Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth

Abstract

Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth.