title: Integrative assessment of potential effects of dioxins and related compounds in wild Baikal seals (Pusa sibirica): application of microarray and biochemical analyses.
abstract: We have previously indicated that accumulation of chlorinated dioxins and related compounds (DRCs) induced cytochrome P450 (CYP) 1A1, 1A2 and 1B1 isozymes in the liver of wild Baikal seals (Pusa sibirica). Here we attempt to assess the potential effects of DRCs triggered by the induction of these CYP1 isozymes in this species, using an integrative approach, combining gene expression monitoring and biochemical assays. To screen genes that may potentially respond to the exposure of DRCs, we constructed a custom cDNA oligo array that can target mRNAs in Baikal seals, and monitored hepatic mRNA expression levels in the wild population. Correlation analyses between the hepatic total 2,3,7,8-tetrachlorodibenzo-p-dioxin toxic equivalents (TEQs) and mRNA levels supported our previous findings that high accumulation of DRCs induces the transcription of CYP1A1, CYP1A2 and CYP1B1 genes. In addition, our integrative assessment indicated that the chronic exposure to DRCs may alter the hepatic transcript levels of genes related to oxidative stress, Fe ion homeostasis, and inflammatory responses. The expression levels of CYP1A2 showed significant positive correlations with levels of malondialdehyde, a biomarker of lipid peroxidation, and of etheno-dA, a DNA adduct, suggesting that the lipid peroxidation may be enhanced through the production of reactive oxygen species (ROS) triggered by CYP1A2 induction. Moreover, there was a positive correlation between heme oxygenase activities and malondialdehyde levels, suggesting the prompted heme degradation by ROS. Fetuin-A levels, which are suppressed by inflammation, showed a significant negative correlation with TEQ levels, and hepcidin levels, which are conversely increased by inflammation, had significant positive correlations with malondialdehyde and etheno-dA levels, implying the progression of inflammation by DRC-induced oxidative stress. Taken together, we propose here that wild Baikal seals may suffer from effects of chronic exposure to DRCs on the induction of CYP1 isozymes, followed by increased oxidative stress, heme degradation and inflammation.
authors.affiliation: Center for Marine Environmental Studies, Ehime University, Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Imaeda
authors.forename: Kei
authors.initials: K
authors.lastname: Nakayama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Udaka
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kunisue
authors.forename: Masako
authors.initials: M
authors.lastname: Ogawa
authors.forename: Tomonari
authors.initials: T
authors.lastname: Matsuda
authors.forename: Saburo
authors.initials: S
authors.lastname: Matsui
authors.forename: Evgeny A
authors.initials: EA
authors.lastname: Petrov
authors.forename: Valeriy B
authors.initials: VB
authors.lastname: Batoev
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Tanabe
authors.forename: Hisato
authors.initials: H
authors.lastname: Iwata
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics / Q000378:metabolism; D018736:DNA Adducts; D004147:Dioxins / Q000633:toxicity*; D004784:Environmental Monitoring / Q000379:methods*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D046048:Seals, Earless / Q000378:metabolism*; D014874:Water Pollutants, Chemical / Q000633:toxicity*
chemical_list: D015415:Biomarkers; D018736:DNA Adducts; D004147:Dioxins; D012333:RNA, Messenger; D014874:Water Pollutants, Chemical; D008315:Malondialdehyde; D019363:Cytochrome P-450 CYP1A1; D006419:Heme Oxygenase (Decyclizing)