2018
Pěnčíková, Kateřina; Svržková, Lucie; Strapáčová, Simona; Neča, Jiří; Bartoňková, Iveta; Dvořák, Zdeněk; Hýžďalová, Martina; Pivnička, Jakub; Pálková, Lenka; Lehmler, Hans-Joachim; Li, Xueshu; Vondráček, Jan; Machala, Miroslav
In: Environmental pollution (Barking, Essex : 1987), vol. 237, pp. 473–486, 2018, ISSN: 1873-6424 0269-7491, (Place: England).
Abstract | Links | BibTeX | Tags: Air Pollutants/*toxicity, Airborne polychlorinated biphenyls, Cell Line, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/metabolism, Endocrine disruption, Endocrine Disruptors/metabolism/*toxicity, Epithelial Cells/drug effects, Humans, HydroxyLated PCBs, Hydroxylation, Metabolism of xenobiotics, Neoplasms/metabolism, Polychlorinated Biphenyls/metabolism/*toxicity, Pregnane X receptor, Receptors, Signal Transduction/drug effects, Steroid/metabolism, Tumor promotion
@article{pencikova_vitro_2018,
title = {In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion.},
author = {Kateřina Pěnčíková and Lucie Svržková and Simona Strapáčová and Jiří Neča and Iveta Bartoňková and Zdeněk Dvořák and Martina Hýžďalová and Jakub Pivnička and Lenka Pálková and Hans-Joachim Lehmler and Xueshu Li and Jan Vondráček and Miroslav Machala},
doi = {10.1016/j.envpol.2018.02.067},
issn = {1873-6424 0269-7491},
year = {2018},
date = {2018-06-01},
journal = {Environmental pollution (Barking, Essex : 1987)},
volume = {237},
pages = {473–486},
abstract = {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.},
note = {Place: England},
keywords = {Air Pollutants/*toxicity, Airborne polychlorinated biphenyls, Cell Line, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/metabolism, Endocrine disruption, Endocrine Disruptors/metabolism/*toxicity, Epithelial Cells/drug effects, Humans, HydroxyLated PCBs, Hydroxylation, Metabolism of xenobiotics, Neoplasms/metabolism, Polychlorinated Biphenyls/metabolism/*toxicity, Pregnane X receptor, Receptors, Signal Transduction/drug effects, Steroid/metabolism, Tumor promotion},
pubstate = {published},
tppubtype = {article}
}
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.
Pěnčíková, Kateřina; Brenerová, Petra; Svržková, Lucie; Hrubá, Eva; Pálková, Lenka; Vondráček, Jan; Lehmler, Hans-Joachim; Machala, Miroslav
Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro. Journal Article
In: Environmental science and pollution research international, vol. 25, no. 17, pp. 16411–16419, 2018, ISSN: 1614-7499 0944-1344, (Place: Germany).
Abstract | Links | BibTeX | Tags: Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism
@article{pencikova_atropisomers_2018,
title = {Atropisomers of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) exhibit stereoselective effects on activation of nuclear receptors in vitro.},
author = {Kateřina Pěnčíková and Petra Brenerová and Lucie Svržková and Eva Hrubá and Lenka Pálková and Jan Vondráček and Hans-Joachim Lehmler and Miroslav Machala},
doi = {10.1007/s11356-017-0683-x},
issn = {1614-7499 0944-1344},
year = {2018},
date = {2018-06-01},
journal = {Environmental science and pollution research international},
volume = {25},
number = {17},
pages = {16411–16419},
abstract = {PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.},
note = {Place: Germany},
keywords = {Androgen receptor, Animals, Atropisomer, Biotransformation, Chiral, Constitutive Androstane Receptor, Cytoplasmic and Nuclear/*chemistry/metabolism, Estrogen receptors, Humans, Polychlorinated biphenyl, Polychlorinated Biphenyls/*chemistry, Pregnane X receptor, Receptors, Stereoisomerism, Steroid/chemistry/metabolism},
pubstate = {published},
tppubtype = {article}
}
PCB 136 is an environmentally relevant chiral PCB congener, which has been found in vivo to be present in form of rotational isomers (atropisomers). Its atropselective biotransformation or neurotoxic effects linked with sensitization of ryanodine receptor suggest that it might interact also with other intracellular receptors in a stereospecific manner. However, possible atropselective effects of PCB 136 on nuclear receptor transactivation remain unknown. Therefore, in this study, atropselective effects of PCB 136 on nuclear receptors controlling endocrine signaling and/or expression of xenobiotic and steroid hormone catabolism were investigated. PCB136 atropisomers were found to exert differential effects on estrogen receptor (ER) activation; (+)-PCB 136 was estrogenic, while (-)-PCB 136 was antiestrogenic. In contrast, inhibition of androgen receptor (AR) activity was not stereospecific. Both PCB136 stereoisomers induced the constitutive androgen receptor (CAR)-dependent gene expression; however, no significant stereospecificity of PCB 136 atropisomers was observed. PCB136 was a partial inducer of the pregnane X receptor (PXR)-dependent gene expression. Here, (-)-PCB 136 was a significantly more potent inducer of PXR activity than (+)-PCB 136. Taken together, the present results indicate that at least two nuclear receptors participating in endocrine regulation or metabolism, ER and PXR, could be regulated in an atropselective manner by chiral PCB 136. The enantioselective enrichment of PCB atropisomers in animal and human tissues may thus have significant consequences for endocrine-disrupting effects of chiral ortho-substituted PCB congeners.