Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) / Chapter Skim
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4 Application to Exposure Assessment
4 Application to Exposure Assessment
Pages 59-72
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From page 59... ...
Despite these challenges, environmental toxicologists have long sought to use the modifications or expression changes of specific biomolecules to determine actual exposures in individuals and in populations. This chapter describes the current status of exposure assessment with biologic molecules as indicators, focusing on the application of toxicogenomic technologies to assess human exposure to environmental agents.
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From page 60... ...
For example, weakly carcinogenic methylating agents such as methyl methanesulfonate produce N7-methylguanine as the predominant DNA adduct, which is also the main DNA lesion formed by potent carcinogens such as N-methyl-N'nitro-N-nitrosourea. The key mutational and carcinogenic effects of these compounds, however, are mainly due to differences in the levels of relatively minor lesions: the strongly mutational adduct O6-methylguanine accounts for only
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From page 61... ...
Greater specificity in tying patterns of change in gene expression to a particular exposure in this way is an important potential advantage of transcriptional profiling and of toxicogenomic technologies in general. For example, whereas many DNA-damaging agents activate p21 expression, other genes respond to UV light, and still others re
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From page 62... ...
Application to Human Exposure Although applying such toxicogenomic technologies to determining human exposure lies in the future, experiments with model organisms or human cells in culture support the transcriptomic approach in its broad outline. In baker's yeast Saccharomyces cerevisiae, exposures to an oxidant (t-butyl hydroperoxide)
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From page 63... ...
Chemical exposures are manifested by two types of proteome changes. In the first, altered gene expression, mRNA stability, protein stability, or some combination of the three alters protein expression levels.
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From page 64... ...
. Changes in protein expression levels were detected in rat liver after treatment with bromobenzene, but few of the protein species involved were identifiable (Heijne et al.
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From page 65... ...
Protein Adducts Some chemical exposures directly modify proteins (for example, through the formation of adducts) , while others perturb endogenous posttranslational modifications.
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From page 66... ...
Metabolomics involves measuring collections of small compounds in cells or biologic fluids, providing considerable biochemical detail in that the measured molecules include both metabolized products of environmental chemicals and endogenous metabolites. Endogenous metabolites may also be persistently changed by exposure, enabling chemical exposures to be detected for longer periods of time than the environmental compounds or their metabolites persist.
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From page 67... ...
As with other approaches, however, development of this technology to generate biomarkers will require performing studies at subtoxic exposures -- the low-level exposure of interest for assessing human exposures. Larger scale work in metabolomics comes from the Consortium for Metabonomic Toxicology, which involves six pharmaceutical companies and the Imperial College of Science, Technology and Medicine, London, U.K.
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From page 68... ...
For example, the kinetic behavior and toxicity of chemicals often depend on metabolism, and toxicogenomic approaches can be used to rapidly identify potential key and rate-limiting enzyme targets whose activities, with further characterization, can be incorporated into PBPK models that better refine dose-dependent toxicity observations. Thus, toxicogenomic data provide mechanistic insights that can help refine the PBPK models used to predict target organ doses and hence provide a more accurate assessment of dose response.
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From page 69... ...
(2002) compared gene expression changes in human keratinocytes exposed to N-methyl-N'-nitro-N-nitrosoguanidine (a DNAalkylating carcinogen)
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From page 70... ...
A hint of this problem can be seen even in the study of individual gene expression. One study sought to test whether DNA sequence differences in the promoter regions of the metallothionein IIA gene could be associated with differences in the inducibility of this defense protein in response to metals (Wu et al.
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From page 71... ...
A large gap exists between the current state of the art, with only a few studies to date having used gene expression analysis successfully to determine occupational exposure. Although high-sensitivity and data-rich toxicogenomic approaches may already be feasible for analyzing human exposure in some settings, applying these technologies to human populations exposed to low-level environmental contaminants will require considerably more development.
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From page 72... ...
Intermediate 4. To enable the further development of toxicogenomic measures of exposure, include transcriptomic, metabolomic, and/or proteomic analysis of samples in large human population studies and studies designed to assess exposures at toxicant levels commonly encountered in the workplace and certain communities1.
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