Metabolic Induction and Early Responses of Mouse Blastocyst Developmental Programming following Maternal Low Protein Diet Affecting Life-Long Health

Abstract

Previously, we have shown that a maternal low protein diet, fed exclusively during the preimplantation period of mouse development (Emb-LPD), is sufficient to induce by the blastocyst stage a compensatory growth phenotype in late gestation and postnatally, correlating with increased risk of adult onset cardiovascular disease and behavioural dysfunction. Here, we examine mechanisms of induction of maternal Emb-LPD programming and early compensatory responses by the embryo. Emb-LPD induced changes in maternal serum metabolites at the time of blastocyst formation (E3.5), notably reduced insulin and increased glucose, together with reduced levels of free amino acids (AAs) including branched chain AAs leucine, isoleucine and valine. Emb-LPD also caused reduction in the branched chain AAs within uterine fluid at the blastocyst stage. These maternal changes coincided with an altered content of blastocyst AAs and reduced mTORC1 signalling within blastocysts evident in reduced phosphorylation of effector S6 ribosomal protein and its ratio to total S6 protein but no change in effector 4E-BP1 phosphorylated and total pools. These changes were accompanied by increased proliferation of blastocyst trophectoderm and total cells and subsequent increased spreading of trophoblast cells in blastocyst outgrowths. We propose that induction of metabolic programming following Emb-LPD is achieved through mTORC1signalling which acts as a sensor for preimplantation embryos to detect maternal nutrient levels via branched chain AAs and/or insulin availability. Moreover, this induction step associates with changes in extra-embryonic trophectoderm behaviour occurring as early compensatory responses leading to later nutrient recovery.

Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos

“…Intrauterine leucine availability is one of the key factors that may affect the predisposition to diseases in adulthood caused by maternal low-protein diet, obesity, type 2 diabetes mellitus and for cardiovascular diseases (Langley et al 1994, Langley-Evans et al 1996, Heywood et al 2004, Eckert et al 2012. We show that an altered maternal nutritional environment is associated with increased embryonic mTORC1 signalling.…”

“…In the mouse, a disruption of the Mtor gene resulted in early embryo lethality (E 5.5) (Gangloff et al 2004). A maternal low-protein diet in mice led to decreased amino acid levels combined with reduced embryonic mTORC1 signalling (E 3.5) (Eckert et al 2012).…”

Low female birth weight and advanced maternal age programme alterations in next-generation blastocyst development

“…fetal growth (Yang et al 2003). Reduced mTORC1 activity was reported in F1 mouse blastocysts from mothers subjected to maternal undernutrition (0-4.25 days) during pregnancy (Eckert et al 2012). As gene expression analysis was performed on blastocysts retrieved from F1 growth-restricted females, this clearly highlights preexisting (epi)genetic alterations that could affect blastocyst metabolism.…”

Effects of perinatal, late foetal, and early embryonic insults on the cardiovascular phenotype in experimental animal models and humans

“…During its passage through the female reproductive tract, the embryo is involved in a highly complex interaction with its environment that includes specifi c signalling [65] and metabolic equilibrium [66,67]. It is obvious that the laboratory conditions used during ART only very imperfectly mimic the conditions of maternal reproductive tract.…”