title: Characterization and Biological Potency of Mono- to Tetra-Halogenated Carbazoles.
abstract: This paper deals with the characterization and aryl hydrocarbon receptor (AhR) agonist activities of a series of chlorinated, brominated, and mixed bromo/chlorocarbazoles, some of which have been identified in various environmental samples. Attention is directed here to the possibility that halogenated carbazoles may currently be emitted into the environment as a result of the production of carbazole-containing polymers present in a wide variety of electronic devices. We have found that any carbazole that is not substituted in the 1,3,6,8 positions may be lost during cleanup of environmental extracts if a multilayer column is utilized, as is common practice for polychlorinated dibenzo-p-dioxin (dioxin) and related compounds. In the present study, (1)H NMR spectral shift data for 11 relevant halogenated carbazoles are reported, along with their gas chromatographic separation and analysis by mass spectrometry. These characterization data allow for confident structural assignments and the derivation of possible correlations between structure and toxicity based on the halogenation patterns of the isomers investigated. Some halogenated carbazoles exhibit characteristics of persistent organic pollutants and their potential dioxin-like activity was further investigated. The structure-dependent induction of CYP1A1 and CYP1B1 gene expression in Ah-responsive MDA-MB-468 breast cancer cells by these carbazoles was similar to that observed for other dioxin-like compounds, and the magnitude of the fold induction responses for the most active halogenated carbazoles was similar to that observed for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). 2,3,6,7-Tetrachlorocarbazole was one of the most active halogenated carbazoles and, like TCDD, contains 4 lateral substituents; however, the estimated relative effect potency for this compound (compared to TCDD) was 0.0001 and 0.0032, based on induction of CYP1A1 and CYP1B1 mRNA, respectively.
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.
authors.forename: Nicole
authors.initials: N
authors.lastname: Riddell
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University , College Station, Texas 77843-4466, United States.
authors.forename: Un-Ho
authors.initials: UH
authors.lastname: Jin
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University , College Station, Texas 77843-4466, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Safe
authors.affiliation: Department of Veterinary Physiology & Pharmacology, Texas A&M University , College Station, Texas 77843-4466, United States.
authors.forename: Yating
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.
authors.forename: Brock
authors.initials: B
authors.lastname: Chittim
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.
authors.forename: Alex
authors.initials: A
authors.lastname: Konstantinov
authors.affiliation: Matson & Associates, Inc. , 331 East Foster Avenue, State College, Pennsylvania 16801, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Parette
authors.affiliation: Ontario Ministry of the Environment , 125 Resources Road, Toronto, Ontario M9P 3 V6, Canada.|Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada.
authors.forename: Miren
authors.initials: M
authors.lastname: Pena-Abaurrea
authors.affiliation: Ontario Ministry of the Environment , 125 Resources Road, Toronto, Ontario M9P 3 V6, Canada.|Department of Chemistry, University of Toronto , Toronto, Ontario M5S 3H6, Canada.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Reiner
authors.affiliation: Ontario Ministry of the Environment , 125 Resources Road, Toronto, Ontario M9P 3 V6, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Poirier
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.
authors.forename: Tomislav
authors.initials: T
authors.lastname: Stefanac
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: McAlees
authors.affiliation: Wellington Laboratories Inc. , 345 Southgate Drive, Guelph, Ontario Canada N1G 3M5.|Department of Chemistry, University of Guelph , Guelph, Ontario N1G 2W1, Canada.
authors.forename: Robert
authors.initials: R
authors.lastname: McCrindle
mesh_terms: D002227:Carbazoles / Q000633:toxicity*; D045744:Cell Line, Tumor; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D054879:Halogenation; D006801:Humans; D006841:Hydrocarbons, Aromatic / Q000633:toxicity; D013058:Mass Spectrometry; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity; D066244:Proton Magnetic Resonance Spectroscopy
chemical_list: D002227:Carbazoles; D006841:Hydrocarbons, Aromatic; D000072317:Polychlorinated Dibenzodioxins; C041514:carbazole; C569463:CYP1A1 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1