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Adaptive Responses by Mouse Early Embryos to Maternal Diet Protect Fetal Growth but Predispose to Adult Onset Disease¹

School of Biological Sciences,³ University of Southampton, Southampton SO16 7PX, United Kingdom Institute of Developmental Sciences,⁴ Developmental Origins of Health and Disease Division, School of Medicine, and MRC Epidemiology Resource Centre,⁵ University of Southampton, Southampton General Hospital, Southampton SO16 0YD, United Kingdom

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 multiligand 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 in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases.

behavior, blastocyst, blood pressure, conceptus, developmental biology, embryo, environment, growth, low protein diet, megalin, preimplantation embryo, yolk sac

¹Supported by NIH as part of the NICHD National Cooperative Program on Female Health and Egg Quality under cooperative agreement U01 HD044635 and with partial support from the Medical Research Council, UK (G9800781). R.P. is in receipt of a Medical Research Council, UK, postgraduate studentship; M.A.H. is supported by the British Heart Foundation.

Correspondence: ²Tom P. Fleming, School of Biological Sciences, University of Southampton, Bassett Crescent East, Southampton, SO16 7PX, United Kingdom. FAX: 44 2380 594459; e-mail: tpf{at}soton.ac.uk

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