In Vitro Screening for Population Variability in Chemical Toxicity
Open Access
- 15 October 2010
- journal article
- research article
- Published by Oxford University Press (OUP) in Toxicological Sciences
- Vol. 119 (2), 398-407
- https://doi.org/10.1093/toxsci/kfq322
Abstract
Immortalized human lymphoblastoid cell lines have been used to demonstrate that it is possible to use an in vitro model system to identify genetic factors that affect responses to xenobiotics. To extend the application of such studies to investigative toxicology by assessing interindividual and population-wide variability and heritability of chemical-induced toxicity phenotypes, we have used cell lines from the Centre d'Etude du Polymorphisme Humain (CEPH) trios assembled by the HapMap Consortium. Our goal is to aid in the development of predictive in vitro genetics-anchored models of chemical-induced toxicity. Cell lines from the CEPH trios were exposed to three concentrations of 14 environmental chemicals. We assessed ATP production and caspase-3/7 activity 24 h after treatment. Replicate analyses were used to evaluate experimental variability and classify responses. We show that variability of response across the cell lines exists for some, but not all, chemicals, with perfluorooctanoic acid (PFOA) and phenobarbital eliciting the greatest degree of interindividual variability. Although the data for the chemicals used here do not show evidence for broad-sense heritability of toxicity response phenotypes, substantial cell line variation was found, and candidate genetic factors contributing to the variability in response to PFOA were investigated using genome-wide association analysis. The approach of screening chemicals for toxicity in a genetically defined yet diverse in vitro human cell-based system is potentially useful for identification of chemicals that may pose a highest risk, the extent of within-species variability in the population, and genetic loci of interest that potentially contribute to chemical susceptibility.Keywords
This publication has 34 references indexed in Scilit:
- Toxicogenetics: population-based testing of drug and chemical safety in mouse modelsPharmacogenomics, 2010
- Are In Vitro Tests Suitable for Regulatory Use?Toxicological Sciences, 2009
- Toxicity Testing in the 21st Century: Bringing the Vision to LifeToxicological Sciences, 2008
- Systems biology and functional genomics approaches for the identification of cellular responses to drug toxicityExpert Opinion on Drug Metabolism & Toxicology, 2008
- Transforming Environmental Health ProtectionScience, 2008
- Toxicity testing in the 21st century: A vision and a strategyReproductive Toxicology, 2008
- A second generation human haplotype map of over 3.1 million SNPsNature, 2007
- Transcriptional Response of Lymphoblastoid Cells to Ionizing RadiationGenome Research, 2003
- The Human Genome Browser at UCSCGenome Research, 2002
- Fingerprinting of Cytochrome P450 and Microsomal Epoxide Hydrolase Gene Expression in Human Blood CellsToxicological Sciences, 2000