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Gene expression of human skin fibroblast cells derived from hypospadias patients in response to low-dose bisphenol A exposure

ABSTRACT: To better understand the molecular basis of the reproductive health effects of bisphenol A (BPA) on humans, a genome-wide screening was applied to identify novel targets of low-dose bisphenol A exposure in huamn skin fibroblast cells (hSFCs) derived from hypospadias patient children. Three hSFCs were collected at National Research Institute for Child Health and Development, Japan. Gene expression profiles of hSFCs were measured at 24 hours after exposure to 10nM BPA, 0.01nM 17β-estradiol (E2) and 1nM 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Differentially expressed genes following chemical treatments were identified by unpaired Student’s t test with P values cut off by 0.05 and fold change of more than 1.2 and selected for the network generation and pathway analysis using Ingenuity Pathways Analysis (IPA) program. As the result, 71 genes (42 downregulated and 29 upregulated), 814 genes (371 downregulated and 443 upregulated), and 824 genes (344 downregulated and 480 upregulated) were identified significantly differently expressed in response to BPA, E2, and TCDD, respectively. The network analysis indicated that the most associated network fuctions of genes genes with altered expression profile derived from microarray analysis were “Endocrine System Disorders, Gastrointestinal Disease, Genetic Disorder”, “Cellular Growth and Proliferation, Skeletal and Muscular System Development and Function, Cell Cycle”, and “Post-Translational Modification, Genetic Disorder, Hematological Disease” in response to BPA, E2, and TCDD, respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE35034 | GEO | 2012/01/13

SECONDARY ACCESSION(S): PRJNA150865

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.

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Gene expression of human skin fibroblast cells derived from hypospadias patients in response to low-dose bisphenol A exposure

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