and is remarkably uniform between individuals. Towards the end of the first trimester the intrauterine environment undergoes radical transformation in association with onset of the maternal arterial circulation and the switch to haemotrophic nutrition. The accompanying rise in intraplacental oxygen concentration poses a major challenge to placental tissues, and extensive villous remodelling takes place at this time. Later in pregnancy a wide variety of stressors are capable of affecting placental growth, but in the human, the most common are nutrient deprivation and vascular compromise. The latter is usually secondary to deficient trophoblast invasion and can induce placental oxidative stress. Closely linked to oxidative stress is endoplasmic reticulum stress, and we recently provided the first evidence that the latter plays a major role in the pathophysiology of intrauterine growth restriction. The endoplasmic reticulum is a key regulator of protein synthesis, exerting its effects through the unfolded protein response. Consequently, we observed multiple blocks to translation initiation and elongation in growth restricted placentas. Nutrient deprivation also modulates protein synthesis through the mTOR pathway, and we demonstrated interactions between this pathway and endoplasmic reticulum stress. Protein synthesis inhibition therefore appears to be a common mechanism for regulating placental development under different adverse conditions.