Chapter 6 - Disruption of Other Receptor Systems: Progesterone and Glucocorticoid Receptors, Peroxisome Proliferator-Activated Receptors, Pregnane X Receptor, and Aryl Hydrocarbon Receptor

Abstract

This chapter describes the mechanisms of action of several intracellular ligand-activated transcription factors: progesterone receptor (PR), glucocorticoid receptor (GR), peroxisome proliferator-activated receptors (PPAR), pregnane X receptor (PXR), and aryl hydrocarbon receptor (AhR). Environmental endocrine-disrupting chemicals (EDCs) have been shown to bind to and activate these receptors, giving a range of specific responses that are measurable in assays based both in vitro and in vivo. Disruption of PR may lead to aberrant proliferation and differentiation in reproductive tissues. The wide cellular distribution of GR and its broad range of functions imply that disruption of GR could lead to more general modulation of immune and stress responses, altered glucose metabolism, and loss of maintenance of body fluid homeostasis. Disruption of PPARs can lead to imbalance of lipid homeostasis and regulation of glucose metabolism, and environmental EDCs acting through this route have been shown to cause obesity and have been termed obesogens. PXR and AhR can bind a wide range of foreign compounds (xenobiotics) and so act as xenobiotic sensors. Target genes of PXR and AhR include cytochrome P450 enzymes involved in metabolism and clearance of foreign compounds. One main side effect, however, is that some of these cytochrome P450 enzymes also regulate synthesis and breakdown of steroid hormones; therefore, some environmental chemicals may act as EDCs by modulating endogenous steroid hormone levels through PXR- or AhR-mediated mechanisms.