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

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 embryoderived 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

Adverse prenatal environment and kidney development: implications for programing of adult disease

“…The data are primarily derived from either rodent (see Watkins et al (2008aWatkins et al ( ,b, 2010) or sheep models (Edwards & McMillen (2002), , 2010, Todd et al 2009, Lie et al 2013, Nicholas et al 2013. As shown in the Table 1, the timing of the periconceptional insult may include oocyte maturation and the preimplantation period.…”

“…Following a low-protein diet around conception, maternal control of insulin and glucose was impaired in association with changes in amino acid levels in both the maternal and blastocyst environment. Furthermore, changes in trophectoderm, inner cell mass, and total cell numbers were observed (Kwong et al 2000, Watkins et al 2008a,b, Eckert et al 2012. These changes in the maternal milieu highlight the importance of understanding the environment around the time of conception.…”

“…Reductions in heart and kidney weights relative to body weight were shown, though tended to be sexually dimorphic (Kwong et al 2000, Watkins et al 2008a. Increases in systolic blood pressure were demonstrated following a period of protein restriction through either the period of oocyte maturation (K3.5 until mating) or the preimplantation (0-3.5/4.5 days of gestation) period in both the mouse and rat (Kwong et al 2000, Watkins et al 2008a. As shown in the Table 1, these outcomes are similar to those following a low-protein diet throughout pregnancy (Woods et al 2004).…”

Epigenetic mechanisms involved in developmental nutritional programming

“…Environmental conditions at these stages may also alter behavior, cardiovascular function and reproductive function throughout postnatal life [57][58][59][60][61][62][63][64] . Low maternal protein consumption or vitamin B and methionine status leads to behavioral and cardiovascular abnormalities in offspring, sex-specific changes in hepatic gene expression in rat fetuses and changes in imprinted gene expression in the rat embryofetal axis [65][66][67][68] . It has recently been shown that in vitro culture conditions, as found in assisted reproduction technology, may affect global patterns of DNA methylation and gene expression.…”

Why it is critical to address the challenge of maternal obesity

“…Animal studies have demonstrated how preimplantation embryos are sensitive to diverse environmental conditions. In studies on mice it was shown how a low-protein maternal diet during the periconceptional period is sufficient to induce increased cardiovascular, metabolic and behavioral abnormalities in adulthood, even when normal nutrition was applied during the rest of pregnancy and in postnatal life (12).…”