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Diastereomers of the brominated flame retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane induce androgen receptor activation in the hepg2 hepatocellular carcinoma cell line and the lncap prostate cancer cell line.

ABSTRACT: BACKGROUND:Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to be maternally transferred in zebrafish. OBJECTIVES:In the present study we investigated interaction energies between TBECH diastereomers (alpha, beta, gamma, and delta) and the hAR, and their ability to activate the receptor and induce prostate-specific antigen (PSA) expression in vitro. METHODS:We performed computational modeling to determine interaction energies between the ligand and the AR ligand-binding site, and measured in vitro competitive binding assays for AR by polarization fluorometry analysis. We used enzyme-linked immunosorbent assays to determine PSA activity in LNCaP and HepG2 cells. RESULTS:We found the gamma and delta diastereomers to be more potent activators of hAR than the alpha and beta diastereomers, which was confirmed in receptor binding studies. All TBECH diastereomers induced PSA expression in LNCaP cells even though the AR present in these cells is mutated (T877A). Modeling studies of LNCaP AR revealed that TBECH diastereomers bound to the receptor with a closer distance to the key amino acids in the ligand-binding domain, indicating stronger binding to the mutated receptor. CONCLUSIONS:The present study demonstrates the ability of TBECH to activate the hAR, indicating that it is a potential endocrine disruptor.

SUBMITTER: Khalaf H

PROVIDER: S-EPMC2799458 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Diastereomers of the brominated flame retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane induce androgen receptor activation in the hepg2 hepatocellular carcinoma cell line and the lncap prostate cancer cell line.

Khalaf Hazem H Larsson Anders A Berg Håkan H McCrindle Robert R Arsenault Gilles G Olsson Per-Erik PE

Environmental health perspectives 20090803 12

<h4>Background</h4>Reported incidences of prostate cancer and masculinization of animals indicate a release of compounds with androgenic properties into the environment. Large numbers of environmental pollutants have been screened to identify such compounds; however, not until recently was 1,2-dibromo-4-(1,2-dibromoethyl)cyclohexane (TBECH) identified as the first potent activator of the human androgen receptor (hAR). TBECH has been found in beluga whales and bird eggs and has also been found to ...[more]

PMID: 20049203

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Project description:Advanced paternal age at fertilization has been suggested to be a risk factor for neurodevelopmental, psychiatric and other disorders in offspring. One emerging hypothesis suggests that altered offspring phenotype is linked with age-related accumulation of epigenetic changes in the sperm of fathers. Given that paternal age is increasing in the developed world, understanding aging-related epigenetic changes in sperm is needed as well as environmental factors that modify such changes. In this study, we characterize age-dependent changes in sperm DNA methylation profiles between young pubertal (postnatal day (PNDs) 65) and mature (PND120) Wistar rats. We also analyze these changes in rats exposed perinatally to 0.2 mg/kg of ubiquitous environmental xenobiotic 2,2’,4,4’-tetrabromodiphenyl ether (BDE-47). Reduced representation bisulfite sequencing (RRBS) libraries were prepared from caudal epididymal sperm DNA and differentially methylated regions (DMRs; ≥ 10x coverage depth, ≥ 3 CpGs per cluster, ≥ 5% methylation change, q < 0.05) were identified via MethPipe package. We identified 21 and 9 exposure-related DMRs in sperm collected on PND65 and PND120, respectively. Two DMRs overlapped between the two time-points. This is the first study to demonstrate that environmentally-relevant perinatal exposure to PBDE results in long-lasting changes in sperm DNA methylation. In control animals, 5,319 age-dependent DMRs were identified, with 99.3% DMRs hypermethylated in mature animals compared to young pubertal rats. These age-related DMRs were enriched for functional categories essential for embryonic development, such as pattern specification, forebrain and sensory organ development, and the Wnt pathway. In BDE-47 exposed rats, sperm DNA methylation was higher in young pubertal and lower in mature animals when compared to controls, which resulted in a significant attenuation in the number of age-dependent DMRs (N = 189) identified in the exposed group. In conclusion, our results indicate that the natural aging process has profound effects on sperm methylation levels and this effect may be modified by environmental exposures. Moreover, our results further support the role of sperm DNA methylation as a likely mechanism by which advanced paternal age is associated with adverse offspring health and development.

Dataset Information

Diastereomers of the brominated flame retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane induce androgen receptor activation in the hepg2 hepatocellular carcinoma cell line and the lncap prostate cancer cell line.

Publications

Diastereomers of the brominated flame retardant 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane induce androgen receptor activation in the hepg2 hepatocellular carcinoma cell line and the lncap prostate cancer cell line.

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