B6C3F1 mice exposed to ozone with 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone and/or dibutyl phthalate showed toxicities through alterations of NF-kappaB, AP-1, Nrf2, and osteopontin.
Toxic effects of ozone, 4-(N-methyl-N-nitrosamino)-1-(3- pyridyl)-1-butanone (NNK), and/or dibutyl phthalate (DBP) were examined through NF-kappaB, AP-1, Nrf2, and osteopontin (OPN) in lungs and livers of B6C3F1 mice. Electrophoretic mobility shift assay (EMSA) indicated that mice treated with combination of toxicants induced high NF-kappaB activities. Expression levels of p105, p65, and p50 proteins increased in all treated mice, whereas IkB activity was inhibited in NNK-, DBP-, and combination-treated ones. All treated mice except ozone-treated one showed high AP-1 binding activities. Expression levels of c-fos, c-jun, junB, jun D, Nrf2, and OPN proteins increased in all treated mice. Additive interactions were frequently noted from two-toxicant combination mice compared to ozone-treated one. These results indicate treatment of mixture of toxicants increased toxicity through NF-kappaB, AP-1, Nrf2, and OPN. Our data could be applied to the elucidation of mechanism as well as the risk assessment of mixture-induced toxicity.
Kim
Min Young
MY
Laboratory of Toxicology, College of Veterinary Medicine and School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea.
Song
Kyung Suk
KS
Park
Gun Ho
GH
Chang
Seung Hee
SH
Kim
Hyun Woo
HW
Park
Jin Hong
JH
Jin
Hwa
H
Eu
Kook Jong
KJ
Cho
Hyun Sun
HS
Kang
Gami
G
Kim
Young Chul
YC
Cho
Myung Haing
MH
D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003993:Dibutyl Phthalate / Q000633:toxicity*; D024202:Electrophoretic Mobility Shift Assay; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B / Q000378:metabolism; D009602:Nitrosamines / Q000633:toxicity*; D053495:Osteopontin; D010126:Ozone / Q000633:toxicity*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018570:Risk Assessment; D012795:Sialoglycoproteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D009602:Nitrosamines; D011518:Proto-Oncogene Proteins; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D053495:Osteopontin; D003993:Dibutyl Phthalate; D010126:Ozone; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone