The overall goal of our research is to investigate mechanisms of chemical toxicity. We are particularly interested in genetic effects. These include examining how chemicals induce mutations, and also determining how different compounds alter gene regulation. Our approaches are primarily molecular, and we apply new technologies to our experimental objectives whenever possible.<\/p>\n
Bacterial Nitroreductases<\/strong><\/p>\n Several nitrosubstituted compounds (NSCs) are potent antimicrobial agents and others are important environmental pollutants. Nitroreductases (NRs) are enzymes that bioactivate NSCs. Our ongoing studies in this area involve cloning and characterizing microbial NRs and examining their mode of regulation. We have shown that NRs may be useful as activating enzymes for Enzyme Prodrug Therapy, a novel cancer chemotherapeutic strategy based on activation of nontoxic prodrugs to cytotoxic products in a tumor-specific manner. MUTAGENESIS AND DNA REPAIR<\/p>\n We have a long-standing interest in determining how compounds that are of considerable human health concern, such as nitroarene, nitroheterocyclic, and aromatic amine compounds, induce mutations. Our approach to this question is primarily molecular biological, and includes the determination of mutational spectra at the DNA sequence level, use of transgenic mouse mutagenesis models, analysis of DNA adducts and metabolites, development of sensitive genotoxicity tests, and the construction of modified DNA substrates that may be used as molecular probes in mutagenesis and DNA repair studies.<\/p>\n Genomics<\/strong><\/p>\n The success of the genome projects has led to the development of powerful microarray technologies. The application of microarray technology to medicine, drug development, and toxicology will push these disciplines forward at a tremendous pace over the next decade. As part of a group at Health Canada, we are applying microarray technology to the investigation of mechanisms of toxic action, and the development and validation of sensitive biomarkers of exposure. Environmental Microbiology<\/p>\n Persistent chemicals can be biotransformed in soil and aquatic environments by bacteria. This can result in complete or partial degradation of the chemicals (bioremediation), and may diminish the toxicity of complex mixtures in the environment. We are interested in examining the pathways which govern the degradation of nitrosubstituted compounds in the environment, and also in determining the biological activity\/toxicity of remediated mixtures.<\/p>\n Mutagenesis and DNA Repair<\/strong><\/p>\n We have a long-standing interest in determining how compounds that are of considerable human health concern, such as nitroarene, nitroheterocyclic, and aromatic amine compounds, induce mutations. Our approach to this question is primarily molecular biological, and includes the determination of mutational spectra at the DNA sequence level, use of transgenic mouse mutagenesis models, analysis of DNA adducts and metabolites, development of sensitive genotoxicity tests, and the construction of modified DNA substrates that may be used as molecular probes in mutagenesis and DNA repair studies.<\/p>\n Environmental Microbiology<\/strong><\/p>\n Persistent chemicals can be biotransformed in soil and aquatic environments by bacteria. This can result in complete or partial degradation of the chemicals (bioremediation), and may diminish the toxicity of complex mixtures in the environment. We are interested in examining the pathways which govern the degradation of nitrosubstituted compounds in the environment, and also in determining the biological activity\/toxicity of remediated mixtures.<\/p>\n Long, AS.,\u00a0 Lemieux, CL., Gagn\u00e9, R., Lambert, IB<\/strong>, White, PA.\u00a0 The Genetic Toxicity of Complex Mixtures of Polycyclic Aromatic Hydrocarbons: Evaluating Dose-Additivity in a Transgenic Mouse Model.\u00a0 Environ Sci Technol, 2017,\u00a0 Accepted following minor revisions.<\/p>\n Meier MJ, Paterson ES, Lambert IB<\/strong>.\u00a0 Use of Substrate-Induced Gene Expression in Metagenomic Analysis of an Aromatic Hydrocarbon-Contaminated Soil.\u00a0 Appl Environ Microbiol. 82(3):897-909,\u00a0 2015.<\/p>\n Yauk, CL., Lambert IB<\/strong>., Meek, ME, Douglas, GR, Marchetti, F.\u00a0 Development of the Adverse Outcome Pathway \u2018alkylation of DNA in male pre-meiotic germ cells leading to heritable mutations\u2019 using the OECD\u2019s Users\u2019 Handbook Supplement.\u00a0 Environmental and Molecular Mutagenesis, 56(9):724-50, 2015.<\/p>\n Lemieux CL, Long AS, Lambert IB<\/strong>, Lundstedt S, Tysklind M, White PA .Cancer risk assessment of polycyclic aromatic hydrocarbon contaminated soils determined using bioassay-derived levels of benzo[a]pyrene equivalents. Environ Sci Technol. 49(3):1797-805, 2015.<\/p>\n Lemieux CL, Long AS, Lambert IB<\/strong>, Lundstedt S, Tysklind M, White PA.\u00a0In vitro mammalian mutagenicity of complex polycyclic aromatic hydrocarbon mixtures in contaminated soils. Environ Sci Technol. 49(3):1787-96. 2015.<\/p>\n Jackson AF, Williams A, Recio L, Waters MD, Lambert IB<\/strong>, Yauk CL. Case study on the utility of hepatic global gene expression profiling in the risk assessment of the carcinogen furan. Toxicol Appl Pharmacol.;274(1):63-77. 2014.<\/p>\n Jackson AF, Williams A, Moffat I, Phillips SL, Recio L, Waters MD, Lambert IB<\/strong>, Yauk CL.\u00a0 Preparation of archival formalin-fixed paraffin-embedded mouse liver samples for use with the Agilent gene expression microarray platform.\u00a0 J Pharmacol Toxicol Methods. 68(2):260-8. 2013.<\/p>\n Bichara, M. Meier, M. Wagner,J. Cordonnier, A. and Lambert, I.B<\/strong>.,\u00a0 Mechanisms of Postreplication repair (PRR) in Escherichia coli\u00a0 Mutation Research, 727(3):104-22, 2011.<\/p>\n Lambert, I.B<\/strong>. Singer, T., Boucher, S.E., Douglas, G.R.\u00a0 Detailed Review of\u00a0 Transgenic Rodent Mutation Assays. Detailed Review Paper for OECD, 1-587,\u00a0 June, 2008 (565 pages). http:\/\/www.oecd.org\/dataoecd\/43\/38\/40830957.pdf<\/a><\/p>\nSelected Publications<\/h2>\n