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.