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Characterization of the impact of life stage on gene -chemical interactions in the liver
Citation:
CORTON, C. Characterization of the impact of life stage on gene -chemical interactions in the liver. Presented at American Aging Association (AGE) Meeting, Raleigh, NC, June 03 - 06, 2011.
Impact/Purpose:
We have carried out a comprehensive analysis of the mRNA expression of XMETs through life stages in mice and humans
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 XME mRNA expression compared to the relatively minor effects of old age. The number of XMETs that differed from adults was 597,467, 77, 5,42, and 93 for GDI9, PND7, PND32, 12 months, 18 months and 24 months, respectively. At all life stages except PND32, under-expressed genes outnumbered over-expressed genes. The altered XMETs included those in all ofthe major metabolic and transport phases including introduction of reactive or polar groups (Phase I), conjugation (Phase II) and excretion (Phase 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 down-regulated. Suppression of malespecific 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. Top canonical pathways were identified using Ingenuity® Pathway Analysis. Protein ubiquitination pathway is affected in both older men and women. We found that age caused minimal numbers of changes 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 Phase III genes. 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 XMEs that may lead to differences in the metabolism of xenobiotics. We have also identified 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. In summary, our analysis revealed dramatic differences in the expression of the XMETs through different life stages. 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 is an abstract of a proposed presentation and does not reflect US EPA policy.)