title: Predictive endocrine testing in the 21st century using in vitro assays of estrogen receptor signaling responses.
abstract: Thousands of environmental chemicals are subject to regulatory review for their potential to be endocrine disruptors (ED). In vitro high-throughput screening (HTS) assays have emerged as a potential tool for prioritizing chemicals for ED-related whole-animal tests. In this study, 1814 chemicals including pesticide active and inert ingredients, industrial chemicals, food additives, and pharmaceuticals were evaluated in a panel of 13 in vitro HTS assays. The panel of in vitro assays interrogated multiple end points related to estrogen receptor (ER) signaling, namely binding, agonist, antagonist, and cell growth responses. The results from the in vitro assays were used to create an ER Interaction Score. For 36 reference chemicals, an ER Interaction Score >0 showed 100% sensitivity and 87.5% specificity for classifying potential ER activity. The magnitude of the ER Interaction Score was significantly related to the potency classification of the reference chemicals (p < 0.0001). ERα/ERβ selectivity was also evaluated, but relatively few chemicals showed significant selectivity for a specific isoform. When applied to a broader set of chemicals with in vivo uterotrophic data, the ER Interaction Scores showed 91% sensitivity and 65% specificity. Overall, this study provides a novel method for combining in vitro concentration response data from multiple assays and, when applied to a large set of ER data, accurately predicted estrogenic responses and demonstrated its utility for chemical prioritization.
authors: Department of Environmental Sciences and Engineering, University of North Carolina , Chapel Hill, North Carolina 27514, United States.
authors: Daniel M
authors: DM
authors: Rotroff
authors: Matt T
authors: MT
authors: Martin
authors: David J
authors: DJ
authors: Dix
authors: Dayne L
authors: DL
authors: Filer
authors: Keith A
authors: KA
authors: Houck
authors: Thomas B
authors: TB
authors: Knudsen
authors: Nisha S
authors: NS
authors: Sipes
authors: David M
authors: DM
authors: Reif
authors: Menghang
authors: M
authors: Xia
authors: Ruili
authors: R
authors: Huang
authors: Richard S
authors: RS
authors: Judson
mesh_terms: D000465:Algorithms; D000818:Animals; D001681:Biological Assay; D052244:Endocrine Disruptors / Q000032:analysis*; D004965:Estrogen Antagonists / Q000032:analysis; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000037:antagonists & inhibitors; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000037:antagonists & inhibitors; D004967:Estrogens / Q000032:analysis; D057166:High-Throughput Screening Assays; D006801:Humans; D061986:MCF-7 Cells; D008956:Models, Chemical; D010575:Pesticides; D015398:Signal Transduction
chemical_list: C506487:ESR1 protein, human; D052244:Endocrine Disruptors; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D010575:Pesticides