Evaluation and QSAR modeling on multiple endpoints of estrogen activity based on different bioassays Huanxiang Liu, Ester Papa, Paola Gramatica * Department of Structural and Functional Biology, QSAR Research Unit in Environmental Chemistry and Ecotoxicology, University of Insubria, via Dunant 3, 21100 Varese, Italy Received 31 January 2007; received in revised form 22 June 2007; accepted 30 July 2007 Available online 19 September 2007 Abstract There is a great need for an effective means of rapidly assessing endocrine-disrupting activity, especially estrogen-simulating activity, due to the large number of chemicals that have serious adverse effects on the environment. Many approaches using a variety of biological screening assays are used to identify endocrine disrupting chemicals. The present investigation analyzes the consistency and peculiarity of information from different experimental assays collected from a literature survey, by studying the correlation of the different endpoints. In addition, the activity values of more widely used selected bioassays have been combined by principle components analysis (PCA) to build one cumulative endpoint, the estrogen activity index (EAI), for priority setting to identify chemicals most likely possessing estrogen activity for early entry into screening. This index was then modeled using only a few theoretical molecular descriptors. The constructed MLR-QSAR model has been statistically validated for its predictive power, and can be proposed as a preliminary evaluative method to screen/prioritize estrogens according to their integrated estrogen activity, just starting from molecular structure. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Endocrine disruptor; QSAR; Environmental estrogens; Principal component analysis (PCA); In vitro assay; Estrogen activity index 1. Introduction Increasing concern is being shown by the scientific com- munity, government regulators, and the public about endo- crine-disrupting chemicals that, in the environment, are adversely affecting human and wildlife health through a variety of mechanisms (Kavlock et al., 1996). Assessing the risk of potential endocrine-disrupting activity is a par- ticularly challenging task. Reliable short-term methods are needed to identify such chemicals in order to evaluate human exposure (Andersen et al., 1999). In general, in vivo methods are expensive and time-consuming, and a variety of short-term assays, mainly in vitro assays, gener- ally called alternative tests, are therefore being applied to identify estrogenic chemicals and to determine the relative potencies for hormonal responses. Some of these assays may be suitable for screening large numbers of chemicals and contaminated media, such as water and food, and may therefore be useful tools for prioritizing chemicals for subsequent more expensive in vivo studies. Although endocrine disruption can be the result of a variety of biologic mechanisms, more data exist for envi- ronmental estrogens than for other classes of activity (Fang et al., 2000). Most of the experimental tests used to screen potential estrogens fall into one of the following three cat- egories: (a) Estrogen Receptor (ER) competitive binding assays, that measure the binding affinity of a chemical for ER; (b) reporter gene assays, that measure ER binding- dependent transcriptional and translational activity; and (c) cell proliferation assays, that measure the increase in cell number of target cells during the exponential phase of pro- liferation (Fang et al., 2000). Although numerous data sets are available in the litera- ture for various estrogenic compounds, resulting from in vivo and in vitro assays, the relationship between these 0045-6535/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.chemosphere.2007.07.071 * Corresponding author. Tel.: +39 0332 421573; fax: +39 0332 421554. E-mail address: paola.gramatica@uninsubria.it (P. Gramatica). www.elsevier.com/locate/chemosphere Available online at www.sciencedirect.com Chemosphere 70 (2008) 1889–1897