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Uterine gene profiles from WT, KIKO (DNA-binding deficient ERα) and aERKO mice treated with estradiol or xenoestrogens

ABSTRACT: Ovariectomized WT, KIKO (DNA-binding deficient ERα) or αERKO female mice were injected (ip) with saline (vehicle), estradiol (E2; 250 ng), bisphenol A (BPA; 750 µg) or 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE; 750 µg) and uteri were collected after 2 or 24 hours. Uterine profiles were compared and indicated the early (2 hour) responses to E2 were highly correlated to the BPA and HPTE profiles. KIKO patterns included overlap with WT but also included distinct responses. Later (24 hour) responses in the KIKO were weaker, indicating DNA binding is needed to maintain the estrogenic response. BPA and HPTE also showed a weakened late response in the WT, suggesting they are impeded estrogens.

ORGANISM(S): Mus musculus

PROVIDER: GSE18168 | GEO | 2009/12/01

SECONDARY ACCESSION(S): PRJNA119519

REPOSITORIES: GEO

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Project description:Bisphenol A (BPA) is primarily used to make polycarbonate plastic, with a global capacity of production exceeding 8 million tons per year. Biomonitoring studies with human urine, blood and tissue samples suggest that humans are subjected to widespread and continuous exposure to BPA. It has been well established that early life exposure to BPA predisposes the prostate gland to carcinogenesis later in life. However, it remains unknown if BPA exposure during adulthood induces benign or neoplastic pathology in the prostate. The main objective of the present study is to determine the effects of BPA exposures during adulthood on the prostate and to characterize the global transcriptional reprogramming underlying endocrine disruption by BPA. We elevated circulating levels of free BPA in Noble rats to the human-relevant internal dose range with BPA-filled Silastic implants while maintaining the physiological levels of testosterone (T) with T-filled implants. Cotreatment with T and 17β-estradiol (E2) was our reference regimen which induced preneoplastic and cancereous lesions. The T + low/high dose of BPA induced prostatic hyperplasia, low-grade prostate intraepithelial neoplasia (LGPIN) and intraepithelial infiltration of T-lymphocytes specifically in the lateral prostate (LP). Using microarray analysis, we delineated specific impacts of low and high dose of BPA (with the T-support) on the gene expression program in LPs. Hierarchical clustering revealed that the endocrine disrupting effects of T + low dose of BPA showed partial resemblance to those of T + high dose of BPA and T+E2. In contrast, the influence of T+ high dose of BPA on the LP transcriptome was completely different from those of T + E2. Further, IPA analysis of specific T+ low or high BPA gene signature identified a transcription factor, HNF4α, as a regulatory hub affecting a number of differentially expressed genes by BPA exposures. These findings suggest that the adult rat prostate is still venerable to the endocrine disrupting effects of BPA. Perhaps chronic exposure to low dose of BPA provides a niche comprising heightened cell proliferation, inflammatory responses and disrupted gene expression program, which favor the onset and development of prostatic benign or malignant diseases in men. Rat lateral prostates were collected from untreated control and treated groups [Testosterone (T) + Estradiol (E2), T + low dose Bisphenol A (low BPA) and T + high BPA] for RNA extraction and hybridization on Affymetrix microarrays. We sought to identify transcriptional signature of BPA exposures in the lateral prostate gland.

Dataset Information

Uterine gene profiles from WT, KIKO (DNA-binding deficient ERα) and aERKO mice treated with estradiol or xenoestrogens

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