Biological and Tumor-Promoting Effects of Dioxin-like and Non-Dioxin-like Polychlorinated Biphenyls in Mouse Liver After Single or Combined Treatment

Abstract

To assess the impact of a mixture containing dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs), male mice were initiated with N-nitroso-diethylamine and subsequently treated with PCB126, an Ah-Receptor agonist, and PCB153, acting via activation of the constitutive androstane receptor. The two congeners were given at two dose levels: the low dose was adjusted to induce ~150-fold increases in cytochrome P450 (Cyp)1a1 (PCB126) and Cyp2b10 mRNAs (PCB153), and the high dose was chosen as twice the low dose. To keep the liver PCB levels constant, mice were given initial loading doses followed by weekly maintenance doses calculated on the basis of the PCBs' half-lives. Mice were treated with the individual congeners (low and high dose) or with a mixture consisting of the low doses of the 2 PCBs. The following results were obtained: (1) the 2 PCBs produced dose-dependent increases in Cyp1a1 and Cyp2b10 mRNA, protein, and activity when given individually; (2) combined treatment caused more than additive effects on Cyp1a1 mRNA expression, protein level, and ethoxyresurofin activity; (3) changes in the levels of several proteins were detected by proteome analysis in livers of PCB-treated mice; (4) besides these biological responses, the individual PCBs caused no significant increase in the number of glucose-6-phospatase (G6Pase)-deficient neoplastic lesions in liver, whereas a moderate significant effect occurred in the combination group. These results suggest weak but significant response-additive effects of the 2 PCBs when given in combination. They also suggest that the Cyp biomarkers tend to overestimate the carcinogenic response produced by the PCBs in mouse liver.

Single step synthesis, characterization and applications of curcumin functionalized iron oxide magnetic nanoparticles

“…PCBs are persistent and potent environmental pollutants, and many efforts are being made to eradicate these from the environment as well protect from their toxic effects (e.g., carcinogenic effects) when absorbed into the body. 41,42 Based on multiple inflammatory studies on PCBs being conducted by numerous research groups, it is thought that they diffuse into cells within 1.0 hour of exposure. A proposed mechanism of protection due to the C-IO MNPs, which is greatest upon prior incubation, is that the nanoparticles need time to transport into the cells to be most effective in protecting against the insult.…”

Effects of PCB126 and PCB153 on telomerase activity and telomere length in undifferentiated and differentiated HL-60 cells

“…Based on those observations, we hypothesized that PCBs may enhance or even produce cell differentiation or/and may result in premature aging and disturbance of function of stem/progenitor cells. In the present study, we investigated the effect of two PCB congeners, representatives of dioxin-like (PCB126) and non-dioxin like (PCB153) congeners, known to activate very different intracellular receptors and metabolic pathways (Kopec et al 2010, Rignall et al 2013), for their effects on differentiation of HL-60 myeloblastic/promyelocytic progenitor-like cells. HL-60 cells have high expression of hTERT mRNA and active telomerase (Yamada et al 2000), consistent with the fact that they are cancer cells.…”

“…PCB126 (3,3’,4,4’,5-pentachlorobiphenyl) and PCB153 (2,2′,4,4′,5,5′-hexachlorobiphenyl) represent two different groups of PCBs that are involved in different regulatory pathways. PCB126 is a dioxin-like (DL) PCB congener that has a high affinity to the Aryl hydrocarbon receptor (AhR) (Rignall et al 2013), while PCB153, a non-dioxin-like (NDL) PCB, is an activator of the constitutive androstane and pregnane X receptor system (CAR/PXR) (Kopec et al 2010, Sakai et al 2006). AhR and CAR/PXR act as transcription factors and regulate expression of defined sets of target genes, like cytochrome P450 (CYP) 1 for the AhR and CYP 2B and 3A for CAR (Bock 1994, Ueda et al 2002).…”

Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure

“…The portion for PCB126 analysis was spiked with a recovery standard, PCB117, then extracted with hexane:acetone (1:1 v/v) using Accelerated Solvent Extractor (Dionex, Sunnyvale, CA) as described previously (Rignall et al 2013). Cells containing only diatomaceous earth and florisil as well as the ongoing precision and recovery (OPR) standard (blanks spiked with all analytes) were extracted along with the hepatic samples.…”

“…Cells containing only diatomaceous earth and florisil as well as the ongoing precision and recovery (OPR) standard (blanks spiked with all analytes) were extracted along with the hepatic samples. After extraction, the samples were spiked with internal standards, PCB30 and PCB204, then concentrated followed by a sulfur clean-up and a final treatment of sulfuric acid as described earlier (Rignall et al 2013). The portion for total extractable lipids was extracted with chloroform:methanol (2:1 v/v) using Accelerated Solvent Extractor (Dionex, Sunnyvale, CA) as described (Bunaciu et al 2007).…”