Polychlorinated biphenyls as inducers of hepatic microsomal enzymes: Structure-activity rules

A number of highly purified polychlorinated biphenyl (PCB) isomers and congeners were synthesized and administered to male Wistar rats at dosage levels of 30 and 150 [mu]mol [middle dot] kg-1. The effects of this in vivo treatment on the drug-metabolizing enzymes were determined by measuring the microsomal benzo[a]pyrene (B[a]P) hydroxylase, dimethylaminoantipyrine (DMAP) N-demethylase and NADPH-cytochrome c reductase enzyme activities, the cytochrome b5 content and the relative peak intensities and spectral shifts of the reduced microsomal cytochrome P-450: CO and ethylisocyanide (EIC) binding difference spectra. The results were compared to the effects of administering phenobarbitone (PB), 3-methylcholanthrene (MC) and PB plus MC (coadministered) to the test animals. The synthetic PCB congeners used in this study included 3,4,4',5-tetrachlorobiphenyl (TCBP-1), 2,3',4,4'-tetrachlorobiphenyl (TCBP-2), 2,3',4,4',5'-pentachlorobiphenyl (PCBP-1), 2,3,4,4',5-pentachlorobiphenyl (PCBP-2), 2,3,3',4,4',5-hexachlorobiphenyl (HCBP-1), 2,3,3',4',5,6-hexachlorobiphenyl (HCBP-2), 2,3,3',5,5',6-hexachlorobiphenyl (HCBP-3), 2,2',3,5,5',6-hexachlorobiphenyl (HCBP-4) and 2,3,3',4,5,5'-hexachlorobiphenyl (HCBP-5) and were used to reappraise the structure-activity rules for PCBs as hepatic microsomal enzyme inducers. The results suggested that (a) PCBs which induce MC or mixed-type activity must be substituted at both para positions, at least two meta positions but not necessarily on the same phenyl ring and can also contain one ortho chloro substituent; (b) due to the considerable structural diversity of the PB-type inducers the rules for induction of this activity by PCB congeners are not readily defined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23229/1/0000162.pd

Comparative estrogenic activity of wine extracts and organochlorine pesticide residues in food.

The human diet contains industrial-derived, endocrine-active chemicals and higher levels of naturally occurring compounds that modulate multiple endocrine pathways. Hazard and risk assessment of these mixtures is complicated by noadditive interactions between different endocrine-mediated responses. This study focused on estrogenic chemicals in the diet and compared the relative potencies or estrogen equivalents (EQs) of the daily consumption of xenoestrogenic organochlorine pesticides in food (2.44 micrograms/day) with the EQs in a single 200-ml glass of red cabernet wine. The reconstituted organochlorine mixture contained 1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)ethane, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, endosulfan-1, endosulfan-2, p,p'-methoxychlor, and toxaphene; the relative proportion of each chemical in the mixture resembled the composition reported in a recent U.S. Food and Drug Administration market basket survey. The following battery of in vitro 17 beta-estradiol (E2)-responsive bioassays were utilized in this study: competitive binding to mouse uterine estrogen receptor (ER); proliferation in T47D human breast cancer cells; luciferase (Luc) induction in human HepG2 cells transiently cotransfected with C3-Luc and the human ER, rat ER-alpha, or rat ER-beta; induction of chloramphenicol acetyltransferase (CAT) activity in MCF-7 human breast cancer cells transfected with E2-responsive cathepsin D-CAT or creatine kinase B-CAT plasmids. For these seven in vitro assays, the calculated EQs in extracts from 200 ml of red cabernet wine varied from 0.15 to 3.68 micrograms/day. In contrast, EQs for consumption of organochlorine pesticides (2.44 micrograms/day) varied from nondetectable to 1.24 ng/day. Based on results of the in vitro bioassays, organochlorine pesticides in food contribute minimally to dietary EQ intake

Partial Characterization of Graphs Having a Single Large Laplacian Eigenvalue

The parameter σ(G) of a graph G stands for the number of Laplacian eigenvalues greater than or equal to the average degree of G. In this work, we address the problem of characterizing those graphs G having σ(G) = 1. Our conjecture is that these graphs are stars plus a (possible empty) set of isolated vertices. We establish a link between σ(G) and the number of anticomponents of G. As a by-product, we present some results which support the conjecture, by restricting our analysis to cographs, forests, and split graphs.Fil: Allem, L. Emilio. Universidade Federal do Rio Grande do Sul; BrasilFil: Cafure, Antonio Artemio. Universidad Nacional de General Sarmiento. Instituto del Desarrollo Humano; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Dratman, Ezequiel. Universidad Nacional de General Sarmiento. Instituto de Ciencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Grippo, Luciano Norberto. Universidad Nacional de General Sarmiento. Instituto de Ciencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Safe, Martin Dario. Universidad Nacional del Sur; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Trevisan, Vilmar. Universidade Federal do Rio Grande do Sul; Brasi

Induction of both cytochromes P-450 and P-448 by 2,3',4,4',5-pentabromobiphenyl, a component of fireMaster

The synthesis and purification of a component of fireMaster BP-6 and fireMaster FF-1, 2,3',4,4',5-pentabromobiphenyl, is described. The compound was found to be a potent inducer of liver microsomal drug-metabolizing enzymes in the rat, enhancing those enzymic activities induced by both phenobarbitone and 3-methylcholanthrene (i.e. cytochromes P-450 and P-448). The pentabromobiphenyl enhanced the activities of benzo[a]pyrene hydroxylase, dimethylamino-antipyrine N-demethylase and NADPH-cytochrome c reductase. The hepatic cytochromes b5 and P-450 were increased and the Soret peak maximum of the latter was shifted to 448.5 nm. The relative peak intensities and spectral shifts for the ethylisocyanide-binding difference spectra confirmed the mixed induction characteristics of 2,3',4,4',5-pentabromobiphenyl.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23338/1/0000278.pd

Induction of drug-metabolizing enzymes by fractionated commercial polybrominated biphenyls (PBBs)

A commercial polybrominated biphenyl mixture was separated chromatographically into two fractions on neutral alumina (AA and AB) and into three fractions on Florisil (FA, FB, and FC) by sequential elution with solvents of increasing polarity. Using established methods, the activity of each fraction as hepatic microsomal cytochrome P-450- and/or cytochrome P-448-dependent monooxygenase enzyme inducers was examined in the male Wister rat. Like the coadministration of phenobarbitone and 3-methylcholanthrene, commercial PBBs, either unfractionated or reconstituted from its various fractions, induced both cytochromes P-450 and P-448. Both cytochromes were also induced by the less-polar fractions AA and FA. In contrast, little or no inductive effects were exhibited by the more polar Florisil fractions, FB and FC, indicating that the ability of commercial PBBs to induce cytochrome P-448 is not due to contaminating brominated dibenzofurans or dibenzodioxins. Unlike the polar Florisil fraction, the more polar alumina fraction, AB, was a potent microsomal enzyme inducer. This fraction was enriched in 2,3,3',4,4',5-hexa- and 2,2',3,3',4,4',5-heptabromobiphenyl and also contained unassigned monochloro derivatives of a penta- and hexabromobiphenyl, namely C12H4Br5Cl and C12 H3Br6Cl, respectively. The data strongly suggest that the biologic effects of the commercial polybrominated biphenyl mixture are due to the various halogenated biphenyls present. These results are discussed in terms of the reported toxic potency of each PBB fraction and with reference to the known biologic activity of individual polybrominated biphenyl congeners or their chloro analogs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24468/1/0000743.pd

New paradigms for teaching and planning the contemporary landscape

As condições de vida nas cidades vêm, desde fins do século XIX, demandando a constante evolução do planejamento e do profissional que o exerce. Este estudo parte da hipótese de descompasso entre a prática profissional do planejador – e a demanda no planejamento da paisagem; seu objetivo é abordar paradigmas do planejamento da paisagem e sua incorporação ao ensino de arquitetura e urbanismo. Analisa as grades curriculares de três cursos de arquitetura e urbanismo em Belo Horizonte, avaliando a formação do profissional para a prática do planejamento.Verificou-se que o ensino aponta algumas diretrizes contemporâneas, mas ainda não é visto como processo – complexo, contínuo e integrado. As recomendações visam formar um profissional crítico, reflexivo e de conhecimento multidisciplinar que contemple as ciências sociais e ambientais, sem o qual não se pode atuar na paisagem urbana da atualidade.The urban conditions of life have, since the XIXth century, posed challenges do the planning profession. This essay looks at the gaps in time between these challenges and the professional responses to urban problems, and in particular the landscape planning responses. Its main objective is to discuss the current and currently shaping paradigms and how they are considered in undergraduate programs. It analyses the curricula of three representative programs in Belo Horizonte, Brasil, evaluating contents and their relationship to contemporary planning needs. Results show that the programs include some important contemporary contents, but present structures badly suited to all-encompassing, process-oriented experiences. Recommendations aim at a critical and reflexive professional, prepared to deal with interdisciplinary issues, concerned with the social sciences and the environment. These qualities seem to be fundamental to responsibly plan the urban contemporary landscape

Cover to Volume 3

The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth

Increased Risk of Diabetes and Polychlorinated Biphenyls and Dioxins: A 24-year follow-up study of the Yucheng cohort

OBJECTIVE—Polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) are important and persistent organic pollutants (POPs) in humans. Recent cross-sectional studies have detected increased concentrations of serum POPs in diabetic patients. We aimed to examine the association between previous high exposures to PCBs and PCDFs and the cumulative incidence of type 2 diabetes and hypertension

Comparative analysis of homology models of the Ah receptor ligand binding domain: Verification of structure-function predictions by site-directed mutagenesis of a nonfunctional receptor

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that mediates the biological and toxic effects of a wide variety of structurally diverse chemicals, including the toxic environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). While significant interspecies differences in AHR ligand binding specificity, selectivity, and response have been observed, the structural determinants responsible for those differences have not been determined, and homology models of the AHR ligand-binding domain (LBD) are available for only a few species. Here we describe the development and comparative analysis of homology models of the LBD of 16 AHRs from 12 mammalian and nonmammalian species and identify the specific residues contained within their ligand binding cavities. The ligand-binding cavity of the fish AHR exhibits differences from those of mammalian and avian AHRs, suggesting a slightly different TCDD binding mode. Comparison of the internal cavity in the LBD model of zebrafish (zf) AHR2, which binds TCDD with high affinity, to that of zfAHR1a, which does not bind TCDD, revealed that the latter has a dramatically shortened binding cavity due to the side chains of three residues (Tyr296, Thr386, and His388) that reduce the amount of internal space available to TCDD. Mutagenesis of two of these residues in zfAHR1a to those present in zfAHR2 (Y296H and T386A) restored the ability of zfAHR1a to bind TCDD and to exhibit TCDD-dependent binding to DNA. These results demonstrate the importance of these two amino acids and highlight the predictive potential of comparative analysis of homology models from diverse species. The availability of these AHR LBD homology models will facilitate in-depth comparative studies of AHR ligand binding and ligand-dependent AHR activation and provide a novel avenue for examining species-specific differences in AHR responsiveness. © 2013 American Chemical Society