Multivariate toxicity profiles and QSAR modeling of non-dioxin-like PCBs – An investigation of in vitro screening data from ultra-pure congeners

Stenberg, Mia; Hamers, Timo; Machala, Miroslav; Fonnum, Frode; Stenius, Ulla; Al-Anati, Lauy; Duursen, Majorie B.M. van; Westerink, Remco H.S.; Fernandes, Elsa C. Antunes; Andersson, Patrik L.

doi:10.1016/j.chemosphere.2011.08.019

Cited by 30 publications

(25 citation statements)

References 31 publications

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“…Substituted positions 2,2′ were not sufficient for proving the antagonistic activity towards AhR (inactive PCBs 19,51,53,95,100,101,104,136). Stenberg et al (2011) clustered a set of 21 PCB congeners, based on their toxicity profiles from 17 different in vitro bioassays. One group included PCBs 19,74,118,122,128,138,153,168,170,180,and 190, in which effects were linked to competition with thyroid hormone thyroxine for binding to the plasma transport protein transthyretin, and anti-AhR and anti-estrogenic activities.…”

Section: Resultsmentioning

confidence: 99%

Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells

Brenerová

Hamers

Kamstra

et al. 2015

Environ Sci Pollut Res

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The relative potencies of non-ortho-substituted coplanar polychlorinated biphenyl (PCB) congeners to activate the aryl hydrocarbon receptor (AhR) and to cause the AhR-dependent toxic events are essential for their risk assessment. Since some studies suggested that abundant non-dioxin-like PCB congeners (NDL-PCBs) may alter the AhR activation by PCB mixtures and possibly cause non-additive effects, we evaluated potential suppressive effects of NDL-PCBs on AhR activation, using a series of 24 highly purified NDL-PCBs. We investigated their impact on the model AhR agonist-induced luciferase reporter gene expression in rat hepatoma cells and on induction of CYP1A1/1B1 mRNAs and deregulation of AhR-dependent cell proliferation in rat liver epithelial cells. PCBs 128, 138, and 170 significantly suppressed AhR activation (with IC50 values from 1.4 to 5.6 μM), followed by PCBs 28, 47, 52, and 180; additionally, PCBs 122, 153, and 168 showed low but still significant potency to reduce luciferase activity. Detection of CYP1A1 mRNA levels in liver epithelial cells largely confirmed these results for the most abundant NDL-PCBs, whereas the other AhR-dependent events (CYP1B1 mRNA expression, induction of cell proliferation in confluent cells) were less sensitive to NDL-PCBs, thus indicating a more complex regulation of these endpoints. The present data suggest that some NDL-PCBs could modulate overall dioxin-like effects in complex mixtures.

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Section: Resultsmentioning

confidence: 99%

Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells

Brenerová

Hamers

Kamstra

et al. 2015

Environ Sci Pollut Res

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“…Whereas still in its infancy, the NEQ faces several challenges before establishment in risk assessment. First, numerous modes of neurotoxicity have been documented (see "Introduction" section), often displaying different SAR requirements (eg, current work and Stenberg et al, 2011), and the question arises regarding what modes and how many modes should be included to establish an NEQ. To date the RyR is the most sensitive target of NDL PCBs and has been included in the development of NEQ schemes (Rayne and Forest, 2010;Simon et al, 2007).…”

Section: Resultsmentioning

confidence: 99%

“…Numerous modes of action have been described that may contribute to neurotoxicity. This includes altered neurotransmitter signaling (Fonnum and Mariussen, 2009;Mariussen and Fonnum, 2001;Wigestrand et al, 2013), altered GABA A receptor activity (Fernandes et al, 2010), altered Ca 2þ homeostasis through several mechanisms (Choi et al, 2016;Gafni et al, 2004;Kodavanti and Tilson, 1997;Pessah et al, 2010;Westerink, 2014), induced reactive oxygen species (Stenberg et al, 2011), altered cell viability (Dickerson et al, 2009), and alterations of neuro/endocrine processes (Bell, 2014;Fonnum and Mariussen, 2009;Kodavanti and Curras-Collazo, 2010). Of the modes identified, a particularly sensitive endpoint is the ability of NDL PCBs to enhance the activity of ryanodine sensitive Ca 2þ channels embedded in the sarco/endoplasmic reticulum (SR/ER), namely, the ryanodine receptor (RyR), in both mammals (Pessah et al, 2006) and fish (Fritsch and Pessah, 2013).…”

mentioning

confidence: 99%

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

et al. 2016

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Nondioxin-like polychlorinated biphenyls (NDL PCBs) activate ryanodine-sensitive Ca 2þ channels (RyRs) and this activation has been associated with neurotoxicity in exposed animals. RyR-active congeners follow a distinct structure-activity relationship and a quantitative structure-activity relationship (QSAR) predicts that a large number of PCBs likely activate the receptor, which requires validation. Additionally, previous structural based conclusions have been established using receptor ligand binding assays but the impact of varying PCB structures on ion channel gating behavior is not understood. We used [ 3 H]Ryanodine ([ 3 H]Ry) binding to assess the RyR-activity of 14 previously untested PCB congeners evaluating the predictability of the QSAR. Congeners determined to display widely varying potency were then assayed with single channel voltage clamp analysis to assess direct influences on channel gating kinetics. The RyR-activity of individual PCBs assessed in in vitro assays followed the general pattern predicted by the QSAR but binding and lipid bilayer experiments demonstrated higher potency than predicted. Of the 49 congeners tested to date, tetra-ortho PCB 202 was found to be the most potent RyR-active congener increasing channel open probability at 200 pM. Shifting meta-substitutions to the paraposition resulted in a > 100-fold reduction in potency as seen with PCB 197. Non-ortho PCB 11 was found to lack activity at the receptor supporting a minimum mono-ortho substitution for PCB RyR activity. These findings expand and support previous SAR assessments; where out of the 49 congeners tested to date 42 activate the receptor demonstrating that the RyR is a sensitive and common target of PCBs.

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“…Even if ndl-PCBs are less toxic than dl-PCBs, it could be considered that they also present a high risk level because of their complex spectrum of adverse effects and their presence as mixtures at higher concentrations in biotic and abiotic matrices (Brunelli et al, 2012;Ferrante et al, 2011;Stenberg et al, 2011). Mixtures of ndl-PCBs are generally assessed on the basis of the six so-called indicator PCBs 52,101,138,153,180) which accounted for approximately 50% of all PCB congeners present in foodstuff (EFSA, 2005).…”

Section: Risk Assessment Of Pahs and Pcbs In Tgrmentioning

confidence: 99%

PAHs and PCBs accumulated by SPMD-based virtual organisms and feral fish in Three Gorges Reservoir, China

Wang

Henkelmann

et al. 2016

Science of The Total Environment

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Multivariate toxicity profiles and QSAR modeling of non-dioxin-like PCBs – An investigation of in vitro screening data from ultra-pure congeners

Cited by 30 publications

References 31 publications

Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells

Pure non-dioxin-like PCB congeners suppress induction of AhR-dependent endpoints in rat liver cells

An Extended Structure–Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors

PAHs and PCBs accumulated by SPMD-based virtual organisms and feral fish in Three Gorges Reservoir, China

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