The Influence of Environmental Exposures on Glucocorticoid Receptor Signaling

Glucocorticoids (GCs) are hormones secreted in response to psychological stress. GCs have systemic effects on the endocrine, metabolic, cardiovascular, immune, reproductive, and central nervous systems. The physiological effects of GCs are mediated by the glucocorticoid receptor (GR), which is expressed in nearly every cell of the body. Environmental chemicals that disrupt GR signaling and/or cortisol homeostasis could adversely affect human health. A major challenge in identifying environmental chemicals that alter GR signaling in humans is a lack of adequate screening methods. The overall objective of this dissertation is to investigate the impact of environmental exposures on GR signaling and human GC levels. Chapter 1 discusses regulation of GC levels and presents evidence that environmental chemicals modulate GR signaling. Chapter 2 provides the field with a new bioassay to assess the endocrine disrupting effects of environmental chemicals on GR signaling. Results from this work demonstrate that this bioassay can be used to identify environmental chemicals that modulate GR activation and to screen serum samples for differences in total GC levels. Chapter 3 examines the persistent effect of early-life arsenic exposure on GC levels in a human population study. This is the first epidemiology study to investigate associations between early-life environmental exposures and GC levels in adulthood. Lastly, Chapter 4 evaluates prediction models of GR ligand mixtures. As a whole, this research aims to inform risk assessment of endocrine disrupting chemicals by developing methods to evaluate their impact on GR signaling and human health