title: Estrogen-regulated genes in rat testes and their relationship to recovery of spermatogenesis after irradiation.
abstract: Despite numerous observations of the effects of estrogens on spermatogenesis, identification of estrogen-regulated genes in the testis is limited. Using rats in which irradiation had completely blocked spermatogonial differentiation, we previously showed that testosterone suppression with gonadotropin-releasing hormone-antagonist acyline and the antiandrogen flutamide stimulated spermatogenic recovery and that addition of estradiol (E2) to this regimen accelerated this recovery. We report here the global changes in testicular cell gene expression induced by the E2 treatment. By minimizing the changes in other hormones and using concurrent data on regulation of the genes by these hormones, we were able to dissect the effects of estrogen on gene expression, independent of gonadotropin or testosterone changes. Expression of 20 genes, largely in somatic cells, was up- or downregulated between 2- and 5-fold by E2. The unexpected and striking enrichment of transcripts not corresponding to known genes among the E2-downregulated probes suggested that these might represent noncoding mRNAs; indeed, we have identified several as miRNAs and their potential target genes in this system. We propose that genes for which expression levels are altered in one direction by irradiation and in the opposite direction by both testosterone suppression and E2 treatment are candidates for controlling the block in differentiation. Several genes, including insulin-like 3 (Insl3), satisfied those criteria. If they are indeed involved in the inhibition of spermatogonial differentiation, they may be candidate targets for treatments to enhance recovery of spermatogenesis following gonadotoxic exposures, such as those resulting from cancer therapy.
authors.affiliation: Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77025, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Olga U
authors.initials: OU
authors.lastname: Bolden-Tiller
authors.forename: Shan H
authors.initials: SH
authors.lastname: Shao
authors.forename: Connie C
authors.initials: CC
authors.lastname: Weng
authors.forename: Gunapala
authors.initials: G
authors.lastname: Shetty
authors.forename: Mahmoud
authors.initials: M
authors.lastname: AbuElhija
authors.forename: Pirjo
authors.initials: P
authors.lastname: Pakarinen
authors.forename: Ilpo
authors.initials: I
authors.lastname: Huhtaniemi
authors.forename: Amin A
authors.initials: AA
authors.lastname: Momin
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: David N
authors.initials: DN
authors.lastname: Stivers
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Liu
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Meistrich
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D000818:Animals; D003433:Crosses, Genetic; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000627:therapeutic use*; D004967:Estrogens / Q000627:therapeutic use*; D005485:Flutamide / Q000627:therapeutic use; D005720:Gamma Rays; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000528:radiation effects; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006727:Hormone Antagonists / Q000627:therapeutic use; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000627:therapeutic use; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D013091:Spermatogenesis / Q000187:drug effects* / Q000528:radiation effects*; D013737:Testis / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D013739:Testosterone / Q000037:antagonists & inhibitors
chemical_list: D000726:Androgen Antagonists; D004967:Estrogens; D006727:Hormone Antagonists; D007328:Insulin; C084797:Leydig insulin-like protein; D035683:MicroRNAs; D009842:Oligopeptides; D011506:Proteins; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D005485:Flutamide; C109238:acyline