title: Editor's Highlight: Interactive Genotoxicity Induced by Environmentally Relevant Concentrations of Benzo(a)Pyrene Metabolites and Arsenite in Mouse Thymus Cells.
abstract: Arsenic and polycyclic aromatic hydrocarbon (PAH) exposures affect many people worldwide leading to cancer and other diseases. Arsenite (As+3) and certain PAHs are known to cause genotoxicity. However, there is limited information on the interactions between As+3and PAHs at environmentally relevant concentrations. The thymus is the primary immune organ for T cell development in mammals. Our previous studies showed that environmentally relevant concentrations of As+3induce genotoxicity in mouse thymus cells through Poly(ADP-ribose) polymerase (PARP) inhibition. Certain PAHs, such as the metabolites of benzo(a)pyrene (BaP), are known to cause DNA damage by forming DNA adducts. In the present study, primary mouse thymus cells were examined for DNA damage following 18 hr in vitro treatments with 5 or 50 nM As+3and 100 nM BaP, benzo[a]pyrene-7,8-dihydrodiol (BP-Diol), or benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). An interactive increase in genotoxicity and apoptosis were observed following treatments with 5 nM As+3+100 nM BP-diol and 50 nM As+3+100 nM BPDE. We attribute the increase in DNA damage to inhibition of PARP inhibition leading to decreased DNA repair. To further support this hypothesis, we found that a PARP inhibitor, 3,4-dihydro-5[4-(1-piperindinyl) butoxyl]-1(2H)-isoquinoline (DPQ), also interacted with BP-diol to produce an increase in DNA damage. Interestingly, we also found that As+3and BP-diol increased CYP1A1 and CYP1B1 expression, suggesting that increased PAH metabolism may also contribute to genotoxicity. In summary, these results show that the suppression of PARP activity and induction of CYP1A1/CYP1B1 may act together to increase DNA damage produced by As+3and PAHs.
authors: Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131.
authors: Huan
authors: H
authors: Xu
authors: Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131.
authors: Fredine T
authors: FT
authors: Lauer
authors: Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131.
authors: Ke Jian
authors: KJ
authors: Liu
authors: Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131.
authors: Laurie G
authors: LG
authors: Hudson
authors: Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, New Mexico 87131 sburchiel@salud.unm.edu.
authors: Scott W
authors: SW
authors: Burchiel
mesh_terms: D000818:Animals; D018053:Arsenites / Q000633:toxicity*; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002478:Cells, Cultured; D018736:DNA Adducts; D004249:DNA Damage; D051379:Mice; D009152:Mutagenicity Tests; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000633:toxicity; D011065:Poly(ADP-ribose) Polymerases; D061251:Primary Cell Culture; D060168:Thymocytes / Q000187:drug effects*
chemical_list: D018053:Arsenites; D018736:DNA Adducts; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D001564:Benzo(a)pyrene; D011065:Poly(ADP-ribose) Polymerases
keywords: CYP1A1; CYP1B1.; arsenite; benzo(a)pyrene metabolites; interactive genotoxicity; primary mouse thymus cells