Detection and measurement of the agonistic activities of PCBs and mono-hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay

Kamata, Ryo; Shiraishi, Fujio; Kageyama, Shiho; Nakajima, Daisuke

doi:10.1016/j.tiv.2015.07.021

Cited by 13 publications

(9 citation statements)

References 32 publications

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“…Other parameters (anti-AhR activity, anti-androgenicity or inhibition of GJIC) were only marginally affected by addition of OH group; however, we found that hydroxylated LC-PCBs were mostly inactive as CAR or PXR inducers, which seems to support the hypothesis that hydroxylation may modulate CAR-mediated activity of PCBs (Kamata et al, 2015).…”

Section: Discussionsupporting

confidence: 72%

“…Previous studies have indicated that NDL-PCBs, including PCB 28, are primarily CAR inducers (Gährs et al, 2013), with only minor contribution to PXR activation. In addition, several LC-PCBs were found to be active in yeast CAR assay (Kamata et al, 2015). However, the information about activities of PCBs in human cells is limited to higher chlorinated PCB congeners (Al-Salman and Plant, 2012; Gährs et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

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In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Pěnčíková

Svržková

Strapáčová

et al. 2018

Environmental Pollution

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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.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Pěnčíková

Svržková

Strapáčová

et al. 2018

Environmental Pollution

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“…A similar mechanism of the formation of OH-PCBs can be anticipated for higher chlorinated PCBs, although factors like ortho -substitution in PCB 126 or isomerism in PCB 95 and PCB 136 may give rise to different OH-PCB forms. Biotransformation of PCBs to OH-PCBs through cytochrome P-450-catalzyed oxidation has also been documented in lower organisms (Kamata et al 2015) and in plants (Ma et al 2016, Zhai et al 2010a, b, 2011b, 2013a).…”

Section: Introductionmentioning

confidence: 97%

Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

Dhakal

Gadupudi

Lehmler

et al. 2017

Environ Sci Pollut Res

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Polychlorinated biphenyls (PCBs), a group of 209 congeners that differ in the number and position of chlorines on the biphenyl ring, are anthropogenic chemicals that belong to the persistent organic pollutants (POPs). For many years, PCBs have been a topic of interest because of their biomagnification in the food chain and their environmental persistence. PCBs with fewer chlorine atoms, however, are less persistent and more susceptible to metabolic attack, giving rise to chemicals characterized by the addition of one or more hydroxyl groups to the chlorinated biphenyl skeleton, collectively known as hydroxylated PCBs (OH-PCBs). In animals and plants, this biotransformation of PCBs to OH-PCBs is primarily carried out by cytochrome P-450-dependent monooxygenases. One of the reasons for infrequent detection of lower chlorinated PCBs in serum and other biological matrices is their shorter half-lives, and their metabolic transformation, resulting in OH-PCBs or their conjugates, such as sulfates and glucuronides, or macromolecule adducts. Recent biomonitoring studies have reported the presence of OH-PCBs in human serum. The occurrence of OH-PCBs, the size of this group (there are 837 mono-hydroxyl PCBs alone), and their wide spectra of physical characteristics (pKa's and log P's ranging over 5 to 6 orders of magnitude) give rise to a multiplicity of biological effects. Among those are bioactivation to electrophilic metabolites that can form covalent adducts with DNA and other macromolecules, interference with hormonal signaling, inhibition of enzymes that regulate cellular concentrations of active hormones, and interference with the transport of hormones. This new information creates an urgent need for a new perspective on these often overlooked metabolites.

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“…Earlier studies have showed that both human and rodent CAR and PXR are activated by non-planar PCBs [ 40 , 41 , 203 ] with a tendency of human CAR being activated efficiently and with a preference of CAR over PXR ( Table 2 ). No clear structure–activity relationship with respect to CAR activation among PCB congeners has been identified [ 41 , 206 ]. Both planar (dioxin-like) and non-planar PCBs have been reported to attenuate EGF signaling in analogy to PB [ 100 , 168 ].…”

Section: Metabolic Effects Of Edc Classes Potentially Mediated By mentioning

confidence: 99%

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

Küblbeck

Niskanen

Honkakoski

2020

Cells

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During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.

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Detection and measurement of the agonistic activities of PCBs and mono-hydroxylated PCBs to the constitutive androstane receptor using a recombinant yeast assay

Cited by 13 publications

References 32 publications

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

In vitro profiling of toxic effects of prominent environmental lower-chlorinated PCB congeners linked with endocrine disruption and tumor promotion

Sources and toxicities of phenolic polychlorinated biphenyls (OH-PCBs)

Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR

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