Alterations of the endocrine system are well established in the aging population. Conditions that arise include diabetes, thyroid complications, osteoporosis, cardiovascular events, and cancer. Heavy metals, such as arsenic, are known endocrine disruptors and chronic exposure through drinking water is linked to a broad range of chronic diseases characteristic to the aging population, including cancer of the urinary bladder. Bladder cancer (BlCa) is a disease of the aging population with an average age of diagnosis at 73 years. BlCa has one of the highest recurrence rates of all solid tumors and the treatment course has a significant effect on quality of life. 20 percent of patients have recurrence of papillary tumors following surgical removal and require frequent surveillance. Furthermore, patients with muscle invasive disease have pelvic recurrence seven to eight months after radical cystectomy. BlCa has a morbid disease process and costs the US 3 billion dollars per year. Furthermore, the majority of patients that lose their lives to BlCa have undergone curative treatment that ultimately fails. Poor understanding of the pathophysiology of BlCa contributes to the lack of effective treatment and also makes it difficult to develop preventative measures to ultimately promote healthy aging. This is important to consider because in less than 50 years, over 25 percent of the US population will be over the age of 65 years. BlCa is most commonly induced by chronic exposure to environmental risk factors throughout life, such as arsenic. Arsenic modulates glucocorticoid receptor (GR), a steroid hormone-activated transcription factor that is protective in the bladder. Angiopoietin-like 4 (ANGPTL4), a protective protein in the bladder, is transcriptionally regulated by GR and is decreased following arsenic exposure. This proposal aims to investigate how endocrine disruption contributes to changes in the urothelium that eventually lead to bladder cancer. I have hypothesized that chronic dysregulation of GR-mediated transactivation of ANGPTL4 disrupts normal physiological processes of the urothelium. I will address this hypothesis by (1) determining the effects of arsenic exposure on ANGPTL4 transcriptional regulation, (2) evaluating the effects of arsenic exposure on GR transactivation, and (3) observing how chronic arsenic exposure promotes cellular transformation due to disruption of GR transcriptional control of ANGPTL4. Further, I will evaluate GR and ANGPTL4 in tissues from young and old mice to validate the results of my findings. A top research priority at the NIA is to characterize age-related alterations in human physiology. It is well established that complex changes occur in the endocrine system of aging individuals. This study explores the effects of glucocorticoid disruption in the bladder for the first-time. Discoveries from these efforts will contribute to the characterization of bladder carcinogenesis as well as the understanding of other age-related conditions linked to alterations of the endocrine system, such as diabetes, immunosuppression, and neurological and behavioral changes.
Alterations of the endocrine system are well established in the aging population and endocrine disruption is well-documented in the development of human cancers. Bladder cancer is a disease of the aging population and lacks effective treatment and prevention options because of poor pathological understanding. This study addresses the role of the disruption of steroid hormones during the physiological changes of the aging bladder for the first time.