No abstract

Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants in consumer goods, such as plastics, electronics, textiles, and construction material. PBDEs have been found in human milk, fat, and blood samples. Rodent studies indicate that PBDEs may be detrimental to neurodevelopment, possibly by lowering thyroid hormone concentrations in blood. In the present study, we determined concentrations of PBDEs and thyroid hormones in human fetal and maternal serum. Patients presenting in labor to Indiana University and Wishard Memorial County hospitals in Indianapolis, who were older than 18 years, were recruited to participate. Twelve paired samples of maternal and cord blood were obtained and analyzed using gas chromatographic mass spectrometry; thyroid hormone concentrations were determined by radioimmunoassay. Six congeners of PBDE were measured in maternal and fetal serum samples. The concentrations of total PBDEs found in maternal sera ranged from 15 to 580 ng/g lipid, and the concentrations found in fetal samples ranged from 14 to 460 ng/g lipid. Individual fetal blood concentrations did not differ from the corresponding maternal concentrations, indicating that measurement of maternal PBDE blood levels is useful in predicting fetal exposure; similarly, other reports have shown a high correlation between PBDE in mother's milk and fetal exposure. In accord with reports on other biologic samples, the tetrabrominated PBDE congener BDE-47 accounted for 53-64% of total PBDEs in the serum. The concentrations of PBDEs found in maternal and fetal serum samples were 20-106-fold higher than the levels reported previously in a similar population of Swedish mothers and infants. In this small sample, there was no apparent correlation between serum PBDEs and thyroid hormone concentrations. Our study shows that human fetuses in the United States may be exposed to relatively high levels of PBDEs. Further investigation is required to determine if these levels are specific to central Indiana and to assess the toxic potential of these exposure levels. Key words: brominated diphenyl ethers, cord blood, human, pregnancy, serum.

BackgroundA previous study from our laboratory showed that polybrominated diphenyl ethers (PBDEs) were metabolized to hydroxylated PBDEs (HO-PBDEs) in mice and that para-HO-PBDEs were the most abundant and, potentially, the most toxic metabolites.ObjectiveThe goal of this study was to determine the concentrations of HO-PBDEs in blood from pregnant women, who had not been intentionally or occupationally exposed to these flame retardants, and from their newborn babies.MethodsTwenty human blood samples were obtained from a hospital in Indianapolis, Indiana, and analyzed for both PBDEs and HO-PBDEs using electron-capture negative-ionization gas chromatographic mass spectrometry.ResultsThe metabolite pattern of HO-PBDEs in human blood was quite different from that found in mice; 5-HO-BDE-47 and 6-HO-BDE-47 were the most abundant metabolites of BDE-47, and 5′-HO-BDE-99 and 6′-HO-BDE-99 were the most abundant metabolites of BDE-99. The relative concentrations between precursor and corresponding metabolites indicated that BDE-99 was more likely to be metabolized than BDE-47 and BDE-100. In addition, three bromophenols were also detected as products of the cleavage of the diphenyl ether bond. The ratio of total hydroxylated metabolites relative to their PBDE precursors ranged from 0.10 to 2.8, indicating that hydroxylated metabolites of PBDEs were accumulated in human blood.ConclusionsThe quite different PBDE metabolite pattern observed in humans versus mice indicates that different enzymes might be involved in the metabolic process. Although the levels of HO-PBDE metabolites found in human blood were low, these metabolites seemed to be accumulating.

BackgroundPrevious studies have shown that polybrominated diphenyl ethers (PBDEs) behave as weak estrogens in animal and cell culture bioassays. In vivo metabolites of PBDEs are suspected to cause these effects.ObjectivesTo identify candidate metabolites, mouse plasma samples were collected after continuous oral and subcutaneous exposure to DE-71, a widely used commercial pentabromodiphenyl ether product, for 34 days.MethodsSamples were extracted, separated into neutral and phenolic fractions, and analyzed by gas chromatographic mass spectrometry.ResultsIn the plasma samples of orally treated animals, 2,2′,4,4′,5,5′-hexabromodiphenyl ether (BDE-153) represented 52% of total measurable PBDEs, whereas it represented only 4.3% in the DE-71 mixture. This suggested that BDE-153 was more persistent than other congeners in mice. Several metabolites were detected and quantitated: 2,4-dibromophenol, 2,4,5-tribromophenol, and six hydroxylated PBDEs. The presence of the two phenols suggested cleavage of the ether bond of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) and 2,2′,4,4′,5-pentabromodiphenyl ether (BDE-99), respectively. The hydroxylated (HO)-PBDEs might come from hydroxylation or debromination/hydroxylation. Among the quantitated hydroxylated metabolites, the most abundant was 4-HO-2,2′,3,4′-tetra-BDE, which suggested that there was a bromine shift during the hydroxylation process. para-HO-PBDEs have been proposed to behave as endocrine disruptors.ConclusionsThere seem to be three metabolic pathways: cleavage of the diphenyl ether bond, hydroxylation, and debromination/hydroxylation. The cleavage of the diphenyl ether bond formed bromophenols, and the other two pathways formed hydroxylated PBDEs, of which para-HO-PBDEs are most likely formed from BDE-47. These metabolites may be the most thyroxine-like and/or estrogen-like congeners among the HO-PBDEs.

Tissue transglutaminase (TG2), an enzyme that catalyzes Ca 2+ -dependent aggregation and polymerization of proteins, is overexpressed in ovarian cancer cells and tumors. We previously reported that TG2 facilitates tumor dissemination using an i.p. xenograft model. Here we show that TG2 modulates epithelial-to-mesenchymal transition (EMT), contributing to increased ovarian cancer cell invasiveness and tumor metastasis. By using stable knockdown and overexpression in epithelial ovarian cancer cells, we show that TG2 induces a mesenchymal phenotype, characterized by cadherin switch and invasive behavior in a Matrigel matrix. This is mediated at the transcriptional level by altering the expression levels and function of several transcriptional repressors, including Zeb1. One mechanism through which TG2 induces Zeb1 is by activating the nuclear factor-κB complex. The effects of TG2 on ovarian cancer cell phenotype and invasiveness translate into increased tumor formation and metastasis in vivo, as assessed by an orthotopic ovarian xenograft model. Highly expressed in ovarian tumors, TG2 promotes EMT and enhances ovarian tumor metastasis by activating oncogenic signaling. [Cancer Res 2009;69(24):9192-201]