Schlezinger Jennifer J.

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Schlezinger
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Jennifer J.
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  • Article
    Generalized concentration addition predicts joint effects of aryl hydrocarbon receptor agonists with partial agonists and cCompetitive antagonists
    (National Institute of Environmental Health Sciences, 2009-12-22) Howard, Gregory J. ; Schlezinger, Jennifer J. ; Hahn, Mark E. ; Webster, Thomas F.
    Background: Predicting the expected outcome of a combination exposure is critical to risk -assessment. The toxic equivalency factor (TEF) approach used for analyzing joint effects of dioxin-like chemicals is a special case of the method of concentration addition. However, the TEF method assumes that individual agents are full aryl hydrocarbon receptor (AhR) agonists with parallel dose–response curves, whereas many mixtures include partial agonists. Objectives: We assessed the ability of generalized concentration addition (GCA) to predict effects of combinations of full AhR agonists with partial agonists or competitive antagonists. Methods: We measured activation of AhR-dependent gene expression in H1G1.1c3 cells after application of binary combinations of AhR ligands. A full agonist (2,3,7,8-tetrachlorodibenzo-p--dioxin or 2,3,7,8-tetrachlorodibenzofuran) was combined with either a full agonist (3,3´,4,4´,5-penta-chloro-biphenyl), a partial agonist (2,3,3´,4,4´-pentachlorobiphenyl or galangin), or an antagonist (3,3´-diindolylmethane). Combination effects were modeled by the TEF and GCA approaches, and goodness of fit of the modeled response surface to the experimental data was assessed using a nonparametric statistical test. Results: The GCA and TEF models fit the experimental data equally well for a mixture of two full agonists. In all other cases, GCA fit the experimental data significantly better than the TEF model. Conclusions: The TEF model overpredicts effects of AhR ligands at the highest concentration combinations. At lower concentrations, the difference between GCA and TEF approaches depends on the efficacy of the partial agonist. GCA represents a more accurate definition of additivity for mixtures that include partial agonist or competitive antagonist ligands.
  • Thesis
    Involvement of Cytochrome P450 1A in the toxicity of aryl hydrocarbon receptor agonists : alteration arachidonic acid metabolism and production of reactive oxygen species
    (Massachusetts Institute of Technology and Woods Hole Oceanographic Institution, 1998-08) Schlezinger, Jennifer J.
    Two cytochrome P4501A-dependent mechanisms of aryl hydrocarbon receptor (AhR) agonist toxicity were examined in the marine teleost scup (Stenotomus chrysops), alteration of arachidonic acid (AA) metabolism and production of reactive oxygen species (ROS). In scup hepatic microsomes, cytochrome P450s including CYP1A and CYP2B-like proteins catalyzed regioselective metabolism of AA to eicosatrienoic and hydroxyeicosatetraenoic acids. Benzo[a]pyrene (BP) treatment induced liver microsomal AA metabolism, but that effect varied with season. Endogenous AA epoxides were recovered from scup liver, heart, and kidney, and their composition in the liver was altered by treatment with BP or 2,3,7,8-tetrachlorodibenzo-p-dioxin. In scup and mammals, the formation of ROS was stimulated by binding of 3,3',4,4-tetrachlorobiphenyl (TCB) to CYP1A, apparently CYP1Al. Attack of that ROS inactivated scup CYP1A. ROS release and inactivation of CYP1A were stimulated only by substrates of CYP1A that are slowly metabolized. In vivo, 3,3',4,4',5- pentachlorobiphenyl (PeCB) potently induced CYP1A mRNA, protein and catalytic activity at low doses (0.01-0.1 mg/kg), suppressed induction of CYP1A protein and catalytic activity at a high dose (1 mg/kg) and transiently induced oxidative stress in scup liver. The suppression of CYP1A induction was organ-dependent, with hepatic CYP1A being most susceptible to inactivation. The results suggest that ROS could be involved in the in vivo suppression of scup liver CYP1A by planar halogenated aromatic hydrocarbons. The reactive oxygen sensitive transcription factor, nuclear factor-KB (NF-KB), was characterized in scup. An NF-KB consensus binding sequence bound specifically to 3 proteins in scup liver, heart and kidney. One protein was recognized by an antibody to mammalian p50. Injection alone appeared to activate NF-KB. BP did not increase the activation ofNF-KB, and PeCB activated NF-KB in only 1 of 2 experiments. Last, CYP1A induction in endothelial cells of the American eel (Anguilla rostrata), a site which may be particularly susceptible to alterations in AA metabolism and ROS production, was described. Eel liver CYP1A responded to BP, 13-naphthoflavone and TCB in a dose-dependent fashion, and induction was correlated with hepatic inducer concentration. Endothelial CYP1A was inducible in a number of organs and was metabolically active. In the rete mirabile, penetration of endothelial CYP1A induction increased with increasing dose of AhR agonists, corresponding with an increase in inducer concentration. A transition from endothelial to epithelial staining occurred in the gill, heart and kidney at high inducer doses.