Long interspersed element-1 is differentially regulated by food-borne carcinogens via the aryl hydrocarbon receptor

Oncogene. 2013 Oct 10;32(41):4903-12. doi: 10.1038/onc.2012.516. Epub 2012 Dec 3.

Abstract

A single human cell contains more than 5.0 × 10(5) copies of long interspersed element-1 (L1), 80-100 of which are competent for retrotransposition (L1-RTP). Recent observations have revealed the presence of de novo L1 insertions in various tumors, but little is known about its mechanism. Here, we found that 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethyl-imidazo[4,5-f]quinoxaline (MeIQx), food-borne carcinogens that are present in broiled meats, induced L1-RTP. This induction was dependent on a cellular cascade comprising the aryl hydrocarbon receptor (AhR), a mitogen-activated protein kinase, and CCAAT/enhancer-binding protein β. Notably, these compounds exhibited differential induction of L1-RTP. MeIQx-induced L1-RTP was dependent on AhR nuclear translocator 1 (ARNT1), a counterpart of AhR required for gene expression in response to environmental pollutants. By contrast, PhIP-induced L1-RTP did not require ARNT1 but was dependent on estrogen receptor α (ERα) and AhR repressor. In vivo studies using transgenic mice harboring the human L1 gene indicated that PhIP-induced L1-RTP was reproducibly detected in the mammary gland, which is a target organ of PhIP-induced carcinoma. Moreover, picomolar levels of each compound induced L1-RTP, which is comparable to the PhIP concentration detected in human breast milk. Data suggest that somatic cells possess machineries that induce L1-RTP in response to the carcinogenic compounds. Together with data showing that micromolar levels of heterocyclic amines (HCAs) were non-genotoxic, our observations indicate that L1-RTP by environmental compounds is a novel type of genomic instability, further suggesting that analysis of L1-RTP by HCAs is a novel approach to clarification of modes of carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogens / toxicity*
  • Cell Line, Tumor
  • Female
  • Food*
  • Genomic Instability / drug effects
  • Humans
  • Imidazoles / toxicity*
  • Long Interspersed Nucleotide Elements / drug effects*
  • Long Interspersed Nucleotide Elements / genetics*
  • Mice
  • Quinoxalines / toxicity*
  • Receptors, Aryl Hydrocarbon / metabolism*

Substances

  • Carcinogens
  • Imidazoles
  • Quinoxalines
  • Receptors, Aryl Hydrocarbon
  • 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline
  • 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine