Sexual Dimorphism of Rat Liver Gene Expression: Regulatory Role of Growth Hormone Revealed by DNA Mi
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Growth hormone (GH) has diverse physiological actions and regulates the tissue-specific expression of numerous genes involved in growth, metabolism and differentiation. Several of the effects of GH on somatic growth and gene expression are sex-dependent and are regulated by pituitary GH secretory patterns, which are sexually differentiated. The resultant sex differences in plasma GH profiles are particularly striking in rodents and are the major determinant of sex differences in pubertal body growth rates and the expression in liver of several cytochrome P450 (CYP) enzymes that metabolize steroids, drugs and environmental chemicals of importance to endocrinology, pharmacology and toxicology. DNA microarray analysis was used to identify rat liver-expressed genes that show sexual dimorphism, and to ascertain the role of GH as a regulator of their sexually dimorphic expression. Adult male and female rats were untreated or were treated with GH by 7-day continuous infusion using an Alzet osmotic minipump. Poly(A) RNA was purified from individual livers and Cy3- and Cy5-labeled cDNA probes co-hybridized to Pan Rat Liver and 5K Rat oligonucleotide microarrays (MWG Biotech, Inc.) representing 5889 unique rat genes. Analysis of differential gene expression profiles identified 37 liver-expressed, female-predominant genes; of these, 27 (73%) were induced by continuous GH treatment of male rats. Moreover, only 3 of 30 genes up-regulated in male rat liver by continuous GH treatment did not display female-dominant expression. Further analysis revealed that 44 of 49 male-predominant genes (90%) were down-regulated in the livers of continuous GH-treated male rats compared with untreated male rats, while only 5 of 49 genes that were down-regulated in male rats by continuous GH treatment were not male-dominant in their expression. Real-time PCR analysis applied to a sampling of 10 of the sexually dimorphic genes identified in the microarray analysis verified their sex- and GH-dependent patterns of regulation. Taken together, these studies establish that GH-regulated gene expression is the major mechanistic determinant of sexually dimorphic gene expression in the rat liver model.