Development of predicitve models to distinguish metals from non-metal toxicants, and individual metal from one another

Background Evaluating the toxicity of chemical mixture and their possible mechanism of action is still a challenge for humans and other organisms. Microarray classifier analysis has shown promise in the toxicogenomic area by identifying biomarkers to predict unknown samples. Our study focuses on identifying gene markers with better sensitivity and specificity, building predictive models to distinguish metals from non-metal toxicants, and individual metal from one another, and furthermore helping understand underlying toxic mechanisms. Results Based on an independent dataset test, using only 15 gene markers, we were able to distinguish metals from non-metal toxicants with 100% accuracy. Of these, 6 and 9 genes were commonly down- and up-regulated respectively by most of the metals. 8 out of 15 genes belong to membrane protein coding genes. Function well annotated genes in the list include ADORA2B, ARNT, S100G, and DIO3. Also, a 10-gene marker list was identified that can discriminate an individual metal from one another with 100% accuracy. We could find a specific gene marker for each metal in the 10-gene marker list. Function well annotated genes in this list include GSTM2, HSD11B, AREG, and C8B. Conclusions Our findings suggest that using a microarray classifier analysis, not only can we create diagnostic classifiers for predicting an exact metal contaminant from a large scale of contaminant pool with high prediction accuracy, but we can also identify valuable biomarkers to help understand the common and underlying toxic mechanisms induced by metals.

[1]  F. Azuaje,et al.  Multiple SVM-RFE for gene selection in cancer classification with expression data , 2005, IEEE Transactions on NanoBioscience.

[2]  K. Mann,et al.  Tungsten: an Emerging Toxicant, Alone or in Combination , 2016, Current Environmental Health Reports.

[3]  Xin Zhou,et al.  MSVM-RFE: extensions of SVM-RFE for multiclass gene selection on DNA microarray data , 2007, Bioinform..

[4]  Youping Deng,et al.  Identification of biomarkers that distinguish chemical contaminants based on gene expression profiles , 2014, BMC Genomics.

[5]  Xiao-tong Zhang,et al.  [Congenital unilateral malformations of lung referred as bronchial foreign bodies]. , 2006, Lin chuang er bi yan hou ke za zhi = Journal of clinical otorhinolaryngology.

[6]  Mitchell S. Wilbanks,et al.  Analysis of Common and Specific Mechanisms of Liver Function Affected by Nitrotoluene Compounds , 2011, PloS one.

[7]  J. Reindel,et al.  RNA expression in the early characterization of hepatotoxicants in Wistar rats by high‐density DNA microarrays , 2001, Hepatology.

[8]  V. Brown,et al.  REACHing for chemical safety. , 2003, Environmental health perspectives.

[9]  Helmut Segner,et al.  Vitellogenin synthesis in primary cultures of fish liver cells as endpoint for in vitro screening of the (anti)estrogenic activity of chemical substances. , 2006, Aquatic toxicology.

[10]  Jack Y. Yang,et al.  A comparative study of different machine learning methods on microarray gene expression data , 2008, BMC Genomics.

[11]  Stephen W. Edwards,et al.  Systems biology and mode of action based risk assessment. , 2008, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  Jun Chen,et al.  Joint analysis of two microarray gene-expression data sets to select lung adenocarcinoma marker genes , 2004, BMC Bioinformatics.

[13]  David J Dix,et al.  Mode of action for reproductive and hepatic toxicity inferred from a genomic study of triazole antifungals. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[14]  F. Collins,et al.  Transforming Environmental Health Protection , 2008, Science.

[15]  M. Valko,et al.  Advances in metal-induced oxidative stress and human disease. , 2011, Toxicology.

[16]  Tung-Shou Chen,et al.  A Novel Anti-classification Approach for Knowledge Protection , 2015, Journal of Medical Systems.

[17]  Youping Deng,et al.  A new approach to construct pathway connected networks and its application in dose responsive gene expression profiles of rat liver regulated by 2,4DNT , 2010, BMC Genomics.

[18]  Constantin F. Aliferis,et al.  GEMS: A system for automated cancer diagnosis and biomarker discovery from microarray gene expression data , 2005, Int. J. Medical Informatics.

[19]  Ian H. Witten,et al.  Data mining in bioinformatics using Weka , 2004, Bioinform..

[20]  R. Judson,et al.  The Toxicity Data Landscape for Environmental Chemicals , 2008, Environmental health perspectives.