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Effects of the Antiestrogen Fulvestrant (ICI 182,780) on Gene Expression of the Rat Efferent Ductules¹

Section of Experimental Endocrinology, Department of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, SP 04044–020 São Paulo, Brazil

ABSTRACT

The efferent ductules express the highest amount of estrogen receptors ESR1 (ERalpha) and ESR2 (ERbeta) within the male reproductive tract. Treatment of rats with the antiestrogen fulvestrant (ICI 182,780) causes inhibition of fluid reabsorption in the efferent ductules, leading to seminiferous tubule atrophy and infertility. To provide a more comprehensive knowledge about the molecular targets for estrogen in the rat efferent ductules, we investigated the effects of ICI 182,780 treatment on gene expression using a microarray approach. Treatment with ICI 182,780 increased or reduced at least 2-fold the expression of 263 and 98 genes, respectively. Not surprisingly, several genes that encode ion channels and macromolecule transporters were affected. Interestingly, treatment with ICI 182,780 markedly altered the expression of genes related to extracellular matrix organization. Matrix metalloproteinase 7 (Mmp7), osteopontin (Spp1), and neuronal pentraxin 1 (Nptx1) were among the most altered genes in this category. Upregulation of Mmp7 and Spp1 and downregulation of Nptx1 were validated by Northern blot. Increase in Mmp7 expression was further confirmed by immunohistochemistry and probably accounted for the decrease in collagen content observed in the efferent ductules of ICI 182,780-treated animals. Downregulation of Nptx1 probably contributed to the extracellular matrix changes and decreased amyloid deposition in the efferent ductules of ICI 182,780-treated animals. Identification of new molecular targets for estrogen action may help elucidate the regulatory role of this hormone in the male reproductive tract.

efferent ductules, estradiol, gene regulation, male reproductive tract

¹ Supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP-PRONEX) grant 2003/10132-0 to C.S.P. and M.F.M.L. C.S.P. was supported by a research fellowship from the Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq). F.Y. was supported by a doctoral fellowship from the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). E.M., E.R.S., and G.R.O.G. were supported by postdoctoral, doctoral, and master fellowships from FAPESP.

Correspondence: ²Maria Fatima M. Lazari, Section of Experimental Endocrinology, Department of Pharmacology, Universidade Federal de São Paulo, Escola Paulista de Medicina, Rua Três de maio 100, INFAR, Vila Clementino, São Paulo, SP 04044–020, Brazil. FAX: 5511 5576 4448; e-mail: lazari{at}farm.epm.br