Age and sex dependent changes in liver gene expression during the life cycle of the rat.
BACKGROUND
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. 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.


RESULTS
An 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.


CONCLUSIONS
These 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.
Center for Functional Genomics, Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Road, Jefferson, Arkansas 72079, USA. joshua.kwekel@fda.hhs.gov
Joshua C
JC
Kwekel
Varsha G
VG
Desai
Carrie L
CL
Moland
William S
WS
Branham
James C
JC
Fuscoe
D000375:Aging / Q000235:genetics*; D000818:Animals; D001835:Body Weight / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008018:Life Cycle Stages / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D025341:Principal Component Analysis; D051381:Rats; D011916:Rats, Inbred F344; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D013997:Time Factors