Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells

K. P. Lu, L. M. Hallberg, J. Tomlinson, K. S. Ramos

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Benzo(a)pyrene (BaP) modulates vascular smooth muscle cells (vSMCs) from a quiescent to proliferative phenotype, a shift associated with activation of L1Md retrotransposon [K.P. Lu, K.S. Ramos, Biochem. Biophys. Res. Commun. 253 (1998) 828-833]. The present studies were conducted to evaluate L1Md activation profiles in murine vSMCs treated with BaP or its oxidative metabolites, and to screen for possible insertional mutations into p53 and retinoblastoma (RB) genes. We also sought to examine the profile of DNA damage and repair in BaP-treated vSMCs. Northern analysis revealed that BaP (0.03-3 μM), and its major reactive 7,8-diol metabolite (0.03-3 μM), activate L1Md gene in a concentration-dependent manner. Two other metabolites, 3-OH BaP and 3,6-BaP quinone (0.03-3 μM), as well as hydrogen peroxide (25-75 μM) also activated L1Md. No insertional mutations into either p53 or RB genes were observed in vSMCs treated with BaP in vitro, although a slight elevation of p53 mRNA was observed as early as 4 h after chemical challenge. Treatment of vSMCs with 3 or 30 μM BaP for 4 h increased unscheduled DNA synthesis (UDS) 1.4- and 2.5-fold, respectively. Challenge with 0.3 μM BaP for 24 h inhibited DNA repair capacity in vSMCs for up to 48 h. These results demonstrate that BaP and its oxidative metabolites activate L1Md retrotransposon in vSMCs, which coupled to DNA damage and inhibition of DNA repair are part of the atherogenic response elicited by BaP and related hydrocarbons.

Original languageEnglish (US)
Pages (from-to)35-44
Number of pages10
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume454
Issue number1-2
DOIs
StatePublished - Nov 6 2000
Externally publishedYes

Fingerprint

Retroelements
Benzo(a)pyrene
Vascular Smooth Muscle
DNA Repair
Smooth Muscle Myocytes
Retinoblastoma Genes
p53 Genes
DNA Damage
Mutation
Hydrocarbons
Hydrogen Peroxide
Phenotype
Messenger RNA
DNA
Genes

Keywords

  • Atherogenesis
  • Benzo(a)pyrene
  • DNA repair
  • Retrotransposons
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

Benzo(a)pyrene activates L1Md retrotransposon and inhibits DNA repair in vascular smooth muscle cells. / Lu, K. P.; Hallberg, L. M.; Tomlinson, J.; Ramos, K. S.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 454, No. 1-2, 06.11.2000, p. 35-44.

Research output: Contribution to journalArticle

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abstract = "Benzo(a)pyrene (BaP) modulates vascular smooth muscle cells (vSMCs) from a quiescent to proliferative phenotype, a shift associated with activation of L1Md retrotransposon [K.P. Lu, K.S. Ramos, Biochem. Biophys. Res. Commun. 253 (1998) 828-833]. The present studies were conducted to evaluate L1Md activation profiles in murine vSMCs treated with BaP or its oxidative metabolites, and to screen for possible insertional mutations into p53 and retinoblastoma (RB) genes. We also sought to examine the profile of DNA damage and repair in BaP-treated vSMCs. Northern analysis revealed that BaP (0.03-3 μM), and its major reactive 7,8-diol metabolite (0.03-3 μM), activate L1Md gene in a concentration-dependent manner. Two other metabolites, 3-OH BaP and 3,6-BaP quinone (0.03-3 μM), as well as hydrogen peroxide (25-75 μM) also activated L1Md. No insertional mutations into either p53 or RB genes were observed in vSMCs treated with BaP in vitro, although a slight elevation of p53 mRNA was observed as early as 4 h after chemical challenge. Treatment of vSMCs with 3 or 30 μM BaP for 4 h increased unscheduled DNA synthesis (UDS) 1.4- and 2.5-fold, respectively. Challenge with 0.3 μM BaP for 24 h inhibited DNA repair capacity in vSMCs for up to 48 h. These results demonstrate that BaP and its oxidative metabolites activate L1Md retrotransposon in vSMCs, which coupled to DNA damage and inhibition of DNA repair are part of the atherogenic response elicited by BaP and related hydrocarbons.",
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