Maternal undernutrition during the preimplantation period of rat development causes blastocyst abnormalities and programming of postnatal hypertension

TLDR

Maternal undernutrition is linked to intrauterine growth restriction, low birth weight, and increased adult hypertension risk, yet the biological mechanisms of fetal programming remain largely unknown. The study aims to investigate the origin, embryonic phenotype, and potential maternal mechanisms underlying programming in a rat model. Researchers used a rat model in which dams received a low‑protein diet only during the preimplantation period (0–4.25 days after mating) before returning to a control diet for the remainder of gestation. Maternal low‑protein diet during preimplantation led to reduced birthweight, altered postnatal growth, hypertension, and organ/body‑weight ratios, while embryos showed decreased cell numbers in the inner cell mass and trophectoderm due to slowed proliferation, and maternal serum exhibited lower insulin and essential amino acids and higher glucose, indicating that a hyperglycaemic, amino‑acid‑depleted environment initiates metabolic stress that irreversibly programs postnatal physiology.

Abstract

ABSTRACT Epidemiological studies have indicated that susceptibility of human adults to hypertension and cardiovascular disease may result from intrauterine growth restriction and low birth weight induced by maternal undernutrition. Although the ‘foetal origins of adult disease’ hypothesis has significant relevance to preventative healthcare, the origin and biological mechanisms of foetal programming are largely unknown. Here, we investigate the origin, embryonic phenotype and potential maternal mechanisms of programming within an established rat model. Maternal low protein diet (LPD) fed during only the preimplantation period of development (0-4.25 days after mating), before return to control diet for the remainder of gestation, induced programming of altered birthweight, postnatal growth rate, hypertension and organ/body-weight ratios in either male or female offspring at up to 12 weeks of age. Preimplantation embryos collected from dams after 0-4.25 days of maternal LPD displayed significantly reduced cell numbers, first within the inner cell mass (ICM; early blastocyst), and later within both ICM and trophectoderm lineages (mid/late blastocyst), apparently induced by a slower rate of cellular proliferation rather than by increased apoptosis. The LPD regimen significantly reduced insulin and essential amino acid levels, and increased glucose levels within maternal serum by day 4 of development. Our data indicate that long-term programming of postnatal growth and physiology can be induced irreversibly during the preimplantation period of development by maternal protein undernutrition. Further, we propose that the mildly hyperglycaemic and amino acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of ‘metabolic stress’, restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages.