While previous studies have found that unknown natural and synthetic organo-bromine compounds (NSOBCs) contributed more than 99% of the total organic bromine (Br) in the environment, there was no efficient method for untargeted screening to identify NSOBCs in environmental matrixes. A novel untargeted method for identifying NSOBCs, based on ultrahigh-resolution mass spectrometry (UHRMS) with the Q Exactive instrument was developed. This method included a data-independent precursor isolation and characteristic fragment (DIPIC-Frag) procedure to identify NSOBCs. A total of 180 successive 5-m/z-wide windows were used to isolate precursor ions. This resulted in a sufficient dynamic range and specificity to identify peaks of Br fragment ions for analysis. A total of 2520 peaks of NSOBC compounds containing Br were observed in sediments from Lake Michigan, United States. A new chemometric strategy which combined chromatographic profiles, isotopic peaks, precursor isolation window information, and intensities was used to identify precursor ions and chemical formulas for detecting NSOBCs. Precursor ions for 2163 of the 2520 NSOBCs peaks (86%) were identified, and chemical formulas for 2071 NSOBCs peaks (82%) were determined. After exclusion of isotopic peaks, 1593 unique NSOBCs were identified and chemical formulas derived for each. Most of the compounds identified had not been reported previously and had intensities which were 100- to 1000-fold greater than the congeners of polybrominated diphenyl ethers (PBDEs). In extracts of sediments, these compounds exhibited variations in intensities (<10(3) to ∼10(8)), m/z values (170.9438-997.5217), retention times on a C18 column (1.0-29.3 min), and the number of Br atoms (1-8). Generally, compounds with greater m/z values had longer retention times and greater numbers of Br atoms. Three compounds were used in a proof-of-concept experiment to demonstrate that structures of some of the screened NSOBCs could be further predicted by combining searching of database libraries and high-resolution MS(2) spectra.

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Characterization of toxicological profiles by use of traditional targeted strategies might underestimate the risk of environmental mixtures. Unbiased identification of prioritized compounds provides a promising strategy for meeting regulatory needs. In this study, untargeted screening of brominated compounds in house dust was conducted using a data-independent precursor isolation and characteristic fragment (DIPIC-Frag) approach, which used data-independent acquisition (DIA) and a chemometric strategy to detect peaks and align precursor ions. A total of 1008 brominated compound peaks were identified in 23 house dust samples. Precursor ions and formulas were identified for 738 (73%) of the brominated compounds. A correlation matrix was used to cluster brominated compounds; three large groups were found for the 140 high-abundance brominated compounds, and only 24 (17%) of these compounds were previously known flame retardants. The predominant class of unknown brominated compounds was predicted to consist of nitrogen-containing compounds. Following further validation by authentic standards, these compounds (56%) were determined to be novel brominated azo dyes. The mutagenicity of one major component was investigated, and mutagenicity was observed at environmentally relevant concentrations. Results of this study demonstrated the existence of numerous unknown brominated compounds in house dust, with mutagenic azo dyes unexpectedly being identified as the predominant compounds.

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Previously unreported natural and synthetic organo-bromine compounds (NSOBCs) have been found to contribute more than 99% of total organic bromine (TOB) in environmental matrices. We recently developed a novel untargeted method (data-independent precursor isolation and characteristic fragment, DIPIC-Frag) and identified ∼2000 NSOBCs in two sediments from Lake Michigan. In this study, this method was used to investigate the distributions of these NSOBCs in 23 surficial samples and 24 segments of a sediment core from Lake Michigan. NSOBCs were detected in all 23 surficial samples and exhibited 10- to 100-fold variations in peak abundance among locations. The pattern of distributions of NSOBCs was correlated with depth of the water column (r(2) = 0.61, p < 0.001). Hierarchical cluster analysis showed that sediments in close proximity exhibited similar profiles of NSOBCs. Distributions of NSOBCs in 24 segments of a sediment core dated from 1766 to 2008 were investigated, and samples from similar depths exhibited similar profiles of NSOBCs. NSOBCs were grouped into four clusters (soft-cluster analysis) with different temporal trends of abundances. 515 and 768 of the NSOBCs were grouped into cluster 1 and cluster 3 with increasing temporal trends, especially since 1950, indicating that abundances of these compounds might have been affected by human activities.

2,2',4,4'-Tetrabromodiphenyl ether (BDE-47), 6-hydroxy-tetrabromodiphenyl ether (6-OH-BDE-47), and 6-methoxy-tetrabromodiphenyl ether (6-MeO-BDE-47) are the most detected congeners of polybrominated diphenyl ethers (PBDEs), OH-BDEs, and MeO-BDEs, respectively, in aquatic organisms. Although it has been demonstrated that BDE-47 can interfere with certain endocrine functions that are mediated through several nuclear hormone receptors (NRs), most of these findings were from mammalian cell lines exposed in vitro. In the present study, embryos and larvae of zebrafish were exposed to BDE-47, 6-OH-BDE-47, and 6-MeO-BDE-47 to compare their accumulation, biotransformation, and bioconcentration factors (BCF) from 4 to 120 hpf. In addition, effects on expression of genes associated with eight different pathways regulated by NRs were investigated at 120 hpf. 6-MeO-BDE-47 was most bioaccumulated and 6-OH-BDE-47, which was the most potent BDE, was least bioaccumulated. Moreover, the amount of 6-MeO-BDE-47, but not BDE-47, transformed to 6-OH-BDE-47 increased in a time-dependent manner, approximately 0.01%, 0.04%, and 0.08% at 48, 96, and 120 hpf, respectively. Expression of genes regulated by the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), and mineralocorticoid receptor (MR) was affected in larvae exposed to 6-OH-BDE-47, whereas genes regulated by AhR, ER, and the glucocorticoid receptor (GR) were altered in larvae exposed to BDE-47. The greatest effect on expression of genes was observed in larvae exposed to 6-MeO-BDE-47. Specifically, 6-MeO-BDE-47 affected the expression of genes regulated by AhR, ER, AR, GR, and thyroid hormone receptor alpha (TRα). These pathways were mostly down-regulated at 2.5 μM. Taken together, these results demonstrate the importance of usage of an internal dose to assess the toxic effects of PBDEs. BDE-47 and its analogs elicited distinct effects on expression of genes of different hormone receptor-mediated pathways, which have expanded the knowledge of different mechanisms of endocrine disrupting effects in aquatic vertebrates. Because some of these homologues are natural products, assessments of risks of anthropogenic PBDE need to be made against the background of concentrations from naturally occurring products. Even though PBDEs are being phased out as flame retardants, the natural products remain.

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