Genomic and Epigenomic Changes in the Liver and Kidney During the Rat Life Cycle

Friday, 14 February 2014
Grand Ballroom C North (Hyatt Regency Chicago)
James C. Fuscoe , FDA, Jefferson, AR
The susceptibility of individuals at the extremes of the population age-distribution (the very young and the very old) and differences between sexes are often not adequately assessed. By understanding the genes expressed in each sex at the various life stages, the assessment of health risk versus benefit can be more rationally determined.  Comprehensive analysis of the transcriptome, including miRNA, and the epigenome in the liver and kidney of Fisher 344 rats from 2 weeks to 2 years of age reveals substantial differences at various life-stages and between the sexes.  In the liver and kidney, the expression of nearly 4000 genes was found to significantly vary with age and/or sex.  Many of these genes are involved in xenobiotic metabolism and transport, processes that impact drug efficacy and safety.  The expression of genes that code for some of the kidney injury protein biomarkers recently qualified by the FDA were found to vary substantially with age and sex, in some cases up to 100-fold.  Such dramatic differences may impact the interpretation of biomarker results. Examination of miRNA expression in the liver showed nearly 200 miRNAs varied with age and/or sex.  Notably, a group of 42 miRNAs was expressed at a relatively high level at 2 weeks of age in both sexes followed by low or no detectable expression at older ages. However, this 2 week-specific miRNA expression was not evident in the kidney.  Analysis of potential target mRNAs for liver miRNAs suggests roles in disease susceptibility involving fibrosis as well as regulation of xenobiotic metabolism related genes. A similar number of kidney miRNAs also displayed sex and age-related changes which may be linked to gene regulation. These differences may be related to age- and sex-specific susceptibilities to adverse drug reactions or disease states. Understanding these differences should improve personalized medicine both in terms of disease prevention and management, and safer use of drugs.