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.
Highlights
In humans, as in all eutherians, prenatal growth relies on the nutrient supply and gas exchange mediated by the placenta
In this study we demonstrate that the fetal, placental and maternal compartments are differentially affected by prolonged maternal protein restriction in mice
Placenta size and function was first to be affected as a result of the low protein diet, as early as E10.5
Summary
As in all eutherians, prenatal growth relies on the nutrient supply and gas exchange mediated by the placenta. The inadequate availability of nutrients and/or oxygen for the fetus due to environmental factors such as maternal malnutrition or deficient blood flow caused by placental insufficiency, frequently results in intrauterine growth restriction (IUGR) [1,2,3]. There is great interest in understanding which changes occur in feto-placental development under stressful conditions and their adaptive role in sustaining fetal growth as well as the demand of energy for the growth and maintenance of the placenta [6, 7]. In humans as well as in animal models, brain weight and neurocranial size of neonates and adults are usually less affected by nutrient restriction than body weight and facial size, which suggest an adaptive “brain sparing” effect [10,11,12,13]. Direct tests of in utero trade off between tissues are deficient and the available studies in humans usually measure overall fetal and placental weight only [14]
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