ToxSci Advance Access originally published online on June 9, 2005
Toxicological Sciences 2005 87(1):97-112; doi:10.1093/toxsci/kfi219
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Gene Expression Profiling of 17ß-Estradiol and Genistein Effects on Mouse Thymus
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Departments of * Veterinary Biosciences, Animal Sciences and Statistics, W.M. Keck Center for Comparative and Functional Genomics, and ¶ Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, Illinois 61802
Received February 3, 2005; accepted June 1, 2005
Estrogen regulates thymic development and involution and modulates immune function. Despite its critical role in thymus, as well as in autoimmune disorders, the mechanism by which estrogen affects the thymus is not well understood. We previously reported that the estrogenic soy isoflavone genistein, as well as 17ß-estradiol (E2), could induce thymic involution, but genistein effects were only partially mediated through estrogen receptors. To provide insights into mechanisms of estrogenic effects in the thymus, we investigated thymic gene expression changes induced by E2 (125 ng/day) and genistein (1500 ppm in feed) in weanling mice using high-density DNA arrays. We identified several E2-responsive genes involved in thymic development and thymocyte signaling during selection and maturation. Functional characterization indicated effects on genes involved in transcription, apoptosis, and the cell cycle. This study also identified changes in several E2-regulated transcripts essential to maintain immune self-tolerance. E2 upregulated more genes than genistein, while genistein downregulated more genes than E2. Though each treatment regulated several genes not altered by the other, there was considerable overlap in the genes regulated by E2 and genistein. Changes in transcription factors and cell cycle factors were consistent with decreases in cell proliferation induced by both genistein and E2. As indicated by the regulation of non-E2-responsive genes, genistein also induced unique effects through non-estrogenic mechanisms. The specific downregulation of the CD4 coreceptor transcript by genistein was consistent with the decline of CD4+ thymocytes in genistein-treated mice in our previous study. This is the first study identifying E2 and genistein target genes in the thymus. These findings provide new mechanistic insights toward explaining estrogen action on thymocyte development, selection, and maturation, as well as the effects of genistein on prenatal and neonatal thymic development and function.
Key Words: immune system; estrogen; T cells; soy; phytoestrogen; autoimmunity.
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  P. S. Cooke, V. Selvaraj, and S. Yellayi Genistein, Estrogen Receptors, and the Acquired Immune Response J. Nutr., March 1, 2006; 136(3): 704 - 708. [Abstract] [Full Text] [PDF]
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