A glucocorticoid signaling-related adverse outcome pathway network links inhaled pollutants with multiple adverse outcomes
Citation:
Edwards, S., A. Scatterday, J. Abedini, M. Nelms, T. Allen, N. Botteri Principato, S. Snow, E. Medlock Kakaley, C. LaLone, V. Wilson, T. Stoker, S. Laws, AND U. Kodavanti. A glucocorticoid signaling-related adverse outcome pathway network links inhaled pollutants with multiple adverse outcomes. SOT Annual Meeting, San Antonio, Texas, March 11 - 15, 2018.
Impact/Purpose:
The Adverse Outcome Pathway (AOP) framework represents a systematic way to organize mechanistic information underlying toxicology, and it is specifically designed to connect early stage molecular perturbations by chemicals and other stressors with adverse outcomes in humans and wildlife. This abstract outlines a case study where the AOP development and use can be explored with an eye towards organizing, integrating, and interpreting toxicology (in vitro and in vivo) data along with existing clinical data from the medical literature. This should expand our understanding of the potential uses and corresponding value of the AOP framework thereby highlighting the value of ORD/EPA work in this area.
Description:
The Adverse Outcome Pathway (AOP) framework represents an ideal tool for integrating diverse data relating chemical exposures to adverse outcomes. Glucocorticoid signaling is tightly controlled and numerous adverse health outcomes have been associated with either elevation or suppression of these glucocorticoids including cardiovascular health, diabetes, growth, gonadal function, osteoporosis, myopathy, and increased disease susceptibility. The requirement for tight regulation of hormone levels leaves this system vulnerable to chronic elevation or depression associated with exposure to environmental stressors. Recently, impacts of air pollutants on glucocorticoid signaling have been identified. A network of AOPs describing glucocorticoid signaling have been developed based on the wealth of mechanistic and clinical data resulting from the long-term use of glucocorticoids as therapeutic agents. This framework has been used to integrate data from chemical structure-based predictions, in vitro toxicity tests, animal toxicology, and human clinical data to evaluate the potential impact of environmental exposures on glucocorticoid dysregulation. The broad range of clinical applications for this class of compounds has resulted in clinical information in humans at a wide variety of doses. In addition, there are both acute and chronic indications for these compounds including diseases, such as congenital adrenal hyperplasia, where lifelong hormone replacement is sometimes required. When considered in the context of the AOP framework, this information can be used to predict the potential impacts of environmental stressors from air, food, and water considering pre-existing disease and the treatment thereof. These studies highlight the value of the AOP framework for integrating information from chemical and non-chemical stressors to provide a holistic view of the etiology of complex diseases. [This is an abstract of a proposed presentation and does not necessarily reflect U.S.EPA policy.]