Adaptive responses by mouse early embryos to maternal diet protect fetal growth but predispose to adult onset disease.
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.
Watkins
Adam J
AJ
School of Biological Sciences, University of Southampton, Southampton SO16 7PX, United Kingdom.
Ursell
Elizabeth
E
Panton
Rose
R
Papenbrock
Thomas
T
Hollis
Lisa
L
Cunningham
Colm
C
Wilkins
Adrian
A
Perry
V Hugh
VH
Sheth
Bhavwanti
B
Kwong
Wing Yee
WY
Eckert
Judith J
JJ
Wild
Arthur E
AE
Hanson
Mark A
MA
Osmond
Clive
C
Fleming
Tom P
TP
D000818:Animals; D001755:Blastocyst / Q000378:metabolism / Q000502:physiology*; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D004198:Disease Susceptibility / Q000209:etiology*; D004475:Ectoderm / Q000378:metabolism / Q000502:physiology; D005260:Female; D047109:Fetal Development / Q000502:physiology*; D008297:Male; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains; D011247:Pregnancy; D039401:Prenatal Nutritional Physiological Phenomena; D015017:Yolk Sac / Q000378:metabolism / Q000502:physiology