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

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.

• Authors: N Okudaira, T Okamura, M Tamura, K Iijma, M Goto, A Matsunaga, M Ochiai, H Nakagama, S Kano, Y Fujii-Kuriyama, Y Ishizaka
• Journal: Oncogene (Oncogene) Vol. 32 Issue 41 Pg. 4903-12 (Oct 10 2013) ISSN: 1476-5594 [Electronic] England
• PMID: 23208499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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