Effects of maternal nutrient restriction on placental morphology and insulin-like growth factor system expressions

Abstract

Uteroplacental insufficiency is one of the major causes of fetal growth restriction (FGR) in developed countries. The pathophysiology is likely the result of fetal undernutrition due to the impairment of nutrient and substrate transfer from the mother to the fetus. Fetal undernutrition due to maternal undernutrition is not a major cause of FGR in developed countries compared to developing countries. However, FGR can be reproducibly created in experimental animals by maternal undernutrition, and is commonly utilized to study the pathophysiology of fetal undernutrition in the fetus and the placenta. The insulin-like growth factor (IGF) system is the principal growth factor involved in regulating normal fetal and placental growth and its aberrant expression is associated with the development of FGR. We hypothesized that placenta undergoes adaptive changes in pregnancies with maternal undernutrition, the effects of which are mediated by the IGF system. 
 Methods: A mouse model of FGR was generated in CD-1 mice using maternal total caloric nutrient restriction. At 6.5 days of pregnancy, mice were randomly assigned to the control group (ad libitum diet) or global nutrient restriction (GNR) diet group (70% of predetermined food intake of each gestational day). FGR can be reproducibly induced in the fetuses without effect in litter size. Placentae were collected at 18.5 days and were fixed in 4% paraformaldehyde. Five mm tissue sections were prepared by standard techniques and were stained with hematoxylin & eosin for morphometry, PAS for glycogen staining, and immunohistochemistry against IGF-I and –II, IGFBP-1, -2 and –3 using specific antisera for cell-specific expression of the IGF system. The morphology of the placentae was analyzed using a computerized image analysis system. 
 Results: Placentae were significantly smaller in FGR mice compared to controls (94±4 mg SEM vs 72±3 mg SEM). Preliminary results demonstrate changes in FGR mouse placentae tended to be a result of a reduction in spongiotrophoblast layer (p = 0.066, one-tailed t-test) while the labyrinthine trophoblast layer was maintained. Morphometric analysis of the labyrinth demonstrated an increase in the diameter of both maternal and fetal vessels with a reduction in the thickness of the interchorial layer. The IGF-I and –II, IGFBP-1, IGFBP-2 and IGFBP-3 immunoreactivity were all reduced in FGR placentae compared to the controls. 
 Conclusion: These findings suggest that maternal nutrient restriction induces changes in the placenta that may potentially lead to improved nutrient and substrate transfer from mother to fetus, in an attempt to maintain fetal viability. However, these compensatory changes are not sufficient to maintain growth. These changes may result from the alteration of expression of the IGF system genes.