Abstract
BackgroundThe identification of estrogen receptors alpha and beta and aromatase in the testis has highlighted the important role of estrogens in regulating spermatogenesis. There is a wealth of information on the deleterious effects of fetal and neonatal exposure of estrogens and xenoestrogens in the testis, including spermiation failure and germ cell apoptosis. However, very little is known about gene transcripts affected by exogenous estradiol exposure in the testis. The objective of the present study was to unveil global gene expression profiles and testicular cell number changes in rats after estradiol treatment.Methods17beta-estradiol was administered to adult male rats at a dose of 100 micrograms/kg body weight in saline daily for 10 days; male rats receiving only saline were used as controls. Microarray analysis was performed to examine global gene expression profiles with or without estradiol treatment. Real time RT-PCR was conducted to verify the microarray data. In silico promoter and estrogen responsive elements (EREs) analysis was carried out for the differentially expressed genes in response to estradiol. Quantitation of testicular cell number based on ploidy was also performed using flow cytometry in rats with or without estradiol treatment.ResultsWe found that 221 genes and expressed sequence tags (ESTs) were differentially expressed in rat testes treated with estradiol compared to the control; the microarray data were confirmed by real time RT-PCR. Gene Ontology analysis revealed that a number of the differentially expressed genes are involved in androgen and xenobiotic metabolism, maintenance of cell cytoskeleton, endocytosis, and germ cell apoptosis. A total of 33 up-regulated genes and 67 down-regulated genes showed the presence of EREs. Flow cytometry showed that estradiol induced a significant decrease in 2n cells (somatic and germ cells) and 4n cells (pachytene spermatocytes) and a marked increase in the number of elongated and elongating spermatids.ConclusionsThis study provides a novel insight into the molecular basis for spermiation failure and apoptosis caused by 17beta-estradiol and it also offers new mechanisms by which adult exposure to environmental estrogens can affect spermatogenesis and fertility.
Highlights
The identification of estrogen receptors alpha and beta and aromatase in the testis has highlighted the important role of estrogens in regulating spermatogenesis
Gene ontology grouping analysis revealed that 55 genes have known functions: a) 16 genes are involved in biological process; b) 46 genes were related to molecular function; c) 7 genes are involved in cellular component (Figure 2)
6 gene transcripts, including steroidogenic acute regulatory protein (Star), hydroxysteroid 11-beta dehydrogenase 1 (Hsd11b1), alcohol dehydrogenase 1 (Adh1), Ces3, Cyp1b1, and Sult1a1 were down-regulated by estradiol, and these genes are present in the somatic cells of testis and they are involved in androgen and xenobiotic metabolism (Table 1)
Summary
The identification of estrogen receptors alpha and beta and aromatase in the testis has highlighted the important role of estrogens in regulating spermatogenesis. There is a wealth of information on the deleterious effects of fetal and neonatal exposure of estrogens and xenoestrogens in the testis, including spermiation failure and germ cell apoptosis. There is a growing interest in studying this hormone in males due to the following two main reasons: 1) the discovery of estrogen receptors alpha (ERα), estrogen receptor beta (ERβ), and aromatase with mutations in ERα [6]. The role of estrogens in spermatogenesis was highlighted by the observations of impaired fertility in aromatase knockout mice. A progressive decrease in fertility with age was observed in the aromatase knockout mice. Spermatogenesis was arrested primarily at early spermiogenic stages, as characterized by an increase in apoptosis and the appearance of multinucleated cells, and a significant reduction in round and elongated spermatids, but no changes were observed in Sertoli cells or earlier germ cells, reflecting the requirement of estrogen for later stages of spermatogenesis [8]
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