Cellular Memory of Adverse Intrauterine Nutrition Associated with Altered Cell Function and Epigenetic Dysregulation

Abstract

Maternal nutritional status can have short-term and long-term effects on offspring growth, development and health. Those born with extremely low birth weight are more likely to develop cardiovascular disease, type 2 diabetes mellitus and obesity in adulthood. However, with the increase in obesity and metabolic syndrome in the developed world, a high fat western diet and/or increased glucose levels during gestation can have similar effects on later adult health. Whether under- or over-nutrition, metabolic disease in the offspring does not manifest until later in life. This suggests there is a memory of exposure established during development that influences the way cells and tissues respond to insults that are characteristic of normal aging or disease pathogenesis. This interplay between environment and genetic outcomes are often mediated by epigenetic mechanisms. We hypothesize that differential patterns of epigenetic marks, such as DNA methylation, are influenced by nutrition during development that results in alterations in gene expression and/or cellular response to stress. The introduction provides a review of the developmental origins of health and disease hypothesis, followed by an analysis of the concept of cellular memory influencing cellular and tissue function in later life. In Chapter 2, we analyze the effects of maternal under- and over- nutrition on DNA methylation and subsequent gene expression in liver tissue from Sprague-Dawley rats, demonstrating an advanced aging phenotype. In Chapter 3, we test the effect of high glucose in utero and in vitro on the stress response of human umbilical cord mesenchymal stromal cells (hUC-MSC). The stress response of in utero glucose-exposed hUC-MSCs to the high glucose and oxidative stress demonstrates an increase in DNA damage and reactive oxygen species possibly due to increased susceptibility to damage from a blunted glutathione peroxidase enzyme response. These studies demonstrate the long-term effects of an adverse environment during development on cell function and ultimately adult health. Together these findings strengthen our understanding of the mechanisms of developmental origins of health and disease.