Doctor of Philosophy
Anatomy and Cell Biology
Dr. Victor Han
Delay of Publication
Fetal undernutrition is a major factor in the pathophysiology of fetal growth restriction (FGR) in many species, including humans. Our hypothesis is that mild maternal nutrient restriction (MNR) in a mouse provides a clinically relevant model to study FGR mechanisms and long-term effects similar to humans and the developmental origins of health and disease (DOHaD) predisposition. A MNR mouse model of FGR was developed by feeding mothers 70% normal daily caloric intake during E6.5 to E18.5 gestation. Significant reduction in fetal weight and fetal liver and lung weights with less impact on brain weight resulted, similar to asymmetric human FGR. To determine autocrine/paracrine and endocrine factors and mechanisms underlying FGR, the insulin-like growth factor (IGF) and glucocorticoid systems were investigated in the liver, placenta and lungs at E18.5 and postnatally. At E18.5, MNR fetal livers increased the expression of growth inhibiting IGF binding proteins (IGFBPs), with corresponding increases in circulating levels. MNR males developed glucose intolerance six months postnatally with pancreatic morphology indicating pathophysiology of underlying glucose intolerance. Glucocorticoids stimulate maturation in fetal organs, however when elevated levels are prolonged, they restrict growth. To determine if glucocorticoids cause aberrant fetal lung maturation with postnatal pulmonary function impairment, we studied circulating glucocorticoids and glucocorticoid metabolizing enzyme 11-b hydroxysteroid dehydrogenase. At E18.5, maternal and fetal plasma corticosterone concentrations were higher in FGR, lung weight disproportionately reduced compared to fetus, fewer type II alveolar cells and decreased SP-A and SP-C expression. At one and three months postnatally, MNR female offsprings demonstrated impaired lung compliance. We investigated placental morphology and function in MNR. At E18.5, MNR caused reduced placental efficiency with placental weight reduced disproportionately compared to the fetus. Placental stereology indicated decreased surface area for nutrient exchange and increased interhemal membrane thickness. Passive and faciliated diffusion was decreased, although secondary active amino acid transport was unchanged. Despite the increased placental IGF-2 mRNA expression, increased IGFBP mRNA expression suggests local sequestation of IGF-2, thus impeding placental growth. These studies demonstrated that mild MNR in a mouse caused asymmetric growth restriction similar to human FGR with gender-specific long-term impact on glucose intolerance (males) and pulmonary dysfunction (females); IGF and glucocorticoid systems may play prominent roles in the pathophysiology.
Albion, Caroline D., "Fetal Growth Restriction: Molecular Mechanisms and Long-Term Outcomes" (2011). University of Western Ontario - Electronic Thesis and Dissertation Repository. Paper 289.
Available for download on Saturday, September 21, 2013