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Characterization of the Impact of Life Stage on Xenobiotic Metabolizing Enzyme Expression and Gene -Chemical Interactions in the Liver
Citation:
CORTON, C., J. S. LEE, W. O. Ward, H. Ren, B. Vallant, AND M. DeVito. Characterization of the Impact of Life Stage on Xenobiotic Metabolizing Enzyme Expression and Gene -Chemical Interactions in the Liver. Presented at International Society for the Study of Xenobiotics (ISSX) Annual Meeting, Atlanta, GA, October 16 - 20, 2011.
Impact/Purpose:
We hope to use the XMET expression patterns and known gene-chemical interactions to predict life stage-specific responses to environmental chemicals and drugs and to test these predictions in relevant in vitro models
Description:
Differences in responses to environmental chemicals and drugs between life stages are likely due in part to differences in the expression of xenobiotic metabolizing enzymes and transporters (XMETs). We have carried out a comprehensive analysis of the mRNA expression of XMETs through life stages in mice and humans. Using full-genome arrays, the mRNA expression of all XMETs and their regulatory proteins was examined during fetal (gestation day (GD) 19), neonatal (postnatal day (PND) 7), prepubescent (PND32), middle age (12 months), and old age (18 and 24 months) in the male C57BL/6J (C57) mouse liver and compared to young adults (2-6 months). Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects ofold age. At all life stages except PND32, under-expressed genes out numbered over-expressed genes. The altered XMETs included those in all of the major metabolic and transport phases including Phase I, II and III. In the fetus and neonate, parallel increases in expression were noted in the dioxin receptor, Nrf2 components and their regulated genes while nuclear receptors and regulated genes were generally downregulated. Suppression of male-specific XMETs was observed at early (GDI9, PND7) and to a lesser extent, later life stages (18 and 24 months). To determine if aged humans exhibit changes in XMET expression, we examined gene expression profiles from young (21-45 years) and old (69+ years) men and women. Five to seven livers per age group were profiled. Compared to mice, there were relatively few consistent changes in gene expression in the livers from aged humans compared to younger humans. We identified 370 genes that were altered between young and old men and 1163 genes that were altered between young and old women. Age caused minimal numbers ofchanges in the gene expression of XMETs (8 in males and 33 in females between young and old). Most of these changes were in the expression of PhaseIIIgenes. The expression of solute carriers increased with age in men while the majority decreased with age in women. These studies indicate that the livers from aging humans exhibit a number of changes in XMETs that may lead to differences in the metabolism of xenobiotics. We have initiated a project to identify chemicals that may be differentially metabolized at different life stages due to the changes in the XMETs. Chemicals were identified using the Comparative Toxicogenomics Database (CTD) in which gene-chemical interactions of interest can be identified and grouped into different functional classes. Preliminary analysis showed that chemicals of similar structure and toxicity mode of action cluster together. In summary, our analysis revealed dramatic differences in the expression of the XMETs through different life stages in the mouse with more subtle differences in older humans. We hope to use the XMET expression patterns and known gene-chemical interactions to predict life stage-specific responses to environmental chemicals and drugs and to test these predictions in relevant in vitro models. (This abstract does not reflect US EPA policy.)