Metabolic and Mitochondrial Dysfunction in Early Mouse Embryos Following Maternal Dietary Protein Intervention1

Abstract

Dietary supply of nutrients, both periconception and during pregnancy, influence the growth and development of the fetus and offspring and their health into adult life. Despite the importance of research efforts surrounding the developmental origins of health and disease hypothesis, the biological mechanisms involved remain elusive. Mitochondria are of major importance in the oocyte and early embryo, particularly as a source of ATP generation, and perturbations in their function have been related to reduced embryo quality. The present study examined embryo development following periconception exposure of females to a high-protein diet (HPD) or a low-protein diet (LPD) relative to a medium-protein diet (MPD; control), and we hypothesized that perturbed mitochondrial metabolism in the mouse embryo may be responsible for the impaired embryo and fetal development reported by others. Although the rate of development to the blastocyst stage did not differ between diets, both the HPD and LPD reduced the number of inner cell mass cells in the blastocyst-stage embryo. Furthermore, mitochondrial membrane potential was reduced and mitochondrial calcium levels increased in the 2-cell embryo. Embryos from HPD females had elevated levels of reactive oxygen species and ADP concentrations, indicative of metabolic stress and, potentially, the uncoupling of oxidative phosphorylation, whereas embryos from LPD females had reduced mitochondrial clustering around the nucleus, suggestive of an overall quietening of metabolism. Thus, although periconception dietary supply of different levels of protein is permissive of development, mitochondrial metabolism is altered in the early embryo, and the nature of the perturbation differs between HPD and LPD exposure.

Mouse early extra-embryonic lineages activate compensatory endocytosis in response to poor maternal nutrition

“…For example, we find in our mouse model that maternal Emb-LPD changes the allocation and ratio of cells within blastocyst lineages with a higher proportion within the outer trophectoderm (TE; progenitor of chorio-allantoic placenta) and a lower complement within the inner cell mass (ICM; progenitor of fetus and primitive endoderm lineage) . This early consequence of poor maternal diet has also been identified by other laboratories using related mouse and large mammal models (Kakar et al, 2005;Mitchell et al, 2009). We also find increased TE proliferation coincides with increased motility and spreading activity of these cells as they outgrow as trophoblasts, probably to increase their invasiveness into the endometrium during implantation .…”

High-protein diet during gestation and lactation affects mammary gland mRNA abundance, milk composition and pre-weaning litter growth in mice

“…Similar results were reported for rats (Daenzer et al, 2002), mice (Langhammer et al, 2006) and pigs exposed in utero to an HP diet, however, others found no differences (Thone-Reineke et al, 2006). As mice dams consumed an HP diet already during the mating period, the reduced litter size probably reflects the detrimental effect of an HP diet during the implantation period as shown by others in mice (Gardner et al, 2004;Mitchell et al, 2009). However, we found no indications for differences in percentage of successful pregnancies.…”

Maternal obesity in mice not only affects fresh embryo quality but also aggravates injury due to vitrification

“…However, we also demonstrated that the embryonic survival and developmental rate differences between obese and control mice were eliminated after embryos were vitrified and thawed, in contrast to the results in domestic animals [18]. A high-fat diet significantly reduced mitochondrial membrane potential in mature oocytes [17], with significant consequences for developmental competence [21][22][23]. Cumulusoocyte complexes (COCs) from mice fed a high-fat diet showed increased expression of the endoplasmic reticulum (ER) stress marker genes ATF4 and GRP78, and increased apoptotic rates were observed in granulosa and cumulus cells of mice fed a highfat diet [17].…”