Abstract
BackgroundAge- and sex-related susceptibility to adverse drug reactions and disease is a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of hepatic genes expressed at various life cycle stages will impact susceptibility to adverse drug reactions. Understanding the basal liver gene expression patterns is a necessary first step in addressing this hypothesis and will inform our assessments of adverse drug reactions as the liver plays a central role in drug metabolism and biotransformation. Untreated male and female F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age. Liver tissues were collected for histology and gene expression analysis. Whole-genome rat microarrays were used to query global expression profiles.ResultsAn initial list of differentially expressed genes was selected using criteria based upon p-value (p < 0.05) and fold-change (+/- 1.5). Three dimensional principal component analyses revealed differences between males and females beginning at 2 weeks with more divergent profiles beginning at 5 weeks. The greatest sex-differences were observed between 8 and 52 weeks before converging again at 104 weeks. K-means clustering identified groups of genes that displayed age-related patterns of expression. Various adult aging-related clusters represented gene pathways related to xenobiotic metabolism, DNA damage repair, and oxidative stress.ConclusionsThese results suggest an underlying role for genes in specific clusters in potentiating age- and sex-related differences in susceptibility to adverse health effects. Furthermore, such a comprehensive picture of life cycle changes in gene expression deepens our understanding and informs the utility of liver gene expression biomarkers.
Highlights
Age- and sex-related susceptibility to adverse drug reactions and disease is a key concern in understanding drug safety and disease progression
Mechanisms of susceptibility may be dependent on non-transcriptional events such as protein expression and modifications, as well as polymorphisms in specific genes and proteins, which lie beyond the scope of the current study
Capturing baseline gene expression profile measurements is a necessary first step in characterizing the suite of genes differentially expressed at various ages
Summary
Age- and sex-related susceptibility to adverse drug reactions and disease is a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of hepatic genes expressed at various life cycle stages will impact susceptibility to adverse drug reactions. Understanding the basal liver gene expression patterns is a necessary first step in addressing this hypothesis and will inform our assessments of adverse drug reactions as the liver plays a central role in drug metabolism and biotransformation. Because the liver is the first and primary line of defense against the potentially toxic effects of oral xenobiotics [6,7], inquiry into its gene expression profiles to assess potential susceptibilities was performed. Not all potential causes of susceptibility were examined, only those gene expression changes associated with sex and age. Some important gene regulatory events may not be evident at the RNA level, in the tissue examined (liver), or in the absence of chemical challenge. Capturing baseline gene expression profile measurements is a necessary first step in characterizing the suite of genes differentially expressed at various ages
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