The 2,2′,4,4′-tetrabromodiphenyl ether hydroxylated metabolites 5-OH-BDE-47 and 6-OH-BDE-47 stimulate estradiol secretion in the ovary by activating aromatase expression

International Journal of Endocrinology

Ptak

2013

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Persistent organic pollutants (POPs), such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polybrominated ethers (PBDEs), chloronaftalens (PCNs), and bisphenol A (BPA), are stable, lipophilic pollutants that affect fertility and cause serious reproductive problems, including ovotoxic action, lack of ovulation, premature ovarian failure (POF), or polycystic ovarian syndrome (PCOS). Most of the representatives of POPs influence the activation of transcription factors, not only activation of aromatic hydrocarbon receptor (AhR), but also the steroid hormone receptors. This minireview will focus on a variety of PAH activities in oocyte, ovary, placenta, and mammary gland. The complexity and diversity of factors belonging to POPs and disorders of the reproductive function of women indicate that the impact of environmental pollution as an important determinant factor in fertility should not be minimize.

Section: Actions On the Ovarymentioning

confidence: 99%

Endocrine-Disrupting Chemicals: Some Actions of POPs on Female Reproduction

International Journal of Endocrinology

Ptak

2013

Self Cite

“…Whereas our recent studies showed that BDE‐47 altered the ratio of ERα to ERβ in favour of ERα, and the hydroxylated metabolites of BDE‐47 increased the expression of both oestrogen receptors in ovarian follicular cells (Karpeta et al ., ). Additionally, our previous studies have shown that 5‐OH‐BDE‐47 and 6‐OH‐BDE‐47 increased oestradiol secretion by stimulating aromatase expression and activity (Karpeta et al ., ). The ability of hydroxylated metabolites of BDE‐47 to activate the expression of both oestrogen receptors (Karpeta et al ., ) and to stimulate oestradiol synthesis by ovarian follicles (Karpeta et al ., ) can lead to excessive exposure of the ovaries to oestrogens.…”

Section: Introductionmentioning

confidence: 97%

“…Additionally, our previous studies have shown that 5-OH-BDE-47 and 6-OH-BDE-47 increased oestradiol secretion by stimulating aromatase expression and activity (Karpeta et al, 2013). The ability of hydroxylated metabolites of BDE-47 to activate the expression of both oestrogen receptors (Karpeta et al, 2014) and to stimulate oestradiol synthesis by ovarian follicles (Karpeta et al, 2013) can lead to excessive exposure of the ovaries to oestrogens. Oestrogens are major regulators of growth and differentiation in normal ovaries but an excess of oestrogens may lead to the development and progression of ovarian carcinomas (O'Donnell et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Different mechanisms of action of 2, 2’, 4, 4’‐tetrabromodiphenyl ether (BDE‐47) and its metabolites (5‐OH‐BDE‐47 and 6‐OH‐BDE‐47) on cell proliferation in OVCAR‐3 ovarian cancer cells and MCF‐7 breast cancer cells

Karpeta

Maniecka

J of Applied Toxicology

2016

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Data concerning the possible action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent cancer are scarce. Some data showed that PBDEs may directly affect breast cancer cells formation and only one research showed increased proliferation of the OVCAR-3 cells, but the results are ambiguous and the mechanisms are not clear. There is growing evidence that not only parent compounds but also its metabolites may be involved in cancer development. The present study was, therefore, designed to determine the effect of BDE-47 and its metabolites (2.5 to 50 ng ml ) on proliferation (BrdU), cell-cycle genes (real-time PCR) and protein expression (Western blot), protein expression of oestrogen receptors (α β), extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase Cα (PKCα) in OVCAR-3 ovarian and MCF-7 breast cancer cells. In OVCAR-3 cells, the parent compound stimulated cell proliferation by activating CDK1, CDK7, E2F1 and E2F2. Independent of time of exposure, BDE-47 had no effect on ERα and ERβ protein expression and ERK1/2 and PKCα phosphorylation. Metabolites had no effect on cell proliferation but increased both ERs protein expression and ERK1/2 and PKCα phosphorylation. In MCF-7 cells, the parent compound displayed no effect on cell proliferation but decreased ERα and increased ERβ protein expression with concomitant induction of PKCα phosphorylation. Both metabolites increased MCF-7 cell proliferation, ERK1/2 and PKCα phosphorylation and decreased ERα and ERβ protein expression.We suggest that studies concerning PBDEs with fewer bromine atoms should be continued to understand environmental links to different hormone-dependent cancers. Copyright © 2016 John Wiley & Sons, Ltd.

“…In conclusion, presented results clearly showed that hydroxylated metabolites of BDE‐47 have stronger inhibitory effects on apoptosis in both ovarian and breast tumor cells than the parent compound (BDE‐47). Moreover, our previous study showed that hydroxylated metabolites of BDE‐47 increased estradiol secretion by ovarian follicles (Karpeta et al, ) and suggest that 5‐OH‐BDE‐47 and 6‐OH‐BDE‐47 may bind with estrogen receptors in place of estradiol, thus triggering estrogenic action in mammary tissue (Karpeta et al, ). Taking into consideration the data showing that in MCF‐7 cell expression of several pro‐apoptotic proteins are markedly increased with estradiol treatment (Lewis et al, ) and data showing that estradiol inhibit apoptosis in ovarian tumorigenesis (Choi et al, ) we may confirm that metabolites are much more potent than the parent compound.…”

Section: Discussionmentioning

confidence: 96%

“…The Environmental Protection Agency has classified only decabromodiphenyl ether as a possible human carcinogen, whereas less-brominated PBDEs are not classified as human carcinogens. According to the results of numerous studies, PBDEs belong to endocrine disrupting compounds (Gregoraszczuk et al, 2008a(Gregoraszczuk et al, , 2008bKarpeta and Gregoraszczuk, 2010;Karpeta et al, 2011Karpeta et al, , 2012Karpeta et al, , 2013Karpeta et al, , 2014Lilienthal et al, 2006). Both ovarian epithelial carcinoma (OVCAR-3) and breast cancer cell (MCF-7) are hormone-dependent cancers.…”

Section: Introductionmentioning

confidence: 99%

Differences in the mechanisms of action of BDE‐47 and its metabolites on OVCAR‐3 and MCF‐7 cell apoptosis

Karpeta

J of Applied Toxicology

2016

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Data concerning possible carcinogenic action of polybrominated diphenyl ethers (PBDEs) in hormone-dependent tissues are limited. Our earlier studies showed that 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) stimulated OVCAR-3 and MCF-7 cell proliferation, while its hydroxylated metabolites (5-OH-BDE-47 and 6-OH-BDE-47) increased estrogen receptors protein expression and extracellular signal-regulated kinase 1/2 and protein kinase Cα phosphorylation in these cell lines. In addition to cell proliferative disorder, a failure in the regulation of apoptosis can also lead to the formation and development of tumors. Therefore, in the present study, we investigated the effect of BDE-47 and its metabolites (2.5-50 ng ml ) on the expression of apoptosis regulatory genes and proteins, caspase-8 and -9 activity and DNA fragmentation induced by extracellular signal-regulated kinase inhibitor (PD098059) and protein kinase Cα inhibitor (Gӧ 6976) in ovarian (OVCAR-3) and breast (MCF-7) cancer cells. In OVCAR-3 cells, BDE-47 upregulated expression of most of the investigated genes and increased protein expression of tumor necrosis factor (TNF)-α, TNF receptor 1, caspase-6, Bcl-xl and caspase-8 activity. Whereas in MCF-7 cells, BDE-47 resulted in the downregulation of most of the investigated genes, and decreased caspase-8 and -9 activity. In both OVCAR-3 and MCF-7 cells, the expression of most of the investigated genes were downregulated by metabolites. Exposure of OVCAR-3 cells to 5-OH-BDE-47 corresponded with a decrease in the protein expression of caspase-6, caspase-9 and Bcl-xl and treatment with 6-OH-BDE-47 decreased Bcl-xl and TNF receptor 1 expression in OVCAR-3 cells and caspase-9 expression in MCF-7 cells. Hydroxylated metabolites of BDE-47 have strong inhibitory effects on apoptosis in ovarian and breast tumor cells and thus should be considered potential carcinogens in hormone-dependent cancers. Copyright © 2016 John Wiley & Sons, Ltd.