HydroxyLated PCBs
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The mechanisms contributing to toxic effects of airborne lower-chlorinated PCB congeners (LC-PCBs) remain poorly characterized. We evaluated in vitro toxicities of environmental LC-PCBs found in both indoor and outdoor air (PCB 4, 8, 11, 18, 28 and 31), and selected hydroxylated metabolites of PCB 8, 11 and 18, using reporter gene assays, as well as other functional cellular bioassays. We focused on processes linked with endocrine disruption, tumor promotion and/or regulation of transcription factors controlling metabolism of both endogenous compounds and xenobiotics. The tested LC-PCBs were found to be mostly efficient anti-androgenic (within nanomolar - micromolar range) and estrogenic (at micromolar concentrations) compounds, as well as inhibitors of gap junctional intercellular communication (GJIC) at micromolar concentrations. PCB 8, 28 and 31 were found to partially inhibit the aryl hydrocarbon receptor (AhR)-mediated activity. The tested LC-PCBs were also partial constitutive androstane receptor (CAR) and pregnane X receptor (PXR) agonists, with PCB 4, 8 and 18 being the most active compounds. They were inactive towards other nuclear receptors, such as vitamin D receptor, thyroid receptor α, glucocorticoid receptor or peroxisome proliferator-activated receptor γ. We found that only PCB 8 contributed to generation of oxidative stress, while all tested LC-PCBs induced arachidonic acid release (albeit without further modulations of arachidonic acid metabolism) in human lung epithelial cells. Importantly, estrogenic effects of hydroxylated (OH-PCB) metabolites of LC-PCBs (4-OH-PCB 8, 4-OH-PCB 11 and 4'-OH-PCB 18) were higher than those of the parent PCBs, while their other toxic effects were only slightly altered or suppressed. This suggested that metabolism may alter toxicity profiles of LC-PCBs in a receptor-specific manner. In summary, anti-androgenic and estrogenic activities, acute inhibition of GJIC and suppression of the AhR-mediated activity were found to be the most relevant modes of action of airborne LC-PCBs, although they partially affected also additional cellular targets.
- MeSH
- buněčné linie MeSH
- endokrinní disruptory metabolismus toxicita MeSH
- epitelové buňky účinky léků MeSH
- hydroxylace MeSH
- látky znečišťující vzduch toxicita MeSH
- lidé MeSH
- nádory metabolismus MeSH
- polychlorované bifenyly metabolismus toxicita MeSH
- receptory cytoplazmatické a nukleární metabolismus MeSH
- signální transdukce účinky léků MeSH
- steroidní receptory metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The hairy root culture of black nightshade (Solanum nigrum) SNC-9O was exposed to 2,2'-dichlorobiphenyl (PCB 4) and 2,6-dichlorobiphenyl (PCB 10) to follow the metabolites produced. The analytical standards of 4-hydroxy-2,2'-dichlorobiphenyl, 5'-hydroxy-2,2'-dichlorobiphenyl, 4-hydroxy-2,6-dichlorobiphenyl, 2-hydroxy-2',6'-dichlorobiphenyl, 3-hydroxy-2',6'-dichlorobiphenyl and 4-hydroxy-2',6'-dichlorobiphenyl have been synthesized. Hydroxy-metabolites of both PCB 4 and PCB 10 were present in the biomass. These appeared mainly as conjugates rather than as free hydroxy-PCBs, both maintained in plant cells. The concentrations of non-conjugated hydroxy-PCBs ranged between 0.9 and 35.2 μg kg(-1) of biomass fresh weight and the concentration of the conjugated ones ranged between 2.0 and 113.0 μg kg(-1) depending on the position of hydroxyl. The para- position of biphenyl (4 or 4') seems to be preferred for hydroxylation. Methoxy-PCBs and hydroxy-methoxy-PCBs have also been identified in plant cells. Hydroxyl in the meta-position (3, 3', 5 or 5') appears to be preferred for methylation in hydroxy-PCBs. Hydroxy-methoxy-PCBs have occurred in the conjugated form as well.
- MeSH
- chromatografie plynová MeSH
- hmotnostní spektrometrie MeSH
- hydroxylace MeSH
- kořeny rostlin metabolismus MeSH
- látky znečišťující životní prostředí chemie metabolismus MeSH
- polychlorované bifenyly chemie metabolismus MeSH
- Solanum nigrum metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- chinony toxicita MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- látky znečišťující životní prostředí toxicita MeSH
- mezerový spoj účinky léků MeSH
- nádory prsu MeSH
- nádory metabolismus MeSH
- polychlorované bifenyly toxicita MeSH
- receptory aromatických uhlovodíků MeSH
- receptory pro estrogeny MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
This paper describes results of two ecological studies design to analyze the incidence of selected malignancies in two populations exposed to polychlorinated hydrocarbons, mostly PCBs and TCDDs/Fs by comparing data available in the National Cancer Registry of the Slovak Republic and National Oncological Registry of the Czech Republic databases for the Slovak Republic (approximately 5M inhabitants) and the Czech Republic (10,3 M inhabitants) to the data relevant for the population of Michalovce District, the Slovak Republic (approximately 112,000 inhabitants) and Uherske Hradiste, the Czech Republic (146,000 inhabitants). Those districts are recognized as PCB-contaminated areas due to production and industrial use of PCBs. Data were analyzed for the 10-year period 1987-1996. The age adjusted world standard ratio (WSR) incidence of thyroid, pancreatic, breast, ovarian, bladder, and brain tumors in females and thyroid, pancreatic, breast, bladder, brain, prostate and testicular tumors in males were compared. Neither PCBs nor TCDDs/Fs appear to contribute to the observed significantly lower incidence of breast and prostate cancer in the Michalovce District and lower bladder cancer incidence in Uherske Hradiste District. However, anti-estrogenic and anti-androgenic properties have been described for hydroxylated and methylsulfonyl PCB metabolites. These properties could contribute to a mechanism through which these metabolites might modulate the development of breast, prostate and bladder cancer. The results of our analysis points to substantial potential problems of risk assessment for cancer incidence in populations exposed to xenobiotics, or more generally, as it relates to a wide spectrum of confoundings of cancer risk factors.
- MeSH
- incidence MeSH
- karcinogeny farmakologie MeSH
- lidé MeSH
- nádory epidemiologie MeSH
- polychlorované bifenyly farmakologie MeSH
- polychlorované dibenzodioxiny farmakologie MeSH
- rizikové faktory MeSH
- vystavení vlivu životního prostředí MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
- Slovenská republika MeSH
Analýzy tuku mateřského mléka prokázaly zvýšený obsah polyhalogenovaných uhlovodíků v sérii vzorků sbíraných v okrese Uherské Hradiště (UH) v porovnání s pěti dalšími oblastmi ČR. Obsah těchto lipofilních xenobiotik odpovídal hodnotám nalezeným v okrese Michalovce sbíraných podle stejného protokolu, kde proti očekávání byl v rámci projektu 5RP PCBRisk QLK 4-2000-00488 přes nepochybný průkaz expozice zjištěn nižší než očekávaný výskyt malignit prsu žen a prostaty mužů. Podle stejného protokolu provedli autoři analýzu výskytu stejného spektra malignit u populace okresu UH v porovnání s výskytem těchto malignit v ČR v průběhu 10 let (1987-1996). Pro sledované období představovala analyzovaná databáze pro ČR ~103 M osobo-roků a pro okres UH ~1,46 M osobo-roků. Statistická významnost byla počítána pomocí dvouvýběrového párového t-testu průměrů programem STATISTICA 6.0. Věkově standardizovaná incidence malignit vztažená na světový standard nebyla v okresu UH vyšší, ale naopak statisticky významně nižší (p<0,01) byla míra rizika výskytu malignit močového měchýře u mužů i žen v porovnání s relevantními daty pro ČR. Výsledky naší studie poukazují na úskalí odhadů míry rizika incidence malignit v populacích exponovaných cizorodým látkám a obecně všem rizikovým faktorům díky širokému spektru zavádějících faktorů. Anti-estrogenní a anti-androgenní vlastnosti popsané u hydroxylovaných a methylsulfonových metabolitů PCB by snad mohly modulovat karcinogenní působení vlastních PCB.
Increased polyhalogenated hydrocarbons were found in breast milk fat samples collected in the Uherské Hradiště (UH) District compared to that of five other sampled regions throughout the Czech Republic. The content of lipophilic xenobiotics corresponded to the values detected in breast milk samples in Eastern Slovakia, Michalovce District, that were collected according to the same protocol within the 5th FP PCBRisk QLK 4-2000-00488. The Michalovce District revealed lower than expected incidence of breast and prostate malignancies. According to the same protocol, the authors performed an analysis of the same spectrum of malignancies in the UH district in comparison with the incidence of malignancies in the Czech Republic in the course of the same time period of ten years (1987-1996). Throughout this ten year period collected dataset for the Czech Republic represents ~103 M and for the UH District ~1.46 M person years. Statistical significance in the difference was evaluated using the two sample paired t-test of the means in STATISTICA 6.0 software. The age adjusted world standard ratio (WSR) incidence was not higher in the UH district but significantly lower (p<0.01). The risk for bladder cancer for the both sexes was observed lower than expected in comparison with relevant data for the Czech Republic. To sum up, the results of our analysis points to substantial potential problems of risk assessment for cancer incidence in populations exposed to xenobiotics, or more generally, as it relates to a wide spectrum of confoundings of cancer risk factors. Lastly, anti-estrogenic and anti-androgenic properties described for hydroxylated and methylsulfonyl PCB metabolites might substantially modulate the carcinogenic potential of PCBs.
- MeSH
- charakteristiky epidemiologické studie MeSH
- financování organizované MeSH
- halogenované uhlovodíky analýza škodlivé účinky MeSH
- hodnocení rizik MeSH
- incidence MeSH
- interpretace statistických dat MeSH
- lidé MeSH
- mateřské mléko MeSH
- nádory močového měchýře epidemiologie MeSH
- nádory epidemiologie MeSH
- polychlorované bifenyly škodlivé účinky MeSH
- registrace MeSH
- vystavení vlivu životního prostředí MeSH
- Check Tag
- lidé MeSH
Metabolites of polychlorinated biphenyls (PCBs)-hydroxylated PCBs (OH-PCBs), chlorobenzyl alcohols (CB-OHs), and chlorobenzaldehydes (CB-CHOs)-were incubated in vitro with the extracellular liquid of Pleurotus ostreatus, which contains mainly laccase and low manganese-dependent peroxidase (MnP) activity. The enzymes were able to decrease the amount of most of the tested OH-PCBs by > 80% within 1 h; the removal of more recalcitrant OH-PCBs was greatly enhanced by the addition of the laccase mediator syringaldehyde. Conversely, glutathione substantially hindered the reaction, suggesting that it acted as a laccase inhibitor. Hydroxylated dibenzofuran and chlorobenzoic acid were identified as transformation products of OH-PCBs. The extracellular enzymes also oxidized the CB-OHs to the corresponding CB-CHOs on the order of hours to days; however, the mediated and nonmediated setups exhibited only slight differences, and the participating enzymes could not be determined. When CB-CHOs were used as the substrates, only partial transformation was observed. In an additional experiment, the extracellular liquid of Irpex lacteus, which contains predominantly MnP, was able to efficiently transform CB-CHOs with the aid of glutathione; mono- and di-chloroacetophenones were detected as transformation products. These results demonstrate that extracellular enzymes of ligninolytic fungi can act on a wide range of PCB metabolites, emphasizing their potential for bioremediation.
- Publikační typ
- časopisecké články MeSH
