Phenotypic Anchoring
Conventional toxicology has employed surrogate markers correlated with toxic responses to monitor adverse outcomes in inaccessible tissues [68]. For example, liver enzymes ALT (alanine aminotransferase) and AST (aspartate aminotransferase) are released following hepatic damage, and levels of these enzymes in serum correlate with histopathological changes in the liver [68,69]. These serum enzyme markers, in conjunction with histopathology, facilitate the "phenotypic anchoring" of molecular expression data [22,26,70]. "Phenotypic anchoring" is the process of determining the relationship between a particular expression profile and the pharmacological or toxicological phe-notype of the organism for a particular exposure or dose and at a particular time [22]. The dose and time alone are often insufficient to define the toxicity experienced by an individual animal; thus another measure of toxicity is needed for full interpretation of the data obtained during a toxicogenomics study. Conversely, the phenotype alone may be insufficient to anchor the molecular profile, since an elevated value for serum ALT can be observed both before peak toxicity (as it rises) and after peak toxicity (as it returns to baseline). Anchoring the molecular expression profile in phenotype, dose, and time helps to define the sequence of key molecular events in the mode-of-action of a toxicant.
Phenotypic anchoring can also be used in conjunction with lower doses to classify agents and to explore the mechanisms of toxicity that occur before histopathological changes are seen. For example, transcriptional changes that occur following both low- and high-dose exposures of acetaminophen were identified, indicating that biological responses can be detected using transcrip-tome measurements before histopathological changes are easily detected [41]. Recent follow-up work shows the accumulation of nitrotyrosine and 8-hydroxy-deoxyguanosine adducts phenotypically anchors an oxidative stress gene expression signature observed with subtoxic dose of acetaminophen (APAP), lending support to the validity of gene expression studies as a sensitive and biologically meaningful endpoint in toxicology [71]. Additionally phenotypic anchoring can help to elucidate a toxicant's mechanism of action, for example, the transcriptional responses in a rat model to superpharmaceutical doses of WAY-144122 (a negative regulator of insulin) were observed before histopathological changes were seen in either liver or ovary, and reflected different mechanisms of toxicity in the two organs [53].
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