Proliferation and phenotypic changes of stromal cells in response to varying estrogen/androgen levels in castrated rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhou Y
PROVIDER: S-EPMC3735307 | biostudies-other | 2009 Jul
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Prepubertal testicular dysfunction and the subsequent development of hypogonadism affects an estimated one in 200 children worldwide. As the testosterone levels are dynamic during development and puberty, traditional hormone treatment regimens are often inadequate, thereby leaving associated physiological conditions unresolved. Therefore, we have investigated the potential therapeutic effect of mature Leydig cell transplantation for the treatment of prepubertal primary hypogonadism through the use of a surgically induced hypogonadistic rat model system. In the experiment, Leydig cells were surgically isolated from mature Sprague-Dawley rats and transplanted into prepubertal recipients. Serum testosterone levels and microscopic analysis of the stained testicular interstitium were compared with sham-treated controls, as well as with castrated and intact rats during sexual development. At 4 weeks post-implantation, serum testosterone was detectable in Leydig cell recipients, but not in surgical controls, and progressively increased as a function of time until reaching levels comparable with sexually mature males at 12 weeks post-implantation. Histological analysis revealed a high rate of Leydig cell survival as well as steroidogenic secretory activity. Therefore, we conclude that mature Leydig cell transplantation in prepubertal hypogonadism recipients has therapeutic potential in rats and merits further investigation for clinical application.
| S-EPMC3735305 | biostudies-other
Project description:Reproductive aging in males is characterized by a diminution in sexual behavior beginning in middle age. We investigated the relationships among testosterone, androgen receptor (AR) and estrogen receptor alpha (ERalpha) cell numbers in the hypothalamus, and their relationship to sexual performance in male rats. Young (3months) and middle-aged (12months) rats were given sexual behavior tests, then castrated and implanted with vehicle or testosterone capsules. Rats were tested again for sexual behavior. Numbers of AR and ERalpha immunoreactive cells were counted in the anteroventral periventricular nucleus and the medial preoptic nucleus, and serum hormones were measured. Middle-aged intact rats had significant impairments of all sexual behavior measures compared to young males. After castration and testosterone implantation, sexual behaviors in middle-aged males were largely comparable to those in the young males. In the hypothalamus, AR cell density was significantly (5-fold) higher, and ERalpha cell density significantly (6-fold) lower, in testosterone- than vehicle-treated males, with no age differences. Thus, restoration of serum testosterone to comparable levels in young and middle-aged rats resulted in similar preoptic AR and ERalpha cell density concomitant with a reinstatement of most behaviors. These data suggest that age-related differences in sexual behavior cannot be due to absolute levels of testosterone, and further, the middle-aged brain retains the capacity to respond to exogenous testosterone with changes in hypothalamic AR and ERalpha expression. Our finding that testosterone replacement in aging males has profound effects on hypothalamic receptors and behavior has potential medical implications for the treatment of age-related hypogonadism in men.
| S-EPMC2879440 | biostudies-literature
Project description:Although the prostate is androgen-dependent, it is also influenced by estrogens, which act via the estrogen receptors ERα and ERβ. In the prostate, ERβ is highly expressed in the epithelium and appears to participate in the regulation of cell proliferation, apoptosis and differentiation. Evidence shows that ERβ is decreased in malignant prostate, suggesting that it plays an important role in protecting this tissue. Despite the relationship between reductions in ERβ and abnormal growth of the gland, little is known about the age-dependent variation of this receptor. Therefore, we aimed to investigate ERβ expression in the prostatic lobes of aging Wistar rats (3 to 24 months). Histopathological alterations, including hyperplasia, intraluminal concretions, nuclear atypia and prostate intraepithelial neoplasias (PIN), were observed in the prostates of aging rats. Epithelial proliferation led to cribriform architecture in some acini, especially in the ventral prostate (VP). In the VP, areas of epithelial atrophy were also observed. Furthermore, in the lateral prostate, there was frequent prostatitis. Immunohistochemistry revealed that the expression of ERβ is reduced in specific areas related to PIN, atrophic abnormalities and cellular atypia in the prostate epithelium of senile rats. Corroborating the involvement of the receptor with proliferative activity, the punctual reduction in ERβ paralleled the increase in cell proliferation especially in areas of PIN and nuclear atypies. The decrease in ERβ reactivity occurred in a hormonal milieu characterized by a constant concentration of estradiol and decreased plasmatic and tissue DHT. This paper is a pioneering study that reveals focal ERβ reduction in the prostate of aging rats and indicates a potential disorder in the ERβ pathway. These data corroborate previous data from humans and dogs that silencing of this receptor may be associated with premalignant or malignant conditions in the prostate.
| S-EPMC4492744 | biostudies-literature
Project description:Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5?-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5?-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by 32P-postlabeling, oxidative DNA damage (8-hydroxyguanosine), and lipid peroxidation at the site within the prostate where this treatment causes cancers, preceding later cancer formation. The non-estrogenic 4-hydroxy metabolite of estradiol, when combined with testosterone, induced prostatic dysplasia within 16 weeks and, after long-term treatment, a very low incidence of prostate cancer (21%). When an estrogen that cannot be hydroxylated (2-fluoroestradiol) was added to this combined treatment with testosterone and 4-hydroxyestradiol, dysplasia frequency after 16 weeks was doubled. These results strongly support the hypothesis, but additional definitive studies are needed which may identify new targets to interfere with these mechanisms that are clinically feasible in humans.
| S-EPMC6545235 | biostudies-literature
Project description:Aberrant regulation of uterine cell growth can lead to endometrial cancer and infertility. To understand the molecular mechanisms of estrogen-induced uterine cell growth, we removed the estrogen receptor ? (Esr1) from mouse uterine stromal cells, where the embryo is implanted during pregnancy. Without ESR1 in neighboring stroma cells, epithelial cells that line the inside of the uterus are unable to grow due to a lack of growth factors secreted from adjacent stromal cells. Moreover, loss of stromal ESR1 caused mice to deliver fewer pups due in part due to inability of some embryos to implant in the uterus, indicating that stromal ESR1 is crucial for uterine cell growth and pregnancy.
| S-EPMC5566397 | biostudies-literature
Project description:A major challenge in the emerging field of toxicogenomics is to define the relationships between chemically induced changes in gene expression and alterations in conventional toxicologic parameters such as clinical chemistry and histopathology. We have explored these relationships in detail using the rodent uterotrophic assay as a model system. Gene expression levels, uterine weights, and histologic parameters were analyzed 1, 2, 4, 8, 24, 48, and 72 hr after exposure to the reference physiologic estrogen 17 beta-estradiol (E2). A multistep analysis method, involving unsupervised hierarchical clustering followed by supervised gene ontology-driven clustering, was used to define the transcriptional program associated with E2-induced uterine growth and to identify groups of genes that may drive specific histologic changes in the uterus. This revealed that uterine growth and maturation are preceded and accompanied by a complex, multistage molecular program. The program begins with the induction of genes involved in transcriptional regulation and signal transduction and is followed, sequentially, by the regulation of genes involved in protein biosynthesis, cell proliferation, and epithelial cell differentiation. Furthermore, we have identified genes with common molecular functions that may drive fluid uptake, coordinated cell division, and remodeling of luminal epithelial cells. These data define the mechanism by which an estrogen induces organ growth and tissue maturation, and demonstrate that comparison of temporal changes in gene expression and conventional toxicology end points can facilitate the phenotypic anchoring of toxicogenomic data.
| S-EPMC1247656 | biostudies-literature
Project description:Singing of songbirds is sensitive to testosterone and its androgenic and estrogenic metabolites in a species-specific way. The hormonal effects on song pattern are likely mediated by androgen receptors (AR) and estrogen receptor alpha (ER?), ligand activated transcription factors that are expressed in neurons of various areas of the songbirds' vocal control circuit. The distribution of AR in this circuit is rather similar between species while that of ER? is species variant and concerns a key vocal control area, the HVC (proper name). We discuss the regulation of the expression of the cognate AR and ER? and putative splice variants. In particular, we suggest that transcription factor binding sites in the promoter of these receptors differ between bird species. Further, we suggest that AR- and ER?-dependent gene regulation in vocal areas differs between species due to species-specific DNA binding sites of putative target genes that are required for the transcriptional activity of the receptors. We suggest that species differences in the distribution of AR and ER? in vocal areas and in the genomic sensitivity to these receptors contribute to species-specific hormonal regulation of the song.
| S-EPMC5790841 | biostudies-literature
Project description:Assessment of genetic variability in heat-tolerant tomato germplasm is a pre-requisite to improve yield and fruit quality under heat stress. We assessed the population structure and diversity in a panel of three Solanum pimpinellifolium (wild tomatoes) and 42 S. lycopersicum (cultivated tomatoes) lines and accessions with varying heat tolerance levels. The DArTseq marker was used for the sequencing and 5270 informative single nucleotide polymorphism (SNP) markers were retained for the genomic analysis. The germplasm was evaluated under two heat stress environments for five yield and flower related traits. The phenotypic evaluation revealed moderate broad-sense heritabilities for fruit weight per plant and high broad-sense heritabilities for fruit weight, number of inflorescences per plant, and number of flowers per inflorescence. The hierarchical clustering based on identity by state dissimilarity matrix and UPGMA grouped the germplasm into three clusters. The cluster analysis based on heat-tolerance traits separated the germplasm collection into five clusters. The correlation between the phenotypic and genomic-based distance matrices was low (r = 0.2, p < 0.05). The joint phenotypic and genomic-based clustering grouped the germplasm collection into five clusters well defined for their response to heat stress ranging from highly sensitive to highly tolerant groups. The heat-sensitive and heat-tolerant clusters of S. lycopersicum lines were differentiated by a specific pattern of minor allele frequency distribution on chromosome 11. The joint phenotypic and genomic analysis revealed important diversity within the germplasm collection. This study provides the basis for efficient selection of parental lines to breed heat-tolerant varieties.
| S-EPMC8067180 | biostudies-literature
Project description:To define endometrial stromal-derived paracrine mediators that participate in estradiol-17? (E2)-induced epithelial proliferation, microarray analysis of gene expression was carried out in mouse uterine epithelial-stromal co-culture systems under the condition of E2 or vehicle (control). Our results demonstrated gene alteration by E2: in epithelial cells, we found up-regulation of 119 genes and down-regulation of 28 genes, while in stroma cells we found up-regulation of 144 genes and down-regulation of 184 genes. A functional enrichment analysis of the upregulated epithelial genes implicated them for proliferation, while upregulated stromal genes were associated with extracellular functions. Quantitative RT-PCR and in situ hybridization results confirmed differential gene expression in both cell cultures and ovariectomized uteri after the above treatments. Based on our identification of stromal secretory factors, we found evidence that suppression by siRNA specifically for Bmp8a and/or Fgf10 in the stromal layer caused significant inhibition of proliferation by E2 in the co-culture system, suggesting Bmp8a and Fgf10 act as paracrine mediators during E2-dependent control of uterine proliferation. The localization of receptors and receptor activation signaling in epithelial cells in both the co-culture system and uteri was consistent with their involvement in ligand-receptor signaling. Interestingly, loss of Bmp8a or Fgf10 also caused abrogation of E2-regulated epithelial receptor signaling in co-culture systems, suggesting that stroma-derived Fgf10 and Bmp8a are responsible for epithelial communication. Overall, stromal Fgf10 and Bmp8a serve as potential paracrine factors for E2-dependent regulation of epithelial proliferation in the uterus.
| S-EPMC4751583 | biostudies-literature
Project description:Infiltrated macrophages may play important roles in the development and progression of benign prostatic hyperplasia (BPH), but the underlying mechanisms remain largely unknown. We found increased macrophages infiltration in human and mouse BPH tissues. By establishing a co-culture transwell system, we found increased migration of macrophages and proliferation of prostate stromal cells during co-culture. Importantly, stromal androgen receptor (AR) could enhance the migration of macrophages and macrophage-mediated stromal cell proliferation. We identified CCL3 as an AR downstream player, and found CCL3 levels were notably increased in human and mouse BPH prostates. Ablation of prostate stromal AR in a mouse BPH model significantly reduced CCL3 expression levels in prostates. Consistently, targeting AR via an AR degradation enhancer, ASC-J9®, or neutralization of CCL3 with an antibody, resulted in suppression of macrophage migration and prostate stromal cell growth. Our study provides mechanistic insights on the regulation of prostate stromal cells by macrophages via stromal AR/CCL3 signaling pathways, which could potentially allow the development of therapeutic approaches for battling BPH with persistent inflammation.
| S-EPMC3365773 | biostudies-literature