Andrew Tantisukarom ER alpha Agonism for Quats and Phthalates Spring 2010 An In Silico Prediction of ER alpha Agonism for Quats and Phthalates Andrew Tantisukarom ABSTRACT Endocrine Disruptors are a growing concern as the female population is experiencing precocious maturation and more seriously a greater incidence of breast cancer Endocrine disruptors or mimickers can be found naturally in the environment but are most prevalent in man made subtances In this study I investigated two classes of compounds Ammonium Quaternary Compounds and Phthalates that are less represented in the literature in respects to Estrogen Receptor alpha ER a agonism which is linked to breast cancer I employed Computational Toxicology an in silico approach using state of the art structure analyses modeling specifically MDL QSAR The study collectively examined 70 quats and phthalates and predicted that 10 compounds showed significant ER a agonism KEYWORDS Computational Toxicology Quaternary Ammonium Compound Breast Cancer MDLQSAR Endocrine Disruptor 1 Andrew Tantisukarom ER alpha Agonism for Quats and Phthalates Spring 2010 INTRODUCTION Endocrine disrupters are hormonally active agents that mimic the function of endogenous bodily hormones of the endocrine system commonly referred to as the hormone system Endocrine systems are found in all mammals birds fish and many other types of living organisms Hormones are involved in just about every biological function Jesperson Via the chemical system of hormones the endocrine system regulates all biological processes in the body from conception through adulthood and into old age including the development of the brain and nervous system the growth and function of the reproductive system as well as metabolism and blood sugar levels FDA 2010 Risks of exposure to endocrine disruptors include adverse effects to the developmental reproductive neurological and immune functions of humans National Library of Medicine 2009 Some notable examples of endocrine disrupting compounds include Diethylstilbestrol DES a prescribed prenatal drug that was halted by the U S Food and Drug Administration in 1971 because it was linked to a rare vaginal cancer U S EPA 2010 Polychlorinated biphenyl PCBs production in the U S stopped in 1977 and later exports and imports in 1979 because of suspected harmful health and environmental effects and more notoriously Dichlorodiphenyltrichloroethane DDT was banned by the U S EPA in 1972 because it posed high risks to the environment and human health ExtoxNet 2002 Currently the population at greatest risk is females as a greater number of the youth reach maturation sooner and as breast cancer rates have risen The incidence of breast cancer was estimated to be approximately 30 greater between 1975 and 2000 Szabo 2006 This is a result of endocrine disruption of estrogen receptors which respond to hormones responsible for female sexual development National Cancer Institute 2006 There are two distinct estrogen receptors in the human body Estrogen Receptoralpha ER a and Estrogen Receptor beta ER b Both bind to the hormone Estrogen as well as other chemicals that act as agonists receptor stimulants or antagonists receptor repressors The two receptors have distinct localizations and concentrations within the body Structural differences between the two allow for a wide range of diverse and complex bodily processes McClure 2001 2 Andrew Tantisukarom ER alpha Agonism for Quats and Phthalates Spring 2010 A wide range of substances both natural and man made are thought to cause endocrine disruption Endocrine disruptors may be found in many everyday products including plastic bottles metal food cans detergents flame retardants food toys cosmetics and pesticides National Library of Medicine 2009 Two classes of compounds used prevalently in industry and in day to day activities are Quaternary Ammonium Compounds Quats and Phthalates Quats are commonly found in surfactants disinfectants and antistatic agents which are present in shampoo spermicidal jellies liquid fabric softeners and dryer anticling strips The food industry uses quats in conjunction with bleach products as a sanitizing agent In addition some are used in surgery as anesthetics Rahn 1974 Phthalates are commonly found in flooring cosmetics soft toys medical equipment i e medical tubing catheters and blood bags and even air fresheners Environmental Working Group 2007 Specifically I am attempting to determine the estrogen stimulating capacity or agonism of two chemical classes Quats and Phthalates I will be employing Computational Toxicology an in silico or computer based modeling method to investigate ER a as experiments have shown a strong link between receptor agonism and breast cancer I am utilizing predictive chemical structure analyses models for ER a to assess the threat of Quats and Phthalates to the female population in respect to breast cancer METHODS The methods employed are based on Computational Toxicology principles of modeling and predicting chemical activity on a specific biological endpoint Computational Toxicology utilizes Quantitative Structure Activity Relationship QSAR modeling software MDL QSAR was the software of choice Figure 1 is a flow chart of how the model was built 3 Andreew Tantisukaro om ER alpha Agonism A for Quats Q and Phthaalates Sppring 2010 R Figurre 1 Modell constructioon flow chaart The methhods employyed through MDL QSAR are seequenced I used th he peer revieewed articlees by Escannde et al 2006 Fitzppatrick et al a 20077 Kostelac et al 20033 Moein et al 2008 Overk et al 2005 andd Pillon et al a 20055 and the chemical databases PubC Chem and bindingdb orgg to researchh compoundds activee on ER a the biologiccal endpointt of interest The comppounds needded to have a correesponding EC50 E or pE EC50 logE EC50 valuee a commoon toxicologgical potenccy measure as MD DL QSAR prredicts in terms of EC550s These compounds c were used to t createe a highly prredictive moodel and for simplicity will w be referreed to as Grooup A Durinng this innitial researcch I also chhose the com mpounds I wiished to test Quaternaryy Ammonium m Comppounds Quats and Phtthalates Theese compouunds will be referred to as Group B B Afterr I found thee SDFs or Structure S Data Format a computer binary b code that t describees one specific s com mpound for Group A and a Group B B If PubChem a chem mical databasse where SDF filess are archivved did not have a valid SDF then t the compound waas
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