Lysine Deprivation during Maternal Consumption of Low-Protein Diets Could Adversely Affect Early Embryo Development and Health in Adulthood

Abstract

The conversion of lysine to glutamate is needed for signaling in all plants and animals. In mouse embryonic stem (mES) cells, and probably their progenitors, endogenous glutamate production and signaling help maintain cellular pluripotency and proliferation, although the source of glutamate is yet to be determined. If the source of glutamate is lysine, then lysine deprivation caused by maternal low-protein diets could alter early embryo development and, consequently, the health of the offspring in adulthood. For these reasons, we measured three pertinent variables in human embryonic stem (hES) cells as a model for the inner cell masses of human blastocysts. We found that RNA encoding the alpha-aminoadipic semialdehyde synthase enzyme, which regulates glutamate production from lysine, was highly expressed in hES cells. Moreover, the mean amount of lysine consumed by hES cells was 50% greater than the mean amount of glutamate they produced, indicating that lysine is likely converted to glutamate in these cells. Finally, hES cells expressed RNA encoding at least two glutamate receptors. Since this may also be the case for hES progenitor cells in blastocysts, further studies are warranted to verify the presence of this signaling process in hES cells and to determine whether lysine deprivation alters early mammalian embryo development.

Environmental Exposures around Conception: Developmental Pathways Leading to Lifetime Disease Risk

“…Second, lysine is reduced in Emb-LPD maternal serum and in blastocysts at E3.5, and also, at trend level, in the UF [46]. Lysine may act as a source of glutamate production and the maintenance of signalling, pluripotency and proliferation in embryonic stem cells, and thus, may also be critical in induction of adverse developmental programming [69]. However, we consider this pathway to be less likely since glutamic acid levels are unchanged in Emb-LPD serum and UF and, indeed, are increased in Emb-LPD blastocysts [46].…”

Amino Acid Transport and Metabolism Regulate Early Embryo Development: Species Differences, Clinical Significance, and Evolutionary Implications

“…As for Thr, Lys is not a preferred substrate of any known transport system in the trophectoderm (e.g., Table 2) [19,36]. However, it may be needed in the ICM for glutamate (Glu) production [24]. We suggest that trophoblast cells take up protein by pinocytosis and hydrolyze the protein to generate Lys as well as Thr for the ICM [24].…”

“…Alternatively, since Ile deficiency is an effective activator of trophoblast endocytosis and lysosome production [44], excess Ile consumption during preimplantation embryo development could conceivably reduce the trophectoderm endocytic uptake of uterine fluid proteins and their digestion in lysosome. A decreased lysosomal protein digestion could limit the supply of threonine and lysine to ICM cells [1,19,24]. (See Section 4 below.)…”

“…It has also been speculated that the other cationic amino acid, Lys, might be deficient in low-protein diets [24]. Both an increase and a decrease in maternal dietary lysine produced smaller fetuses/birth weights in rats, e.g., [59,60].…”

“…However, it may be needed in the ICM for glutamate (Glu) production [24]. We suggest that trophoblast cells take up protein by pinocytosis and hydrolyze the protein to generate Lys as well as Thr for the ICM [24]. The transport of Lys across the plasma membrane of ES and their progenitor cells in the ICM has not, to our knowledge, been characterized.…”