Combined exposure to X-irradiation followed by N-ethyl-N-nitrosourea treatment alters the frequency and spectrum of Ikaros point mutations in murine T-cell lymphoma.
Ionizing radiation is a well-known carcinogen, but its potency may be influenced by other environmental carcinogens, which is of practical importance in the assessment of risk. Data are scarce, however, on the combined effect of radiation with other environmental carcinogens and the underlying mechanisms involved. We studied the mode and mechanism of the carcinogenic effect of radiation in combination with N-ethyl-N-nitrosourea (ENU) using doses approximately equal to the corresponding thresholds. B6C3F1 mice exposed to fractionated X-irradiation (Kaplan's method) followed by ENU developed T-cell lymphomas in a dose-dependent manner. Radiation doses above an apparent threshold acted synergistically with ENU to promote lymphoma development, whereas radiation doses below that threshold antagonized lymphoma development. Ikaros, which regulates the commitment and differentiation of lymphoid lineage cells, is a critical tumor suppressor gene frequently altered in both human and mouse lymphomas and shows distinct mutation spectra between X-ray- and ENU-induced lymphomas. In the synergistically induced lymphomas, we observed a low frequency of LOH and an inordinate increase of Ikaros base substitutions characteristic of ENU-induced point mutations, G:C to A:T at non-CpG, A:T to G:C, G:C to T:A and A:T to T:A. This suggests that radiation doses above an apparent threshold activate the ENU mutagenic pathway. This is the first report on the carcinogenic mechanism elicited by combined exposure to carcinogens below and above threshold doses based on the mutation spectrum of the causative gene. These findings constitute a basis for assessing human cancer risk following exposure to multiple carcinogens.
National Institute of Radiological Sciences, Chiba, Japan. skakinum@nirs.go.jp
Shizuko
S
Kakinuma
Mayumi
M
Nishimura
Yoshiko
Y
Amasaki
Mayumi
M
Takada
Kazumi
K
Yamauchi
Satomi
S
Sudo
Yi
Y
Shang
Kazutaka
K
Doi
Shinji
S
Yoshinaga
Yoshiya
Y
Shimada
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D045643:DNA Repair Enzymes / Q000235:genetics; D004307:Dose-Response Relationship, Radiation; D005038:Ethylnitrosourea / Q000633:toxicity*; D005260:Female; D051740:Ikaros Transcription Factor / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D019656:Loss of Heterozygosity; D016399:Lymphoma, T-Cell / Q000235:genetics; D051379:Mice; D017354:Point Mutation; D014965:X-Rays / Q000009:adverse effects*
D002273:Carcinogens; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D045643:DNA Repair Enzymes; D005038:Ethylnitrosourea