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. 2016 Mar 28;11(3):e0152227.
doi: 10.1371/journal.pone.0152227. eCollection 2016.

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

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

Paula N Gonzalez et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Maternal, placental and fetal weights at different developmental stages.
E: embryonic day. The error bar represents the mean ± SD. *Different from control, P<0.051; **Different from control, P<0.01.
Fig 2
Fig 2. Changes in skull and brain size in the low protein fetuses.
Coordinates of landmarks (A) and centroid size of the cranium (B), face (C) and neurocranium (D), by treatment and age. Units in μm. Coordinates of landmarks and semilandmarks digitized in sections of sagittal and axial planes of the brain (E). White lines represent the places where the transversal and sagittal sections were measured. Brain centroid size at E18.5 in the low protein and control groups (F). The error bar represents the mean ± SD. **Different from control, P<0.01. *Different from control, P<0.05.
Fig 3
Fig 3. Relationship between fetal skull size and body weight in low protein and control groups.
A) Linear regressions between log centroid size (CS) and log body weight (BW) for the cranium, face and neurocranium; B) residuals of linear regressions between log CS and BW. Triangles: low protein group; circles: control group; empty symbols: E17.5; filled symbols: E18.5.
Fig 4
Fig 4. Analysis of skull shape based on three‐dimensional craniofacial landmarks.
A) Distribution of specimens of low protein (LP) and control (C) groups along the between-group principal components (bg-PC). Ellipses represent the specimens of each group within the 1SD confidence interval. B) Shape changes corresponding to the observed extremes in the positive and negative directions of first two components shown as a warped surface of a mouse skull. C) Shape variance within each experimental group and age measured in units of Procrustes distance.
Fig 5
Fig 5. Decrease of junctional zone area in low protein placentas at E10.5, E17.5 and E18.5.
A) In situ hybridization for Tpbpa, marker of junctional zone. Purple area: junctional zone; dashed area: parietal trophoblast giant cells (P-TGC); B) Bars represent average area of given placenta layer on a histological section ± SD. *Different from control, P<0.05; **Different from control, P<0.01; Dec: decidua; JZ: junctional zone; Lab: labyrinth; P-TGC: parietal trophoblast giant cells. Scale bar– 1 mm. C) Principal component analysis of the areas of the three main placenta layers for the control (C) and low protein groups (LP). The bars represent the loading of each variable on the first two principal components (PC).
Fig 6
Fig 6. Expression of seven prolactin family genes, Pcdh12 and Tpbpa in control and low protein placentas at E10.5, E17.5 and E18.5.
Missing bars mean that the particular gene is not expressed at the given developmental stage. *Different from control, p<0.05. The error bar represents the mean ± SD. C–control group; LP–low protein group.
Fig 7
Fig 7. Schematic summary of the effects of low protein diet on placental, fetal and maternal weight and on the head size.
C–control group; LP–low protein group; red color–weight significantly reduced as compared to the control group of the same age; blue color–cranial and brain size significantly different from the control of the same age.

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