ENDOCRINE DISRUPTING CHEMICALS ALTER STEROID TRANSPORT PROTEINS AND STEROID FREE AND BOUND FRACTIONS

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Joshua Philip Mogus (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The effects of endocrine disrupting chemicals (EDCs) on the development of sexually dimorphic characteristics in vertebrates have been studied extensively for over sixty years. Throughout this time , studies have focused mainly on the disrupted steroidogenesis and steroid signaling pathways. Often , only freely suspended plasma steroids were reported , despite the fact that a large portion of plasma steroids are bound to circulating steroid transport proteins. When bound to transport proteins , steroids have reduced binding to steroid nuclear and membrane receptors and increased binding to transport protein receptors. Thus , steroid transport proteins regulate steroid activity. Sexually dimorphic characteristics of tissues require specific concentrations and milieus of steroids during development and disruption of these steroid milieus leads to abnormal differentiation. Therefore , it is likely that the developing organism also requires specific free and bound ratios depending on the sex. However , few studies have addressed the effects of EDCs on sexual dimorphism of steroid transport proteins and steroid fractions despite the impact that transport proteins have on steroid signaling , development , and physiology. To address this , I first summarize the current literature on the regulation of transport proteins , their interactions with steroid signaling , and how transport proteins are affected by environmental contaminates. These findings are culminated into a new model of steroid signaling that includes transport protein mediated pathways. Second , using HPLC-MS/MS , I show that a normal sexual dimorphism exists in free and bound steroid ratios for the steroids progesterone , corticosterone , testosterone , and 17[beta]-estradiol. Additionally , I found a normal sexual dimorphism in the ratio of the bound precursor progesterone , to its potent metabolites , with females having higher progesterone to metabolite ratios than those in males. When exposed to the model EDC , Vinclozolin , sexual dimorphism of free and bound steroids was lost , with males and females responding to disruption in different ways. The disruption of plasma steroid ratios was found in the absence of changes to liver steroid transport protein concentrations. The results of this study show that steroid free and bound ratios as well as ratios of precursor to metabolite steroids can be altered by EDCs. This study clearly shows that future work in determining effects of EDC should also determine free and bound fractions of steroids to better understand effects of contaminants.

Additional Information

Publication

Thesis

Language: English

Date: 2018

Keywords

steroid receptor, steroid signaling

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