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Effects of bisphenol A on gene expression in adipocytes from lean children: association to metabolic disorders

ABSTRACT: Bisphenol A (BPA) is a xenobiotic endocrine disrupting chemical. In vitro and in vivo studies indicated that BPA alters endocrine-metabolic pathways in adipose tissue increasing the risk of developing metabolic disorders. BPA effects on human adipocytes, specifically in children, are poorly investigated. To investigate in childhood the effect of exposure to BPA on metabolic disorders we analyzed in vitro the effects of environmentally relevant doses of BPA on gene expression of mature human adipocytes from pre-pubertal lean patients and on related physiological outcomes. Adipocytes from children were treated in vitro with BPA and gene expression was evaluated by qRT-PCR. Genome wide analyses were performed using GeneChip® Human Gene 1.0 ST array. Lipid content in adipocytes was estimated by ORO staining and Triglyceride Quantification Kit. Secreted IL-1β, in adipocytes culture medium, and insulin, in PANC-1 culture medium, were performed using ELISA assays. BPA was found to promote up-regulation of ERα and ERRγ, and down-regulation of GPR30 expression modulating estrogen signaling and following a non-linear dose-response. Microarray data analysis demonstrated that BPA increases the gene expression of pro-inflammatory cytokines and lipid metabolism-related FABP4 and CD36 in adipocytes. PCSK1 resulted the most interesting gene being down-regulated by BPA thus impairing insulin production in pancreas. BPA promotes inflammation and lipid metabolism dysregulation in adipocytes from lean children. Moreover, PCSK1 can be a key gene in BPA action modulating insulin production. Exposure to BPA in childhood may be an important risk factor in developing obesity and metabolic disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58516 | GEO | 2015/07/09

SECONDARY ACCESSION(S): PRJNA252814

REPOSITORIES: GEO

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Project description:Background: Exposure to the endocrine-disrupting chemical bisphenol A (BPA) is correlated with obesity and promotes adipogenesis of human preadipocytes into mature adipocytes. However, the mechanism of action of BPA-induced human adipogenesis in vitro remains to be fully characterized. Methods: In this study, potential mechanisms of BPA-induced adipogenesis in primary human preadipocytes were evaluated using gene expression microarray analysis. Preadipocytes from donors with normal body mass indexes were differentiated in the presence of 50 M-BM-5M BPA or 1 M-BM-5M dexamethasone (DEX) for 48 hours. Results: Microarray analysis revealed 235 up-regulated and 138 down-regulated genes following BPA treatment, including sterol regulatory element binding factor 1 (SREBF1), a key transcription factor known to regulate many components of lipid metabolism and adipogenesis. For DEX treated preadipocytes, 1136 genes were up-regulated, including the adipogenic marker lipoprotein lipase, while 1031 genes were down-regulated. Ingenuity Pathway Analysis was used to identify functional annotations of the gene expression changes associated with response to BPA and DEX treatments. BPA exposure was associated with expression changes in the genes involved in the accumulation of triacylglycerol while DEX was linked to metabolism of triacylglycerol and cleavage of fatty acids. The analysis also revealed enrichment of genes in pathways known to be associated with BPA exposure including thyroid-receptor/retinoic X receptor (TR/RXR) activation, mammalian target of rapamycin (mTOR) signaling and cholesterol biosynthesis, whereas DEX treatment was linked to cholesterol biosynthesis and ethanol degradation. Interestingly, alterations in the mTOR pathway in response to BPA did not occur in DEX-treated preadipocytes. Conclusions: Our data suggest that potential mechanisms of action of BPA-induced adipogenesis involve SREBF1, the TR/RXR and the mTOR pathways. The study used 40 samples in total which included 5 replicates (cells from 5 unique donors) of 8 different treatments. The 8 treatments were as follows: 1) untreated (negative) control for 48 hours, 2) 25 uM BPA treated for 48 hours, 3) 50 uM BPA treated for 48 hours, 4) untreated (negative) control + insulin for 48 hours, 5) 25 uM BPA + insulin treated for 48 hours, 6) 50 uM BPA + insulin treated for 48 hours, 7) 1uM Dexamethasone + insulin treated for 48 hours, 8) 1uM Dexamethasone + insulin treated for 96 hours.

Project description:Development of insulin resistance is a key pathogenic component underlying metabolic syndrome and Type 2 diabetes (T2DM). Despite its importance, the molecular mechanisms underlying insulin resistance are poorly understood. Genome-wide association studies for T2DM and other metabolic traits have led to the identification of many candidate SNPs, but the majority of these SNPs are noncoding and determination of associated causal genes and/or specific tissue sites of action have been difficult. Adipocytes are critical regulators of mammalian metabolic homeostasis, with important effects on appetite, satiety, glucose and lipid homeostasis, energy expenditure, blood pressure, and immune function. Although insulin resistance (IR) in skeletal muscle, the major source of glucose disposal, is responsible for the bulk of the hyperglycemia observed in T2DM, muscle IR KO mice are generally healthy, IR also occurs in adipocytes, and inflammation within adipose tissue has been proposed as a primary mediator of IR, resulting in excess release of free fatty acids as well as alterations in adipokine release. Absence of adipose tissue, as observed in various lipodystrophies, or adipocyte-specific knockout of genes such as GLUT4 or insulin receptor, also alter systemic IR and T2DM risk. Transcriptional changes in adipocytes associated with metabolic disease. Despite the importance of adipocytes to metabolic disease, we have a poor understanding of how the adipocyte transcriptome changes in the disease state. Studies investigating transcriptional changes in whole adipose tissue have shown decreases in genes involved in adipogenesis, as well as alterations in inflammation, mitochondrial metabolism, lipid metabolism, detoxification, and insulin signaling. However, the vast majority of these studies use total adipose tissue samples, which does not allow for the exclusive evaluation of gene expression in mature adipocytes due to the substantial number of nonadipocyte cells (immune cells, fibroblasts, endothelial cells, pre-adipocytes, and mesenchymal cells) that also reside in adipose tissue. This is particularly relevant when studying metabolic disorders related to obesity-associated insulin resistance because these conditions are characterized by an increased influx of inflammatory cells into the adipose tissue.

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Effects of bisphenol A on gene expression in adipocytes from lean children: association to metabolic disorders

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