Uncoupling of cytochrome P450 1A and stimulation of reactive oxygen species production by co-planar polychlorinated biphenyl congeners

Oral administration of PCBs induces proinflammatory and prometastatic responses

“…It appears that increased cellular oxidation induced by coplanar PCBs is related to the interaction with the AhR and activation of the cytochrome P450 1A (CYP1A) subfamily (Alsharif et al, 1994;Safe and Krishnan, 1995). It was demonstrated that PCB77 can uncouple the catalytic cycle of CYP1A1, allowing heme iron within the active site of this enzyme complex to act as a Fenton catalyst and generating hydroxyl radicals from hydrogen peroxide (Schlezinger et al, 1999;Schlezinger et al, 2006). Other coplanar PCBs, such as PCB126 and PCB169 also markedly increased cellular oxidative stress in vascular endothelial cells, brain, and hepatic tissues (Twaroski et al, 2001;Hassoun et al, 2002;Ramadass et al, 2003) with superoxide anions being a major reactive oxygen species.…”

Mixture-specific gene expression in zebrafish ( Danio rerio ) embryos exposed to perfluorooctane sulfonic acid (PFOS), perfluorohexanoic acid (PFHxA) and 3,3′,4,4′,5-pentachlorobiphenyl (PCB126)

“…The binding of AhR-agonist molecules on AhR2 results in the translocation of the complex to the nucleus and to its binding to a regulatory sequence in cyp1a promoter to induce its transcription (Schmidt and Bradfield, 1996). The exacerbate activity of Cyp1a is known to increase the reactive oxygen species content and to cause oxidative stress (Schlezinger et al, 2006) which is highly toxic to the organism. In addition, it was previously suggested that the energetic costs required to metabolize and excrete contaminants cause a negative impact on growth (Rowe et al, 2001).…”

“…A hyperactivity of Cyp1a was reported to increase the reactive oxygen species content, thus inducing oxidative stress (Schlezinger et al, 2006;Schlezinger et al, 1999). Despite a high induction in cyp1a expression under all conditions involving PCB126 exposure, a low oxidative stress response (upregulation of gpx1a) was only reported in the presence of PCB126+PFHxA and PCB126+PFOS+PFHxA.…”

“…Moreover, related studies used different models such as in vitro (Hagenaars et al, 2008;Liu et al, 2007;Oakes et al, 2005) and ex vivo (Schlezinger et al, 2006) models. A previous study on zebrafish embryos reported induction of gpx1a from concentrations of 50 μg/L PCB126 and even higher concentrations were required for apoptosis induction (Liu et al, 2015), which is in accordance with the present results.…”

“…PCB126 is recognized as a strong inducer of biotransformation enzymes (i.e. Cyp1a) via the aryl hydrocarbon receptor (AhR) pathway (Hahn, 2001), subsequently triggering toxicity mainly via oxidative stress (Liu et al, 2015;Schlezinger et al, 2006). The present study hypothesized that the presence of PFOS and PFHxA would increase the activation of the toxicity pathways of PCB126.…”