Department of Environmental Sciences and Engineering, University of North Carolina , Chapel Hill, North Carolina 27514, United States.
Environ Sci Technol. 2014;48(15):8706-16. doi: 10.1021/es502676e. Epub 2014 Jul 10.
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.
数千种环境化学物质因其具有内分泌干扰物 (ED) 的潜力而受到监管审查。体外高通量筛选 (HTS) 测定法已成为一种用于优先考虑与 ED 相关的动物整体测试的潜在工具。在这项研究中，对包括农药活性和惰性成分、工业化学品、食品添加剂和药物在内的 1814 种化学物质进行了 13 种体外 HTS 测定法的小组评估。该体外测定小组调查了与雌激素受体 (ER) 信号相关的多个终点，即结合、激动剂、拮抗剂和细胞生长反应。体外测定的结果用于创建 ER 相互作用评分。对于 36 种参考化学物质，ER 相互作用评分>0 对分类潜在 ER 活性的灵敏度为 100%，特异性为 87.5%。ER 相互作用评分的大小与参考化学物质的效力分类显著相关 (p<0.0001)。还评估了 ERα/ERβ 选择性，但相对较少的化学物质对特定同工型表现出显著的选择性。当应用于具有体内子宫增重数据的更广泛的化学物质组时，ER 相互作用评分的灵敏度为 91%，特异性为 65%。总体而言，这项研究提供了一种新的方法，用于组合来自多个测定的体外浓度反应数据，并且当应用于大量 ER 数据时，它可以准确预测雌激素反应，并证明其在化学物质优先排序方面的实用性。
