Differential Fetal Responses to Maternal Nutrient Restriction: A Population Variance Approach.

Abstract

Recent studies have demonstrated that, although important, birth weight alone is an insufficient indicator of fetal growth and postnatal health and well-being. Using the undernourished sheep model, it is widely accepted that maternal nutrient restriction (NR) results in offspring that are smaller at birth than counterparts from adequately fed ewes. However, closer examination of these cohorts reveals a highly variable response to maternal nutrient stress, as might be expected in an outbred animal. Our objective was to identify and further investigate fetuses benefiting from a positive adaptive response to this nutritional stress, as evidenced by normal fetal weight, compared to those exhibiting intrauterine growth restriction (IUGR). To identify subpopulations of ewes able to support normal fetal growth despite inadequate nutrition, multiparous Suffolk ewes were made pregnant by transfer of a single embryo into the uterus on Day 5.5 post-estrus. Pregnancy was confirmed by ultrasound on Day 28. Beginning on Day 35 of pregnancy and continuing throughout the study, ewes were fed 50% of the NRC requirements. An additional group of ewes received 100% of their NRC recommended intake throughout the study to serve as a control. On Day 125 of pregnancy, ewes were necropsied and fetal and placental tissues were collected. Results of subsequent analyses identified unique organ specific patterns in gene expression segregating these three distinct fetal sub-populations. Interestingly, in some instances NR non-IUGR fetuses exhibit gene expression patterns similar to control fed animals, while in other cases both NR non-IUGR and IUGR fetuses exhibit a similar pattern of gene expression that is vastly different than that of fetuses from control fed ewes. These intriguing results highlight the need for a more comprehensive assessment of the intrauterine environment during fetal development to predict short- and long-term health of the offspring. This knowledge will prove useful for identifying windows of potential intervention. Further, these studies highlight the value of alternative outbred animal models such as the sheep for understanding dynamic processes regulating fetal growth and development.