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Background: The widespread use of phthalates as plasticizers has raised public health concerns regarding their adverse effects, including an association with cancer. Although animal investigations have suggested an association between phthalate exposure and hepatocellular carcinoma, the mechanisms are unknown. Methods: The hepatocellular carcinoma cell line Huh7 was treated with benzyl butyl phthalate (BBP), and then analyzed by total internal reflection fluorescence microscopy, confocal microscopy and double immunogold transmission electron microscopy. Following BBP treatment, mRNA levels were measured by RT-PCR, protein levels were measured using western blot, and vascular endothelial growth factor levels were measured by an enzyme-linked immunosorbent assay. Cell migration and invasion assays were evaluated by transwell, and angiogenesis were performed by a tube formation assay. Nude mice were used to investigate metastasis and angiogenesis in vivo. Results: BBP affected hepatocellular carcinoma progression through the aryl hydrocarbon receptor (AhR) and that benzyl butyl phthalate (BBP) stimulated AhR at the cell surface, which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR through a nongenomic action involving G-protein signaling rather than the classical genomic AhR action. BBP treatment promoted cell migration and invasion in vitro and metastasis in vivo via the AhR/Gβ/PI3K/Akt/NF-κB pathway. In addition, BBP induced both in vitro and in vivo angiogenesis through the AhR/ERK/VEGF pathway. Conclusions: These findings suggest a novel nongenomic AhR mechanism involving G-protein signaling induced by phthalates, which contributes to tumor progression of hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Environmental hormones play important roles in regulating the expression of genes involved in cell proliferation, drug resistance, and breast cancer risk; however, their precise role in human breast cancer cells during cancer progression remains unclear. To elucidate the effect of the most widely used industrial phthalate, n-butyl benzyl phthalate (BBP), on cancer progression, we evaluated the results of BBP treatment using a whole human genome cDNA microarray and MetaCore software and selected candidate genes whose expression was changed by more than ten-fold by BBP compared with controls to analyze the signaling pathways in human breast cancer initiating cells (R2d). A total of 473 genes were upregulated, and 468 were downregulated. Most of these genes are involved in proliferation, epithelial-mesenchymal transition, and angiogenesis signaling. BBP induced the viability, invasion and migration, and tube formation in vitro, and Matrigel plug angiogenesis in vivo of R2d and MCF-7. Furthermore, the viability and invasion and migration of these cell lines following BBP treatment was reduced by transfection with a small interfering RNA targeting the mRNA for lymphoid enhancer-binding factor 1; notably, the altered expression of this gene consistently differentiated tumors expressing genes involved in proliferation, epithelial-mesenchymal transition, and angiogenesis. These findings contribute to our understanding of the molecular impact of the environmental hormone BBP and suggest possible strategies for preventing and treating human breast cancer. [ABSTRACT FROM AUTHOR]

Phthalates are environmental hormone-like molecules that are associated with breast cancer risk and are involved in metastasis, a process that requires the epithelial-mesenchymal transition (EMT). However, few studies have addressed the potential effects of phthalates on stem cells. Here we tested the hypothesis that phthalates such as butyl benzyl phthalate and di-n-butyl phthalate induce EMT in R2d cells, a stem cell-derived human breast epithelial cell line that is responsive to estradiol for tumor development. We observed that phthalates induced EMT as evidenced by morphological changes concomitant with increased expression of mesenchymal markers and decreased expression of epithelial markers. Molecular mechanism studies revealed that histone deacetylase 6 (HDAC6) is required for phthalate-induced cell migration and invasion during EMT in vitro and metastasis into the lungs of nude mice. We also constructed a series of mutant HDAC6 promoter fragments and found that the transcription factor AP-2a plays a novel role in regulating the HDAC6 promoter. Furthermore, phthalates stimulated estrogen receptors and triggered the downstream EGFR-PKA signaling cascade, leading to increased expression of AP-2a in the nucleus. We also observed that phthalates increased expression of the PP1/HDAC6 complex and caused Akt activation and GSK3β inactivation, leading to transcriptional activation of vimentin through the β-catenin-TCF-4/LEF1 pathway. Understanding the signaling cascades of phthalates that activate EMT through HDAC6 in breast epithelial stem cells provides the identification of novel therapeutic target for human breast cancer. [ABSTRACT FROM AUTHOR]

The environmentally present group of chemical phthalates, or phthalate esters, has been recognized as a rising threat to public health, including cancer. While most studies have addressed the estrogenic effects of phthalates in malignancies of the breast and the prostate, little is known about their role in the etiology of hormone-independent cancer. Here we show that treatments with the phthalates n-butyl benzyl phthalate (BBP) and dibutyl phthalate (DBP) at 1 µM induced proliferation (BBP, 3.2-fold; DBP, 3.2-fold), migration (BBP, 2.6-fold; DBP, 2.6-fold), invasion (BBP, 2.7-fold; DBP, 3.1-fold), and tumor formation (EC50: BBP, 0.12 µM; DBP, 0.22 µM) in estrogen receptor (ER)-negative breast cancer cells (MDA-MB-231). We further demonstrate that phthalates stimulated the cell surface aryl hydrocarbon receptor (AhR) and triggered the downstream cyclic AMP (cAMP)-PKACREB1 signaling cascade. The pathway led to increased expression of HDAC6, which facilitated nuclear assembly of the β-catenin-LEF1/TCF4 transcriptional complex and transactivation of the c-Myc oncogene. This nongenomic pathway emanated from the phthalate-induced AhR promoted tumorigenesis of ER-negative breast cancer. Collectively, our findings revealed a novel oncogenic mechanism of phthalates in breast cancer independent from their estrogenic activities. [ABSTRACT FROM AUTHOR]

This study demonstrates a noncatalytic, low-pressure, and room-temperature process for methane partial oxidation into syngas by using a microwave plasma torch reactor. The experimental results showed that the elevation of the inlet O2/CH4 molar ratio, pressure, and applied power led to the outlet H2/CO molar ratios decreased from 3.32 (at O2/CH4 = 0.3, 13.3 kPa, and 160 W) to 0.81 (at O2/CH4 = 1.5, 93.3 kPa, and 600 W). At O2/CH4 = 0.5, the higher selectivity and yield of syngas, and a H2/CO molar ratio of about 2 could be obtained simultaneously. In addition, the maximum yield of syngas per unit mole of methane consumed could be achieved at a higher pressure, although a higher methane conversion was performed at a lower pressure. Based on these, this study suggests that the operating conditions of O2/CH4 = 0.5 and near atmospheric pressure (93.3 kPa) would be the most appropriate combination for converting methane into syngas. Under the conditions, the selectivities of He and CO reached 97.6 and 99.2%, respectively, accompanied with H2/CO = 1.97 at 600 W. [ABSTRACT FROM AUTHOR]