title: Polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin induce intrachromosomal recombination in vitro and in vivo.
abstract: Polychlorinated aromatic hydrocarbons such as polychlorinated biphenyls and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are extremely stable and widely distributed environmental pollutants. These chemicals are animal carcinogens and probable human carcinogens, and TCDD is possibly one of the most potent toxins ever evaluated by the United States Environmental Protection Agency. Polychlorinated aromatic hydrocarbons score negatively in most genotoxicity assays, including the Ames (Salmonella) assay. Although their mechanism of toxicity is not well understood, they induce aryl hydrocarbon (AH) hydroxylases and bind to the AH receptor, which is believed to mediate toxicity. Here, we determine effects of polychlorinated aromatic hydrocarbons in genotoxicity assays that score for DNA deletions by intrachromosomal recombination in vivo and in vitro. In this study, TCDD, Aroclor 1221, and Aroclor 1260 induced deletions in vivo in the mouse embryo; Aroclor 1221 and Aroclor 1260 induced deletions in yeast. We also show that the induced deletion events did not correlate with induction of AH hydroxylase. None of the tested compounds induced CYP1A-associated ethoxyresorufin-O-deethylase activity in mouse embryos or in vitro. These results clearly demonstrate a genotoxic activity of polychlorinated aromatic hydrocarbons in vitro and in vivo, which is independent of induction of cytochrome P450 activity. Because genetic instability and deletions may be mechanistically involved in carcinogenesis, these results may encourage further research to determine whether such genotoxic mechanisms may be useful for cancer risk assessment of polychlorinated aromatic hydrocarbons.
authors.affiliation: Department of Molecular and Cellular Toxicology, Harvard School of Public Health, Boston, Massachusetts 02115, USA. schiestl@mbcrr.harvard.edu
authors.forename: R H
authors.initials: RH
authors.lastname: Schiestl
authors.forename: J
authors.initials: J
authors.lastname: Aubrecht
authors.forename: W Y
authors.initials: WY
authors.lastname: Yap
authors.forename: S
authors.initials: S
authors.lastname: Kandikonda
authors.forename: S
authors.initials: S
authors.lastname: Sidhom
mesh_terms: D000818:Animals; D001140:Aroclors / Q000494:pharmacology* / Q000633:toxicity; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology* / Q000633:toxicity; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D004249:DNA Damage; D004271:DNA, Fungal / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000494:pharmacology; D008741:Methyl Methanesulfonate; D051379:Mice; D008810:Mice, Inbred C57BL; D009152:Mutagenicity Tests; D011078:Polychlorinated Biphenyls / Q000494:pharmacology* / Q000633:toxicity; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology* / Q000633:toxicity; D011247:Pregnancy; D011995:Recombination, Genetic / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects; D017384:Sequence Deletion
chemical_list: D001140:Aroclors; D002273:Carcinogens; D004271:DNA, Fungal; D006023:Glycoproteins; D000072317:Polychlorinated Dibenzodioxins; C026987:aroclor 1260; C032739:aroclor 1221; D008741:Methyl Methanesulfonate; D011078:Polychlorinated Biphenyls; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2