| 1. |
- Li, Xueshu, et al.
(författare)
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Nontarget analysis reveals gut microbiome-dependent differences in the fecal PCB metabolite profiles of germ-free and conventional mice
- 2021
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Ingår i: Environmental Pollution. - : Elsevier BV. - 0269-7491 .- 1873-6424. ; 268
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian polychlorinated biphenyl (PCB) metabolism has not been systematically explored with nontarget high-resolution mass spectrometry (Nt-HRMS). Here we investigated the importance of the gut microbiome in PCB biotransformation by Nt-HRMS analysis of feces from conventional (CV) and germ-free (GF) adult female mice exposed to a single oral dose of an environmental PCB mixture (6 mg/kg or 30 mg/kg in corn oil). Feces were collected for 24 h after PCB administration, PCB metabolites were extracted from pooled samples, and the extracts were analyzed by Nt-HRMS. Twelve classes of PCB metabolites were detected in the feces from CV mice, including PCB sulfates, hydroxylated PCB sulfates (OH-PCB sulfates), PCB sulfonates, and hydroxylated methyl sulfone PCBs (OH-MeSO2-PCBs) reported previously. We also observed eight additional PCB metabolite classes that were tentatively identified as hydroxylated PCBs (OH-PCBs), dihydroxylated PCBs (DiOH-PCBs), monomethoxylated dihydroxylated PCBs (MeO-OH-PCBs), methoxylated PCB sulfates (MeO-PCB sulfates), mono-to tetra-hydroxylated PCB quinones ((OH)(x)-quinones, x = 1-4), and hydroxylated polychlorinated benzofurans (OH-PCDF). Most metabolite classes were also detected in the feces from GF mice, except for MeO-OH-PCBs, OH-MeSO2-PCBs, and OH-PCDFs. Semi-quantitative analyses demonstrate that relative PCB metabolite levels increased with increasing dose and were higher in CV than GF mice, except for PCB sulfates and MeO-PCB sulfates, which were higher in GF mice. These findings demonstrate that the gut microbiome plays a direct or indirect role in the absorption, distribution, metabolism, or excretion of PCB metabolites, which in turn may affect toxic outcomes following PCB exposure.
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| 2. |
- Liu, Yanna, et al.
(författare)
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Hundreds of Unrecognized Halogenated Contaminants Discovered in Polar Bear Serum
- 2018
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 57:50, s. 16401-16406
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Tidskriftsartikel (refereegranskat)abstract
- Exposure of polar bears (Ursus maritimus) to persistent organic pollutants was discovered in the 1970s, but recent evidence suggests the presence of unknown toxic chemicals in their blood. Protein and phospholipid depleted serum was stirred with polyethersulfone capillaries to extract a broad range of analytes, and nontarget mass spectrometry with fragmentation flagging was used for detection. Hundreds of analytes were discovered belonging to 13 classes, including novel polychlorinated biphenyl (PCB) metabolites and many fluorinated or chlorinated substances not previously detected. All analytes were detected in the oldest (mid-1980s) archived polar bear serum from Hudson Bay and Beaufort Sea, and all fluorinated classes showed increasing trends. A mouse experiment confirmed the novel PCB metabolites, suggesting that these could be widespread in mammals. Historical exposure and toxic risk has been underestimated, and these halogenated contaminants pose uncertain risks to this threatened species.
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| 3. |
- Sethi, Sunjay, et al.
(författare)
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Comparative Analyses of the 12 Most Abundant PCB Congeners Detected in Human Maternal Serum for Activity at the Thyroid Hormone Receptor and Ryanodine Receptor
- 2019
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 53:7, s. 3948-3958
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Tidskriftsartikel (refereegranskat)abstract
- Polychlorinated biphenyls (PCBs) pose significant risk to the developing human brain; however, mechanisms of PCB developmental neurotoxicity (DNT) remain controversial. Two widely posited mechanisms are tested here using PCBs identified in pregnant women in the MARBLES cohort who are at increased risk for having a child with a neurodevelopmental disorder (NDD). As determined by gas chromatography-triple quadruple mass spectrometry, the mean PCB level in maternal serum was 2.22 ng/mL. The 12 most abundant PCBs were tested singly and as a mixture mimicking the congener profile in maternal serum for activity at the thyroid hormone receptor (THR) and ryanodine receptor (RyR). Neither the mixture nor the individual congeners (2 fM to 2 μM) exhibited agonistic or antagonistic activity in a THR reporter cell line. However, as determined by equilibrium binding of [3H]ryanodine to RyR1-enriched microsomes, the mixture and the individual congeners (50 nM to 50 μM) increased RyR activity by 2.4-19.2-fold. 4-Hydroxy (OH) and 4-sulfate metabolites of PCBs 11 and 52 had no TH activity; but 4-OH PCB 52 had higher potency than the parent congener toward RyR. These data support evidence implicating RyRs as targets in environmentally triggered NDDs and suggest that PCB effects on the THR are not a predominant mechanism driving PCB DNT. These findings provide scientific rationale regarding a point of departure for quantitative risk assessment of PCB DNT, and identify in vitro assays for screening other environmental pollutants for DNT potential.
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| 4. |
- Zhang, Chun-Yun, et al.
(författare)
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Metabolism of 3-Chlorobiphenyl (PCB 2) in a Human-Relevant Cell Line : Evidence of Dechlorinated Metabolites
- 2022
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 56:17, s. 12460-12472
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Tidskriftsartikel (refereegranskat)abstract
- Lower chlorinated polychlorinated biphenyls (LC-PCBs) and their metabolites make up a class of environmental pollutants implicated in a range of adverse outcomes in humans; however, the metabolism of LC-PCBs in human models has received little attention. Here we characterize the metabolism of PCB 2 (3-chlorobiphenyl), an environmentally relevant LC-PCB congener, in HepG2 cells with in silico prediction and nontarget high-resolution mass spectrometry. Twenty PCB 2 metabolites belonging to 13 metabolite classes, including five dechlorinated metabolite classes, were identified in the cell culture media from HepG2 cells exposed for 24 h to 10 μM or 3.6 nM PCB 2. The PCB 2 metabolite profiles differed from the monochlorinated metabolite profiles identified in samples from an earlier study with PCB 11 (3,3′-dichlorobiphenyl) under identical experimental conditions. A dechlorinated dihydroxylated metabolite was also detected in human liver microsomal incubations with monohydroxylated PCB 2 metabolites but not PCB 2. These findings demonstrate that the metabolism of LC-PCBs in human-relevant models involves the formation of dechlorination products. In addition, untargeted metabolomic analyses revealed an altered bile acid biosynthesis in HepG2 cells. Our results indicate the need to study the disposition and toxicity of complex PCB 2 metabolites, including novel dechlorinated metabolites, in human-relevant models.
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