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1.  PCB153 reduces Telomerase Activity and Telomere Length in Immortalized Human Skin Kerantinocytes (HaCaT) but not in Human Foreskin Keratinocytes (NFK) 
Toxicology and Applied Pharmacology  2011;259(1):115-123.
Polychlorinated Biphenyls (PCBs), ubiquitous environmental pollutants, are characterized by long term-persistence in the environment, bioaccumulation, and biomagnification in the food chain. Exposure to PCBs may cause various diseases, affecting many cellular processes. Deregulation of the telomerase and the telomere complex leads to several biological disorders. We investigated the hypothesis that PCB153 modulates telomerase activity, telomeres and reactive oxygen species resulting in the deregulation of cell growth. Exponentially growing immortal human skin keratinocytes (HaCaT) and normal human foreskin keratinocytes (NFK) were incubated with PCB153 for 48 and 24 days, respectively, and telomerase activity, telomere length, superoxide level, cell growth, and cell cycle distribution were determined. In HaCaT cells exposure to PCB153 significantly reduced telomerase activity, telomere length, cell growth and increased intracellular superoxide levels from day 6 to day 48, suggesting that superoxide may be one of the factors regulating telomerase activity, telomere length and cell growth compared to untreated control cells. Results with NFK cells showed no shortening of telomere length but reduced cell growth and increased superoxide levels in PCB153-treated cells compared to untreated controls. As expected, basal levels of telomerase activity were almost undetectable, which made a quantitative comparison of treated and control groups impossible. The significant down regulation of telomerase activity and reduction of telomere length by PCB153 in HaCaT cells suggest that any cell type with significant telomerase activity, like stem cells, may be at risk of premature telomere shortening with potential adverse health effects for the affected organism.
doi:10.1016/j.taap.2011.12.015
PMCID: PMC3288560  PMID: 22210444
polychlorinated biphenyls (PCBs); telomere; telomerase; superoxide; cell growth; skin keratinocytes
2.  Airborne polychlorinated biphenyls (PCBs) reduce telomerase activity and shorten telomere length in immortal human skin keratinocytes (HaCat) 
Toxicology letters  2011;204(1):64-70.
PCBs, a group of 209 individual congeners, are ubiquitous environmental pollutants and classified as probable human carcinogens. One major route of exposure is by inhalation of these industrial compounds, possibly daily from inner city air and/or indoor air in contaminated buildings. Hallmarks of aging and carcinogenesis are changes in telomere length and telomerase activity. We hypothesize that semi-volatile PCBs, like those found in inner city air, are capable of disrupting telomerase activity and altering telomere length. To explore this possibility, we exposed human skin keratinocytes to a synthetic Chicago Airborne Mixture (CAM) of PCBs, or the prominent airborne PCB congeners, PCB28 or PCB52 for up to 48 days and determined telomerase activity, telomere length, cell proliferation, and cell cycle distribution. PCBs 28, 52 and CAM significantly reduced telomerase activity from days 18–48. Telomere length was shortened by PCB52 from day 18 and PCB28 and CAM from days 30 on. All PCBs decreased cell proliferation from day 18; only PCB52 produced a small increase of cells in G0/G1 of the cell cycle. This significant inhibition of telomerase activity and reduction of telomere length by PCB congeners suggest a potential mechanism by which these compounds could lead to accelerated aging and cancer.
doi:10.1016/j.toxlet.2011.04.012
PMCID: PMC3109099  PMID: 21530622
polychlorinated biphenyls (PCB); telomere; telomerase; cell cycle; air pollution; mixture
3.  Development of a Synthetic PCB Mixture Resembling the Average Polychlorinated Biphenyl Profile in Chicago Air 
Environment international  2009;36(8):819-827.
Studies of environmental and toxic effects of polychlorinated biphenyls (PCBs) are ideally performed with PCB mixtures reflecting the composition of environmental PCB profiles to mimic actual effects and to account for complex interactions among individual PCB congeners. Unfortunately, only a few laboratory studies employing synthetic PCB mixtures have been reported, in part because of the challenges associated with the preparation of complex PCB mixtures containing many individual PCB congeners. The objective of this study was to develop a PCB mixture that resembles the average PCB profile recorded from 1996 to 2002 at a satellite station of the Integrated Atmospheric Deposition Network located at the Illinois Institute of Technology (IIT) in Chicago, Illinois, using commercial PCB mixtures. Initial simulations, using published Aroclor profiles, showed that a mixture containing 65% Aroclor 1242 and 35% Aroclor 1254 was a good approximation of the target profile. A synthetic Chicago air mixture (CAM) was prepared by mixing the respective Aroclor's in this ratio, followed by GC/MS/MS analysis. Comparison of the PCB profile of the synthetic mixture with the target profile suggests that the synthetic PCB mixture is a good approximation of the average IIT Chicago air profiles (similarity coefficient cos θ = 0.82; average relative percent difference = 84%). The synthetic CAM was also a reasonable approximation of the average of 184 PCB profiles analyzed in 2007 at 37 sites throughout Chicago as part of the University of Iowa Superfund Basic Research Program (isbrp), with a cos θ of 0.70 and an average relative percent difference of 118%. While the CAM and the two Chicago air profiles contained primarily di- to pentachlorobiphenyls, higher chlorinated congeners, including congeners with seven or eight chlorine atoms, were underrepresented in the synthetic CAM. The calculated TCDD toxic equivalency quotients of the synthetic CAM (2.7 ng/mg PCB) and the IIT Chicago air profile (1.6 ng/mg PCB) were comparable, but lower by two orders of magnitude than the isbrp Chicago air profile (865 ng/mg PCB) due to surprisingly high PCB 126 levels in Chicago air. In contrast, the calculated neurotoxic equivalency quotients of the CAM (0.33 mg/mg PCB) and the two Chicago air profiles (0.44 and 0.30 mg/mg PCB, respectively) were similar. This study demonstrates the challenges and methods of creating and characterizing synthetic, environmental mixtures of PCBs.
doi:10.1016/j.envint.2009.03.003
PMCID: PMC2888912  PMID: 19375801
Airborne PCBs; Aroclor; PCB homologue; Toxic Equivalency Quotient; TEQ; Neurotoxic Equivalency Quotient; NEQ; PCB atropisomers
4.  3-Methylcholanthrene (3-MC) and 4-Chlorobiphenyl (PCB3) genotoxicity is gender-related in Fischer 344 transgenic rats 
Environment international  2010;36(8):970-979.
Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants with myriad biological effects, including carcinogenicity. We present data showing gender-specific genotoxicity in Fischer 344 transgenic BigBlue rodents exposed to 4-chlorobiphenyl (PCB3), a hydroxylated metabolite, and the positive control 3-methylcholanthrene (3-MC) where female rats are more resistant to the genotoxic effects of the test compounds compared to their male counterparts. This difference is further highlighted through our examination of gene expression, organ-specific weight changes, and tissue morphology. The purpose of the present study was to explores the complex and multifaceted issues of lower molecular weight PCBs as initiators of carcinogenesis, by examining the mutagenicity of PCB3, a hydroxylated metabolite (4′-OH-PCB3), and 3-methylcholanthrene (3-MC, positive control) in a transgenic rodent model. Previous findings indicated that PCB3 is mutagenic in the liver of male BigBlue transgenic rats under identical exposure conditions. We expected that female rats would be equally, if not more sensitive than male rats, since a 2-year carcinogenesis bioassay with Sprague-Dawley rats and commercial PCB mixtures reported much higher liver cancer rates in female than in male rats. The current study, however, revealed a similar trend in the mutation frequencies across all four treatment groups in females as reported previously in males, but increased variability among animals within each group and a lower overall effect, led to non significant differences in mutation frequencies. A closer analysis of the possible reasons for this negative result using microarray, organ weight and histology data comparisons shows that female Fischer 344 rats 1) had a higher baseline mutation frequency in the corn oil control group and greater variability than male rats; 2) responded with robust gene expression changes, which may also play a role in our observation of 3) highly increased liver, spleen, and lung weight in 3-MC and PCB3-treated animals and thus changed distribution and kinetics of the test compounds. Our analysis indicates that female transgenic BigBlue Fischer 344 rats are more resistant to PCB3 and 3-MC genotoxicity compared to their male counterparts.
doi:10.1016/j.envint.2010.07.006
PMCID: PMC2949545  PMID: 20739065
Polychlorinated biphenyl; PCB3; 3-methylcholanthrene; 3-MC; gender difference; genotoxicity; biotransformation; carcinogenicity
5.  Electrostatic and aspheric influence of the fluoro-substitution of 4-bromodiphenyl ether (PBDE 3) 
Accurate structure determinations by X-ray crystal analysis and computation using semi-empirical self-consistent field molecular orbital calculations are described and compared for 4-bromodiphenyl ether (PBDE 3), the 13C6-isotopic labeled PBDE 3 (13C6-PBDE 3) and its five corresponding monofluorinated analogues (F-PBDEs 3): 2-fluoro-4-bromodiphenyl ether (F-PBDE 3-2F), 2′-fluoro-4-bromodiphenyl ether (F-PBDE 3-2′F), 3-fluoro-4-bromodiphenyl ether (F-PBDE 3-3F), 3′-fluoro-4-bromodiphenyl ether (F-PBDE 3-3′F) and 4′-fluoro-4-bromodiphenyl ether (F-PBDE 3-4′F). The synthesis and full characterization by means of 1H, 13C, 19F nuclear magnetic resonance spectroscopy and mass spectrometry of the F-PBDEs 3 are presented for the first time. Intermolecular interactions for PBDE 3 and the F-PBDEs 3 isomers were dominated by weak C-H(F,Br) ····π and C-H····F interactions. The bond lengths of C-F varied between 1.347(2) Å and 1.362(2) Å, C4-Br between 1.880(3) Å and 1.904(19) Å. Both correlated with electron-density differences as determined by 13C shifts, but not with the strength of C-F couplings. The interior ring angles at ipso-fluoro-substitution increased to 121.95° due to hyperconjugation by p-π-orbital overlapping, a phenomenon that was also computed. An attraction between the vicinal fluoro-and bromo-substituents was not determined, as seen in fluoro-substituted chlorobiphenyls. The torsion angles measured and computed for the series of PBDE 3 and F-PBDEs 3 differed strongly from each other. Since the ether linkage (an average of 2.76 Å) provides more distance and the bonds are flexible up to a certain range, the influence of a fluoro-substituent is only detectable in PBDEs with high ortho-substitution. A concordance of computed and measured torsion angles can be observed with increasing size and/or grade of substitution comparing mono- to tetra- fluoro-, chloro-, bromo- and methyl-substitutions in the ortho-positions of diphenyl ether. Differences between computational versus measured data demonstrates a strong need to evaluate the results against independent techniques to conclude structure receptor activity relationships of PBDEs. Any discussion of the Ah or other biological receptor activity of certain PBDEs should take this in consideration. For the first time a complete overview of known and hypothetical biological activities of PBDEs is presented.
doi:10.1107/S0108768107067079
PMCID: PMC3120100  PMID: 18204217
6.  Receptor interactions by polybrominated diphenyl ethers versus polychlorinated biphenyls: a theoretical Structure-activity assessment 
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.
doi:10.1016/j.etap.2007.10.017
PMCID: PMC2746664  PMID: 19768137
polybrominated diphenyl ethers; PBDEs; polychlorinated biphenyls; PCBs; AhR; CAR; PXR; ER; AR; PR; DHT; TH; T3; T4; IGF; PPAR; RyR; GR; GABA; Conformation; Constitution; Binding affinity; Polarizability; Hydrophilicity; Gibbs free solvation energy; Inductive effects; Mesomeric effects
7.  2-(4′-CHLOROPHENYL)-1,4-BENZOQUINONE INCREASES THE FREQUENCY OF MICRONUCLEI AND SHORTENS TELOMERES 
The toxicity of polychlorinated biphenyls (PCBs) has been attributed widely to receptor-mediated effects, buttressed by the popularity of the Toxic Equivalency Factor. We propose that a crucial toxic mechanism of lower-chlorinated PCBs is their enzymatic biotransformation to electrophiles, including quinoid metabolites, that bind intracellular sulfhydryl groups, such as those found in microtubulin and enzymes like telomerase. To test this hypothesis, we have examined micronuclei induction, cell cycle, and telomere shortening in cells in culture. Our findings show a large increase in micronuclei frequency and cell cycle perturbation in V79 cells, and a marked decrease in telomere length in HaCaT cells exposed to 2-(4′-chlorophenyl)-1,4-benzoquinone (PCB3pQ).
doi:10.1016/j.etap.2007.10.022
PMCID: PMC2346440  PMID: 18438462
PCB; micronucleus; DNA; telomere shortening; sulfhydryl binding
8.  Influence of Dietary Fat on the Enantioselective Disposition of 2,2′,3,3′,6,6′-Hexachlorobiphenyl (PCB 136) in Female Mice 
Although ingestion is the major route of exposure to polychlorinated biphenyls (PCBs), dietary factors altering their absorption and excretion are only poorly understood. In the present study, (±)-PCB 136 was administered orally to female C57BL/6 mice fed an unrefined (URD, 10% fat) or high fat (HFD, 40% fat) diet to investigate the effect of the dietary fat content on the disposition of PCBs. Three days after administration, PCB levels in the adipose tissue were significantly lower in HFD animals than URD animals, partly due to a higher excretion rate of PCB 136 in the HFD group. (+)-PCB 136 was enriched in all organs and in feces. In both groups, enantiomeric fractions in feces increased each day after administration. We hypothesize that low EF (enantiomeric fraction) values in feces excreted within 24 hours of exposure are due to the presence of undigested, racemic PCB. Higher EF values in feces excreted after two and three days are due to excretion of previously absorbed PCBs. Overall, our study suggests that the EF value may be a good tool to investigate the absorption and excretion of PCBs in vivo.
doi:10.1016/j.fct.2007.09.072
PMCID: PMC2289907  PMID: 17950514
polychlorinated biphenyls; enantiomeric fraction; dietary fat; absorption; bioavailability; excretion; feces
9.  Metabolism of aflatoxin B1 by rat hepatic microsomes induced by polyhalogenated biphenyl congeners. 
The metabolism of aflatoxin B1 to aflatoxins M1 and Q1 by rat liver microsomes from animals pretreated with polychlorinated or polybrominated biphenyl congeners depended on the structure of the halogenated biphenyl inducers. Microsomes from rats treated with phenobarbital (PB) or halogenated biphenyls that exhibit PB-type activity preferentially enhanced the conversion of aflatoxin B1 to aflatoxin Q1. In contrast, microsomes from rats treated with 3-methylcholanthrene (MC) or halogenated biphenyls that exhibit MC-type induction activity increased the metabolism of aflatoxin B1 to aflatoxin M1. The coadministration of PB and MC produced microsomes that exhibited both types of induction activity (mixed type) in catalyzing the oxidative metabolism of diverse xenobiotic agents. However, PB-plus-MC-induced hepatic microsomes from immature male Wistar rats preferentially increased the metabolism of aflatoxin B1 to aflatoxin M1 but did not enhance the conversion of aflatoxin B1 to aflatoxin Q1. Comparable results were observed with microsomes from rats pretreated with halogenated biphenyls classified as mixed-type inducers; moreover, in some cases there was a significant decrease in the conversion of aflatoxin B1 to aflatoxin Q1 (compared with that of controls treated with corn oil).
PMCID: PMC238464  PMID: 2988440
10.  Physiological Studies on Ergot: Further Studies on the Induction of Alkaloid Synthesis by Tryptophan and Its Inhibition by Phosphate 
Journal of Bacteriology  1972;112(2):791-796.
The failure of l-leucine to stimulate ergot alkaloid production in a synthetic medium indicates that the previously observed stimulation by tryptophan and tryptophan analogues does not merely represent a nutritional effect. Tryptophan, but not mevalonate or 5-methyltryptophan, is able to overcome the inhibition of alkaloid synthesis by high levels of inorganic phosphate. Therefore, high phosphate levels seem to limit the synthesis of tryptophan; they may, in addition, prevent induction of alkaloid synthesis by preventing accumulation of tryptophan. Experiments which indicate a 2- to 3-fold temporary increase of intracellular free tryptophan and a 20- to 25-fold increase of tryptophan synthetase activity during the transition period between growth and alkaloid production phase are in agreement with the previously postulated induction of alkaloid synthesis by tryptophan. The latter experiments also indicate 4- to 6-fold repression of this enzyme by tryptophan.
PMCID: PMC251488  PMID: 5086659
11.  Reductive inactivation of digitoxin by Eubacterium lentum cultures. 
The obligate anaerobe Eubacterium lentum inactivated the cardiac glycoside digitoxin by reducing the double bond in the lactone ring. This conversion was quantitative when the substrate was incubated at a concentration of 10 micrograms/ml. The reduction reaction coincided with the growth phase of the bacterium. The stereochemical configuration at C-20 of the reduction product dihydrodigitoxin was found to be R. Incubation of digitoxigenin and its mono- and bisdigitoxosides individually with E. lentum led to the formation of their respective dihydro derivatives. The configuration at C-20 of these reduced metabolites was also found to be R.
PMCID: PMC203778  PMID: 3579289
12.  Reduction of digoxin to 20R-dihydrodigoxin by cultures of Eubacterium lentum. 
The anaerobic bacterium Eubacterium lentum, a common constituent of the intestinal microflora, inactivates digoxin by reducing the unsaturated lactone ring. Reduction of the cardiac glycoside by growing cultures of E. lentum ATCC 25559 proceeded in a stereospecific manner, with the 20R-dihydrodigoxin constituting more than 99% of the product formed. This is in contrast to the 3:1 ratio of 20R and 20S epimers formed in the chemical catalytic hydrogenation. Formation of the reduced glycosides proceeded quantitatively when an overall concentration of 10 micrograms/ml was added to the cultures. E. lentum did not hydrolyze the digitoxose sugars from C-3 of the parent glycoside. However, the synthetically prepared sugar-hydrolyzed metabolites (digoxigenin, digoxigenin monodigitoxoside, and digoxigenin bisdigitoxoside) were reduced to the corresponding dihydro metabolites. Repetition of the experiments with a feces sample from a volunteer who was known to be a converter of digoxin to dihydrodigoxin gave results identical to those obtained with pure E. lentum cultures.
PMCID: PMC239061  PMID: 3729400

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