Date of Award

January 2022

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Shannon Whirledge

Abstract

Endocrine disruptors are exogenous chemicals that interfere with the functions of the endocrine system and can cause adverse developmental, reproductive, and neurological effects. Unlike toxic effects that may be evident immediately, disruption to the endocrine system may impact complex signaling pathways that take years or generations to discover. Current toxicology testing does not routinely incorporate endpoints that would identify potential endocrine disruptors. The objective of this study was to evaluate the endocrine disrupting potential of a broad range of industrial chemicals, specifically focusing on four chemicals with predicted activity on the glucocorticoid receptor (GR): 4-nonylphenol, bisphenol A (BPA), butylated hydroxytoluene (BHT), and phenolphthalein (PP). These chemicals are used in detergents, paints, pesticides, personal care products, and plastics. We have focused on glucocorticoids because these hormones play a critical role in reproduction, development, metabolism, and overall physiological homeostasis. Their actions are mediated by GR, a transcription factor that is necessary for life. Thus, endocrine disrupting chemicals that alter glucocorticoid signaling have the potential to alter the physiology of several organs and tissues. Human liver (HepG2) and Ishikawa (uterine) cell lines were used to study the effects of these chemicals on metabolism and reproduction, respectively. In Ishikawa and HepG2 cells, the industrial chemicals differentially regulated the transcript levels of both glucocorticoid responsive genes studied (GILZ and PER1). Interestingly, the effects of industrial chemical on gene expression varied by cell type. Additionally, the industrial chemicals altered the phosphorylation status of two phosphorylated GR proteins (pGR-211 and pGR-226). A combination of chemicals causes unique effects compared to individual chemicals. Collectively, this suggests that the evaluated chemicals demonstrate gene- and cell-type specific effects. These findings demonstrate that the endocrine disrupting potential of commonly used industrial chemicals is an underappreciated potential source of toxicity.

Comments

This is an Open Access Thesis.

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