title: Long-term exposure to low-concentrations of Cr(VI) induce DNA damage and disrupt the transcriptional response to benzo[a]pyrene.
abstract: Living organisms are exposed on a daily basis to widespread mixtures of toxic compounds. Mixtures pose a major problem in the assessment of health effects because they often generate substance-specific effects that cannot be attributed to a single mechanism. Two compounds often found together in the environment are the heavy metal chromium and the polycyclic aromatic hydrocarbon benzo[a]pyrene (B[a]P). We have examined how long-term exposure to a low concentration of Cr(VI) affects the transcriptional response to B[a]P, a second toxicant with an unrelated mechanism of action. Growth of mouse hepatoma cells for 20 passages in medium with 0.1 or 0.5 μM Cr(VI) increases DNA damage and apoptosis while decreasing clonogenic ability. Treated cells also show transcriptome changes indicative of increased expression of DNA damage response and repair genes. In them, B[a]P activates cancer progression pathways, unlike in cells never exposed to Cr(VI), where B[a]P activates mostly xenobiotic metabolism pathways. Cells grown in Cr(VI) for 20 passages and then cultured for an additional 5 passages in the absence of Cr(VI) recover from some but not all the chromium effects. They show B[a]P-dependent transcriptome changes strongly weighted toward xenobiotic metabolism, similar to those in B[a]P-treated cells that had no previous Cr(VI) exposure, but retain a high level of Cr(VI)-induced DNA damage and silence the expression of DNA damage and cancer progression genes. We conclude that the combined effect of these two toxicants appears to be neither synergistic nor additive, generating a toxic/adaptive condition that cannot be predicted from the effect of each toxicant alone.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States.
authors.forename: Jerald L
authors.initials: JL
authors.lastname: Ovesen
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States.
authors.forename: Mario
authors.initials: M
authors.lastname: Medvedovic
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati College of Medicine, 3223 Eden Avenue, Cincinnati, OH 45267, United States. Electronic address: Alvaro.Puga@uc.edu.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Puga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002274:Carcinogens, Environmental / Q000008:administration & dosage / Q000633:toxicity*; D045744:Cell Line, Tumor; D002857:Chromium / Q000008:administration & dosage / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000187:drug effects*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D051379:Mice; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects
chemical_list: D002274:Carcinogens, Environmental; D002857:Chromium; C074702:chromium hexavalent ion; D001564:Benzo(a)pyrene
keywords: B[a]P; Chromium; Complex mixtures; Gene expression; Heavy metals; Transcriptome