Although polychlorinated biphenyl (PCBs) production, and new uses for PCBs, was halted in the 1970s in the United States, PCBs continue to be used in closed systems and persist in the environment, accumulating in fatty tissues. PCBs are efficacious inducers of drug metabolism and may increase oxidative events and alter many other biochemical and morphologic parameters within cells and tissues. The goal of the present study was to evaluate the effects of a single, very low dose of PCB 126 (3,3′,4,4′,5-pentachlorobiphenyl), a coplanar, dioxin-like PCB congener and aryl hydrocarbon receptor (AhR) agonist, on the redox status, metals homeostasis, antioxidant enzymes, and cellular morphology. To examine these parameters, male Sprague-Dawley rats were fed a purified AIN-93 basal diet containing 0.2 ppm selenium for two weeks, then administered a single i.p. injection of corn oil (5 ml/kg body weight) or 1 μmol PCB 126/kg body weight (326 μg/kg body weight) in corn oil. Rats were maintained on the diet for an additional two weeks before being euthanized. This dose of PCB 126 did not later feed intake or growth, but significantly increased liver weight (42%) and hepatic microsomal cytochrome P-450 (CYP1A) enzyme activities (10-40-fold increase). Hepatic zinc, selenium, and glutathione levels were significantly decreased 15%, 30%, and 20%, respectively, by PCB 126. These changes were accompanied by a 25% decrease in selenium-dependent glutathione peroxidase activity. In contrast, hepatic copper levels were increased 40% by PCB 126. PCB 126-induced pathology was characterized by hepatocellular hypertrophy and mild steatosis in the liver and a mild decrease in cortical T-cells in the thymus. This controlled study in rats fed a purified diet shows that even a single, very low dose of PCB 126 that did not alter feed intake or growth, significantly perturbed redox and metals homeostasis and antioxidant and enzyme levels in rodent liver.

Accurate structure determinations by X-ray crystal analysis and computation using semi-empirical self-consistent field molecular orbital calculations are described and compared for five monofluorinated analogues of 4-chlorobiphenyl, i.e. 2-fluoro-4-chlorobiphenyl, 2'-fluoro-4-chlorobiphenyl, 3-fluoro-4-chlorobiphenyl, 3'-fluoro-4-chlorobiphenyl and 4'-fluoro-4-chlorobiphenyl. Intermolecular interactions for all monofluorinated isomers are dominated by phenyl-phenyl stacking and C-H-phenyl interactions. C-F bond lengths varied between 1.341 and 1.374 A, C-Cl between 1.733 and 1.765 A, and both correlate with electron-density differences as determined by (13)C NMR shifts. The interior ring angles at ipso-fluoro substitution increase up to 122.2-124.2 degrees due to hyperconjugation by 2p-pi-orbital overlapping, a phenomenon that was also reflected in the computer calculation. The angles of C-F and C-Cl relative to the aromatic ring for vicinal fluoro- and chloro substituents show an attraction, not a repulsion, between the adjacent F and Cl substituents. This finding is explained on the basis of electron donor and acceptor properties. The dihedral angles of ortho-substituted biphenyls show that monofluoro substitution results in slightly smaller increases compared with chlorine, while additional ortho-fluorination results in little further change in the dihedral angle. In contrast, ortho-chlorination strongly decreases the co-planarity. This is likely to be due to interior ring-angle distortion and the size of the halogen substituent. Fluoro substitution does indeed affect the planarity of the PCB3 analogues, but these effects are minor compared with chloro substitution. Fluorine tagging offers promise for use in in vitro and in vivo studies. Differences in computational versus measured data emphasize the need to use a variety of methods to ascertain the true nature of the physical properties of a compound.

The extensive body of literature regarding the interaction of polychlorinated biphenyls (PCBs) with transcription factors (receptors) has great value to understand similarities and distinctions and in formulating hypotheses regarding the activity of polybrominated diphenyl ethers (PBDEs) toward those same receptors. Our goal is to present the most comprehensive overview of PBDE effects on AhR, CAR, PXR, ER, AR, PR, DHT, TH, T3, T4 and IGF, as well as hypothetical biological activities of PPAR, RyR, GR and GABA. Aside the influence of the conformation of the ligand, we discuss its constitution influencing the binding affinity: size and polarizability, hydrophilicity, Gibbs free energy of solvation, inductive and mesomeric effects. We evaluate the techniques to determine the biologically relevant conformation of these halogenated hydrocarbons, including computation methods, X-ray and microwave spectroscopy. A novel fluoro-tagged ligand approach holds promise as tools for illuminating the steric and electronic effects in ligand-receptor interaction. Based on our assessment, we predict that PBDEs do not exhibit AhR activity themselves, but impurities are responsible for these effects.

Hormonally-sensitive tissues, like the prostate, ovary and breast, increasingly studied as targets of environmental chemicals, are sources of an enzyme potentially capable of transforming and activating xenobiotics to highly reactive metabolites. Our study specifically addresses the question of whether prostaglandin H synthase (PGHS) can activate phenolic metabolites of polychlorinated biphenyls (PCBs). We found that human recombinant PGHS-2 catalyzed the oxidation of ortho (2′, 3′-, 3′,4′-) and para (2′,5′-) dihydroxy 4-chlorobiphenyl metabolites to their corresponding quinones. These were trapped in situ with N-acetyl cysteine and the reaction products were isolated and characterized by liquid chromatography coupled mass spectrometry and 1 H and heteronuclear ( 1 H-13 C) nuclear magnetic resonance spectroscopy. Both mono-and di-N-acetyl cysteine Michael addition adducts were identified, with the 2′,3′-, and 2′,5′-dihydroxy metabolites predominantly forming mono-N-acetyl cysteine adducts, while the 3′,4′-dihydroxy predominantly formed disubstituted N-acetyl cysteine adducts. These studies clearly demonstrate that the phenolic metabolites of these environmental pollutants are activated by PGHS, as co-substrates, to highly reactive electrophilic PCB quinones, with a potential for protein and DNA damage, especially in non-hepatic tissues where the enzyme is found.