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

Abstract

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.

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

“…A previous study has indicated that LC-PCBs are not major AhR ligands; however, their anti-AhR activities were not addressed (Takeuchi et al, 2017). Here, we observed that, similar to some higher chlorinated PCB congeners (Brenerová et al, 2016), PCB 8, 11 and 31 inhibited that the AhR-mediated activity, although less efficiently than PCB 28 (Brenerová et al, 2016; this study).…”

“…The dioxin-like coplanar PCBs (DL-PCBs) activate the aryl hydrocarbon receptor (AhR) and this is considered their principle mode of action (Van den Berg et al, 2006). In contrast, the most abundant environmental non-dioxin-like PCBs (NDL-PCBs) do not activate the AhR, and there is no generally accepted risk concept for these compounds (Hamers et al, 2011), although some NDL-PCBs have been shown to inhibit the AhR transcriptional activity (Brenerová et al, 2016; Ovesen et al, 2011). Nevertheless, NDL-PCBs exert numerous specific modes of action linked with carcinogenicity, neurotoxicity or endocrine disruption (Gore et al, 2015; Grandjean and Landrigan, 2006; Lauby-Secretan et al, 2013).…”

Integrated transcriptomics and metabolomics reveal signatures of lipid metabolism dysregulation in HepaRG liver cells exposed to PCB 126

“…These complex effects cannot be assessed within the current research framework and new methodologies are urgently needed (Tsatsakis et al 2017). It is generally considered that the effects of chemical mixtures that act as AhR agonists can be approximately deduced using additive mathematical models (Brenerova et al 2016). Although it can be assumed that the effects detected in this study may not be specific to PCB 126 but generalizable to other AhR agonists, it should be noted that some non-dioxin-like PCB congeners cause non-additive effects by altering AhR activation by PCB mixtures (Brenerova et al 2016).…”

Environmental mechanisms of orofacial clefts

“…While dioxins and PCBs are known to induce OFCs (Courtney & Moore, 1971; Watanabe & Sugahara, 1981), the endogenous ligand 2‐(1′H‐indole‐3′‐carbonyl)‐thiazole‐4‐carboxylic acid methyl ester (ITE) does not appear to affect orofacial development (Henry, Bemis, Henry, Kende, & Gasiewicz, 2006). Additionally, some AHR ligands are nonactivating and can prevent AHR signaling through competitive inhibition (Brenerova et al, 2016; Guyot, Chevallier, Barouki, & Coumoul, 2013). AHR ligands often occur in the environment as a mixture of activating and nonactivating ligands, each competing for AHR with different binding affinities and SARs (Geier et al, 2018).…”

“…Co‐exposure of HCB and TCDD reduced the incidence of cleft palate compared to TCDD exposure alone, suggesting that HCB competes with TCDD for binding AHR (Morrissey, Harris, Diliberto, & Birnbaum, 1992). Nondioxin‐like PCBs have been shown to suppress the response to TCDD or PCB‐126 (a dioxin‐like PCB) exposure in rat liver cells in vitro (Brenerova et al, 2016). PCB exposures are therefore a possible risk for OFCs, but this depends on exposure context including the presence or absence of other AHR ligands.…”