Characterization of the Impact of Life Stage on Xenobiotic Metabolizing Enzyme Expression and Gene - Chemical Interactions in the Liver

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 with the goal of using the information to predict differences in chemical responsiveness between life stages.  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 adults (2-6 months).  Fetal and neonatal life stages exhibited dramatic differences in XMET mRNA expression compared to the relatively minor effects of old age.  At all life stages except PND32, under-expressed genes outnumbered over-expressed genes and included those in Phases 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 down-regulated.  Suppression of male-specific XMETs was observed at early (GD19, 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.  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 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 which may lead to differences in the transport of xenobiotics.  We have initiated a project to identify chemicals that may be differentially metabolized or transported at different life stages due to changes in XMETs.  Using the Comparative Toxicogenomics Database (CTD), chemicals were identified which interacted with proteins with functions that affect the metabolism or transport of the chemical.  Preliminary analysis of the differences between the fetus and adult 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.  XMET expression patterns and known gene-chemical interactions could be used to predict life stage-specific responses to environmental chemicals and drugs.  These predictions could be validated in relevant in vitro models. (This abstract does not reflect US EPA policy.)