Prediction of PAH mutagenicity in human cells by QSAR classification

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous pollutants of high environmental concern. The experimental data of a mutagenicity test on human B-lymphoblastoid cells (alternative to the Ames bacterial test) for a set of 70 oxo-, nitro- and unsubstituted PAHs, detected in particulate matter (PM), were modelled by Quantitative Structure-Activity Relationships (QSAR) classification methods (k-NN, k-Nearest Neighbour, and CART, Classification and Regression Tree) based on different theoretical molecular descriptors selected by Genetic Algorithms. The best models were validated for predictivity both externally and internally. For external validation, Self Organizing Maps (SOM) were applied to split the original data set. The best models, developed on the training set alone, show good predictive performance also on the prediction set chemicals (sensitivity 69.2–87.1%, specificity 62.5–87.5%). The classification of PAHs according to their mutagenicity, based only on a few theoretical molecular descriptors, allows a preliminary assessment of the human health risk, and the prioritisation of these compounds. 1Presented at CMTPI 2007: Computational Methods in Toxicology and Pharmacology Integrating Internet Resources (Moscow, Russia, September 1–5, 2007).

[1]  E. Papa,et al.  Approaches for externally validated QSAR modelling of Nitrated Polycyclic Aromatic Hydrocarbon mutagenicity , 2007, SAR and QSAR in environmental research.

[2]  S. Lin,et al.  Trace determination of nitrated polycyclic aromatic hydrocarbons using liquid chromatography with on-line electrochemical reduction and fluorescence detection , 2003 .

[3]  H S Rosenkranz,et al.  Relationship between polarographic reduction potential and mutagenicity of nitroarenes. , 1984, Mutation research.

[4]  Jure Zupan,et al.  Kohonen and counterpropagation artificial neural networks in analytical chemistry , 1997 .

[5]  W. Busby,et al.  Mutagenicity of benzo[a]pyrene and dibenzopyrenes in the Salmonella typhimurium TM677 and the MCL-5 human cell forward mutation assays. , 1995, Mutation research.

[6]  K. Sakamoto,et al.  Size distributions of mutagenic compounds and mutagenicity in atmospheric particulate matter collected with a low-pressure cascade impactor , 2004 .

[7]  F. Guengerich,et al.  Comparative metabolism of 1-, 2-, and 4-nitropyrene by human hepatic and pulmonary microsomes. , 1999, Cancer research.

[8]  R. Boggia,et al.  Genetic algorithms as a strategy for feature selection , 1992 .

[9]  L. Verschaeve,et al.  Genotoxicity of PM10 and extracted organics collected in an industrial, urban and rural area in Flanders, Belgium. , 2004, Environmental research.

[10]  P. Fu.  Metabolism of nitro-polycyclic aromatic hydrocarbons. , 1990, Drug metabolism reviews.

[11]  Lutz Müller,et al.  Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens I. Sensitivity, specificity and relative predictivity. , 2005, Mutation research.

[12]  W. Thilly,et al.  Bioassay-directed chemical analysis of Los Angeles airborne particulate matter using a human cell mutagenicity assay , 1998 .

[13]  Peter C Jurs,et al.  Predicting the genotoxicity of polycyclic aromatic compounds from molecular structure with different classifiers. , 2003, Chemical research in toxicology.

[14]  L. Hall,et al.  QSAR Modeling Based on Structure-Information for Properties of Interest in Human Health , 2005, SAR and QSAR in environmental research.

[15]  D. Warshawsky,et al.  Metabolic activation of polycyclic and heterocyclic aromatic hydrocarbons and DNA damage: a review. , 2005, Toxicology and applied pharmacology.

[16]  L. Kier.  Distinguishing Atom Differences in a Molecular Graph Shape Index , 1986 .

[17]  C. Hansch,et al.  Structure-activity relationships of chemical mutagens and carcinogens. , 1991, The Science of the total environment.

[18]  B H Margolin,et al.  Prediction of chemical carcinogenicity in rodents from in vitro genetic toxicity assays. , 1987, Science.

[19]  H. Rosenkranz,et al.  Mutagenicity and carcinogenicity of nitroarenes and their sources in the environment. , 1986, Critical reviews in toxicology.

[20]  Roberto Todeschini,et al.  Handbook of Molecular Descriptors , 2002 .

[21]  Jure Zupan,et al.  Neural networks in chemistry , 1993 .

[22]  L Zhang,et al.  The structure-activity relationship of skin carcinogenicity of aromatic hydrocarbons and heterocycles. , 1992, Chemico-biological interactions.

[23]  P. Jurs,et al.  Computer-assisted structure-activity studies of chemical carcinogens: a polycyclic aromatic hydrocarbon data set. , 1980, Toxicology and Applied Pharmacology.

[24]  J. Ashby,et al.  Prediction of Salmonella mutagenicity. , 1996, Mutagenesis.

[25]  J. Durant,et al.  Mutagenicity of C24H14 PAH in human cells expressing CYP1A1. , 1999, Mutation research.

[26]  H S Rosenkranz,et al.  Mutagenicity and genotoxicity of nitroarenes. All nitro-containing chemicals were not created equal. , 1983, Mutation research.

[27]  B. Ames,et al.  Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. , 1975, Mutation research.

[28]  Paola Gramatica,et al.  The Importance of Being Earnest: Validation is the Absolute Essential for Successful Application and Interpretation of QSPR Models , 2003 .

[29]  R. Benigni.  Structure-activity relationship studies of chemical mutagens and carcinogens: mechanistic investigations and prediction approaches. , 2005, Chemical reviews.

[30]  A. Debnath,et al.  Quantitative structure‐activity relationship investigation of the role of hydrophobicity in regulating mutagenicity in the Ames test: 2. Mutagenicity of aromatic and heteroaromatic nitro compounds in Salmonella typhimurium TA100 , 1992, Environmental and molecular mutagenesis.

[31]  J. Durant,et al.  Human cell mutagenicity of oxygenated, nitrated and unsubstituted polycyclic aromatic hydrocarbons associated with urban aerosols. , 1996, Mutation research.

[32]  Paola Gramatica,et al.  Quantitative structure-activity relationship modeling of polycyclic aromatic hydrocarbon mutagenicity by classification methods based on holistic theoretical molecular descriptors. , 2007, Ecotoxicology and environmental safety.

[33]  P. Fu,et al.  Transforming activity of selected polycyclic aromatic hydrocarbons and their nitro-derivatives in BALB/3T3 A31-1-1 cells. , 1994, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[34]  A. Basu,et al.  Mutagenicity of nitroaromatic compounds. , 2000, Chemical research in toxicology.