Molecular Mechanisms of Polybrominated Diphenyl Ethers (BDE-47, BDE-100, and BDE-153) in Human Breast Cancer Cells and Patient-Derived Xenografts

Abstract

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in household materials. Their environmental persistence has led to continuous human exposure and significant tissue levels. Three PBDE congeners (BDE-47, BDE-100, and BDE-153) have been frequently detected in human serum. Although these compounds appear to possess endocrine disrupting activity, studies are largely missing to determine the biological mechanisms of PBDEs in breast cancer cells. Here, we assessed PBDE bioactivities with three complementary strategies: receptor binding/activity assays; nonbiased RNA-sequencing analysis using an estrogen-dependent breast cancer cell line MCF-7aroERE; and in vivo assessments using patient-derived xenograft (PDX) models of human breast cancer. According to the results from in vitro experiments, the PBDE congeners regulate distinct nuclear receptor signaling pathways. BDE-47 acts as a weak agonist of both estrogen receptor a (ERa) and estrogen-related receptor a (ERRa); it could stimulate proliferation of MCF-7aroERE and induced expression of ER-regulated genes (including cell cycle genes). BDE-153 was found to act as a weak antagonist of ERa. BDE-100 could act as (1) an agonist of aryl hydrocarbon receptor (AhR), inducing expression of CYP1A1 and CYP1B1 and (2) as a very weak agonist/antagonist of ERa. In vivo, a mixture of the three congeners with ratios detected in human serum was tested in an ERþ PDX model. The mixture exhibited estrogenic activity through apoptosis/cell cycle regulation and increased the expression of a proliferation marker, Ki-67. These results advance our understanding of the mechanisms of PBDE exposure in breast cancer cells.

Chronic BDE-47 Exposure Aggravates Malignant Phenotypes and Chemoresistance by Activating ERK Through ERα and GPR30 in Endometrial Carcinoma

“…Additionally, BDE-47 had no effect on ERK phosphorylation in the two cell lines (25). In contrast, Kanaya et al recently reported that BDE-47 stimulated proliferation of an estrogen-dependent breast cancer cell line MCF-7aroERE and induced ER-regulated genes expression, which suggested that BDE-47 acted as a weak agonist of both ERα and estrogen-related receptor α (ERRα) (32). One previous case-control study from our laboratory demonstrated that BDE-47 level was positively with breast-cancer risk regardless of ER stratification (33).…”

“…The concentration used in this BDE-47 exposure model is based on the dose-response experiment and the data shown previously in other in vitro systems (34, 50–52). Recently, Kanaya compared with in vitro breast cancer cell culture treatment at dosage of 10 μM to the published human serum/tissue concentrations of PBDEs (BDE-47 included), and concluded that the maximum concentrations observed in human serum and tissue concentrations were ~1,300 and 350 times lower than 10 μM, respectively (32). Therefore, future study will be needed to advance understanding the effect of environmentally relevant low-dose PBDEs on the progression and chemoresistance of EC cells in vitro and in vivo , which will help to answer the critical question whether real-life BDE-47 exposure could be a risk of human EC and resistance factor for chemotherapy.…”

Single-cell RNA-sequencing analysis of estrogen- and endocrine-disrupting chemical-induced reorganization of mouse mammary gland

“…To replicate physiologically relevant exposures, we assessed the relationship between dosage and both the ratio and murine sera levels of the three PBDEs congeners. The ratio was adjusted to reflect human exposure of three major PBDEs detected 47 . Compared to the highest concentration scenario in human exposure (i.e., maximum observed serum concentration), the mouse serum concentration in this study was 10–30 times higher than human exposure 47 .…”

“…The ratio was adjusted to reflect human exposure of three major PBDEs detected 47 . Compared to the highest concentration scenario in human exposure (i.e., maximum observed serum concentration), the mouse serum concentration in this study was 10–30 times higher than human exposure 47 . After one-week of treatment, mice were euthanized to collect blood and mammary glands.…”

Environmental Carcinogenesis at the Single-Cell Level

“…The capability for scRNAseq to capture high-resolution transcriptional data also allows for profiling of cell populations by utilizing differentially expressed genes as signatures for gene ontology scoring. This method opens possibilities into identifying subpopulations based on function rather than comparison with gene lists in literature (13,14). Another emerging method used to analyze single cell data is through mapping ligand-receptor relationships at the cellular level.…”