A Low-Protein Diet during Gestation in Rats Activates the Placental Mammalian Amino Acid Response Pathway and Programs the Growth Capacity of Offspring1–3

Abstract

Placental efficiency is a predictor of fetal growth and development, which is also controlled by maternal gestational health and diet. The present study investigated the effects of a gestational low-protein diet on offspring growth capacity as well as the diet’s contribution to altered expression of placental genes associated with the mammalian amino acid response (AAR) pathway. To assess these outcomes, timed-pregnant Sprague Dawley rats were fed a control (C) diet with 18% protein or a low-protein (LP) diet with 9% protein throughout gestation (Expt. 1) or throughout gestation and lactation (Expt. 2). Placentas were collected during natural delivery and quantitative RT-PCR and Western-blot analyses were performed to determine placental mRNA and protein levels. By the end of the lactation period, offspring of dams fed the LP diet had stunted growth in both experiments. mRNA expression of target genes in the AAR pathway, such as activating transcription factor-3 (Atf3), asparagine synthetase (Asns), and Sodium-dependent neutral amino acid transporter-2 (Snat2), was greater in placentas of rats fed the LP diet compared with controls, as were placental ATF4 and p-eIF2α protein levels. The increase in mRNA expression of AAR pathway-associated genes was correlated with the stunting of offspring growth (Atf3: R2 = 0.32, P = 0.086; Asns: R2 = 0.44, P < 0.05; Snat2:R2 = 0.33, P = 0.084). Our study showed that the mammalian AAR pathway in placenta is upregulated by a maternal low-protein diet and this activation may act as a cue for the fetus to develop an adaptive response suited to their predicted postnatal environment, i.e. a more favorable phenotype for their survival.