title: 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.affiliation: 1] Department of Intractable Diseases, National Center for Global Health and Medicine (NCGM), Shinjuku-ku, Tokyo, Japan [2] Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Okudaira
authors.forename: T
authors.initials: T
authors.lastname: Okamura
authors.forename: M
authors.initials: M
authors.lastname: Tamura
authors.forename: K
authors.initials: K
authors.lastname: Iijma
authors.forename: M
authors.initials: M
authors.lastname: Goto
authors.forename: A
authors.initials: A
authors.lastname: Matsunaga
authors.forename: M
authors.initials: M
authors.lastname: Ochiai
authors.forename: H
authors.initials: H
authors.lastname: Nakagama
authors.forename: S
authors.initials: S
authors.lastname: Kano
authors.forename: Y
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: Y
authors.initials: Y
authors.lastname: Ishizaka
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D002273:Carcinogens / Q000633:toxicity*; D045744:Cell Line, Tumor; D005260:Female; D005502:Food; D042822:Genomic Instability / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D020084:Long Interspersed Nucleotide Elements / Q000187:drug effects* / Q000235:genetics*; D051379:Mice; D011810:Quinoxalines / Q000633:toxicity*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*
chemical_list: D002273:Carcinogens; D007093:Imidazoles; D011810:Quinoxalines; D018336:Receptors, Aryl Hydrocarbon; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine