Embryo

Adaptive Responses by Mouse Early Embryos to Maternal Diet Protect Fetal Growth but Predispose to Adult Onset Disease

Abstract
Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD) fed exclusively during mouse preimplantation development leads to offspring with increased weight from birth, sustained hypertension and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multi-ligand megalin (LRP2) receptor, and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that the onset of adult disease markers, notably excess weight and hypertension, can derive from physiological mechanisms of developmental plasticity activated within the preimplantation embryo to stabilize conceptus growth and enhance fitness in a nutrient restricted environment.

Key words: Behavior • Embryo • Environment • Conceptus • Developmental biology

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