Investigating the effects of chemical exposure, demographic, and lifestyle factors on steroid hormone receptor bioactivity in human populations

Humans are exposed to a wide variety of chemicals from different sources, in both environmental and occupational settings. Numerous chemicals have been shown to exert endocrine disrupting properties, affecting normal function of the endocrine system. These are known as endocrine disrupting chemicals (EDCs). EDCs significantly impact public health by contributing to adverse health outcomes, including disrupted hormonal functions, impaired reproductive health, and metabolic diseases. Most of the epidemiological studies examining the adverse health effects of disrupted hormonal functions measure the levels of endogenous hormones and their carrier proteins and therefore may miss hormonal effects of EDCs. The endogenous hormones are traditionally measured by radioimmunoassay, enzyme-linked immunosorbent assay, and tandem mass spectrometry (MS/MS) and therefore lack any information on the biological effects of chemical exposure. As a result, novel methods that simultaneously capture both endogenous and exogenous chemicals modulating the hormone receptor signaling provide a better assessment of the combined effects of chemical exposure on hormonal functions. Herein, we show that the Chemical-Activated LUciferase gene eXpression (CALUX) assay is useful and can be used in epidemiologic research as an alternative method to measure total biological effects of chemical exposures on hormone receptor function. This dissertation aims to assess the effects of chemical exposure and other factors including race/ethnicity, alcohol consumption, and Indigenous American ancestry on hormone receptor bioactivities in human plasma/serum. Chapter 1 provides a review of the broadly relevant literature, including the endocrine system, functions of the hormone receptors, EDCs, factors modulating hormonal functions, and adverse health outcomes associated with EDC exposure. Chapter 2 focuses on a study that applied the estrogen receptor (ER)- and androgen receptor (AR)-mediated CALUX assays to measure serum estrogenic and androgenic bioactivities in workers occupationally exposed to trichloroethylene (TCE). This study not only provides evidence that occupational exposure to chemicals affects hormone receptor function, but it also is the first study to demonstrate that TCE is associated with elevated estrogenic bioactivity, which warrants further research on TCE and the estrogen related pathway. In Chapter 3, the CALUX assays were applied to assess the serum estrogenic, androgenic, and glucocorticogenic bioactivities in formaldehyde (FA) exposed workers. This study indicates that FA exposure does not affect hormone bioactivity measured in exposed workers. These TCE and FA human studies demonstrate the feasibility of CALUX assays on measuring hormone bioactivity in occupationally exposed subjects. Chapter 4 applies the CALUX assay to explore the influence of demographic and lifestyle factors on plasma glucocorticogenic bioactivity in a larger study of 503 women who participated as controls in the San Francisco Bay Area Breast Cancer Study. This study reports that race/ethnicity, alcohol intake and Indigenous American ancestry influence plasma glucocorticogenic bioactivity, which could explain observed disparities in disease outcomes. Finally, in Chapter 5, the main findings of this dissertation are summarized and future research is suggested.

Advisor: Smith, Martyn T