Gene expression profile by 2,3,7,8-tetrachlorodibenzo-p-dioxin in the liver of wild-type (AhR+/+) and aryl hydrocarbon receptor-deficient (AhR-/-) mice.

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants that cause various biological effects on mammals. The purpose of our study was to identify the genes involved in hepatotoxicity and hepatocarcinogenesis caused by TCDD. C57BL/6 (AhR+/+, wild type) and B6.129-AhR /J (AhR-/-, knock out) mice were injected i.p. with a single treatment of TCDD at the dose of 100 microg/kg body weight. Relative liver weight was significantly increased at 72 hr after TCDD treatment without an apparent histopathological change in AhR+/+ mice (p<0.05). TCDD treatment also significantly increased activity of serum alanine aminotransferase in AhR-/- mice (p<0.05). The liver was analyzed for gene expression profiles 72 hr later. As compared with AhR-/- mice, the expression of 51 genes (>3-fold) was changed in AhR+/+ mice; 28 genes were induced, while 23 genes were repressed. Most of the genes were associated with chemotaxis, inflammation, carcinogenesis, acute-phase response, immune responses, cell metabolism, cell proliferation, signal transduction, and tumor suppression. This study suggests that the microarray analysis of genes in the liver of AhR+/+ and AhR-/- mice may help to clarify the mechanism of AhR-mediated hepatotoxicity and hepatocarcinogenesis by TCDD.

Full text

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FULL PAPER Toxicology
Gene Expression Profile by 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in the Liver of Wild-
Type (AhR+/+) and Aryl Hydrocarbon Receptor-Deficient (AhR–/–) Mice
Chang Yong YOON1), Misun PARK1), Bang Hyun KIM1), Ji Yeon PARK1), Mun Suk PARK1), Youn Kyoung JEONG1),
Hyugsung KWON1), Hai Kwan JUNG1), HoIl KANG1), Yong Soon LEE2) and Beom Jun LEE3)*
1)Department of Toxicology, National Institute of Toxicological Research, Seoul 122–704, 2)Department of Veterinary Public Health,
College of Veterinary Medicine, Seoul National University, Seoul 151–742 and 3)Department of Veterinary Public Health, Research
Institute of Veterinary Medicine and College of Veterinary Medicine, Chungbuk National University, Cheongju 361–763, Korea
(Received 2 February 2006/Accepted 1 March 2006)
ABSTRACT. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most toxic environmental pollutants that cause various biological
effects on mammals. The purpose of our study was to identify the genes involved in hepatotoxicity and hepatocarcinogenesis caused by
TCDD. C57BL/6 (AhR+/+, wild type) and B6.129-AhR<tm1Bra>/J (AhR–/–, knock out) mice were injected i.p. with a single treatment
of TCDD at the dose of 100 µg/kg body weight. Relative liver weight was significantly increased at 72 hr after TCDD treatment without
an apparent histopathological change in AhR+/+ mice (p<0.05). TCDD treatment also significantly increased activity of serum alanine
aminotransferase in AhR–/– mice (p<0.05). The liver was analyzed for gene expression profiles 72 hr later. As compared with AhR–
/– mice, the expression of 51 genes (>3-fold) was changed in AhR+/+ mice; 28 genes were induced, while 23 genes were repressed.
Most of the genes were associated with chemotaxis, inflammation, carcinogenesis, acute-phase response, immune responses, cell metab-
olism, cell proliferation, signal transduction, and tumor suppression. This study suggests that the microarray analysis of genes in the
liver of AhR+/+ and AhR–/– mice may help to clarify the mechanism of AhR-mediated hepatotoxicity and hepatocarcinogenesis by
TCDD.
KEY WORDS: gene expression, liver, microarray, TCDD.
J. Vet. Med. Sci. 68(7): 663–668, 2006
Dioxins are a heterogeneous mixture of chlorinated
dibenzo-p-dioxin and dibenzofuran (PCDD and PCDF) con-
geners. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is
considered to be most toxic of the dioxin congeners [37, 43].
TCDD induces a variety of biological responses including
induction of cytochrome P-4501A (CYP1A), reproductive
and developmental defects, immunotoxicity, thymus atro-
phy, epothelial disorders, liver damage, wasting syndrome,
and cancer [13, 26]. There is an overflow of data indicating
that TCDD is a potent tumor promoter in rat and mouse liver
and lung, as well as in mouse skin [20, 27, 31, 36]. TCDD
causes tumor promotion by interfering with intracellular
signal transduction pathways related to growth factors and
cytokines such as transforming growth factor (TGF) and
interleukin-1β (IL-1β) [18, 20, 24, 27, 31, 36, 42]. In addi-
tion, TCDD exposure results in reactive oxygen species pro-
duction and an oxidative stress response in adult and fetal
tissues of experimental animals. The reactive oxygen spe-
cies may in turn oxidize DNA bases, leading to strand
breakage or clastogenic effects [31]. Nevertheless, the
mechanism of TCDD-induced carcinogenesis is incom-
pletely understood.
TCDD binds to the cytosolic AhR, cytosolic ligand-acti-
vated transcription factor. This receptor has the potential to
up-regulate and down-regulate the expression of a large
number of genes with diverse functions, including those of
the Ah gene battery, such as CYP1A1 and CYP1A2 [18, 24,
42]. Activation of the AhR is clearly associated with a cel-
lular oxidative stress response, mediated in part by the
induction of cytochrome P450 [31]. AhR is widely
expressed in mammalian tissues, and it is hypothesized that
initial binding to the AhR is linked to the broad spectrum of
biochemical and toxic responses observed in laboratory ani-
mals and cells exposed to TCDD and other halogenated aro-
matic contaminants that bind the AhR [27]. Animal
experiments revealed that lipophilic TCDD accumulated
mostly in the liver and to less extent in fat tissue through
absorption from intestine [18]. Concerning the liver, epide-
miologic studies in accidently exposed populations revealed
hepatotoxicity, and chronic TCDD treatment promoted liver
tumor formation in laboratory animals [18]. TCDD has also
proved to be positive in cell transformation assays in cul-
tured rodent and human cells [18]. Although several previ-
ous studies analyzed the gene expression profiles of
hepatocyte cell line cells treated with TCDD using cDNA
microarray [10, 42] and gene expression profiling approach
to in vivo material using serial analysis of gene expression
(SAGE) [18], there are few reports on the expression of spe-
cific reactive genes against hepatotoxicity of TCDD.
Therefore, in this study to identify the specific genes
involved in hepatotoxicity and hepatocarcinogenesis
induced by TCDD, we analyzed the differences of gene
expression profile in the liver of AhR+/+ and AhR–/– mice.
MATERIALS AND METHODS
Chemical: TCDD (purity > 99%) was purchased from
*CORRESPONDENCE TO: LEE, B. J., Department of Veterinary Public
Health, College of Veterinary Medicine Chungbuk National Uni-
versity, Cheongju 361–763, Korea.

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C. Y. YOON ET AL.
664
Cerilliant Cambridge Isotope Laboratory, Inc. (Andover,
MA, U.S.A.). TCDD was dissolved in acetone and diluted
in corn oil as described [15].
Mice: 10-week-old C57BL/6 male mice (AhR+/+) and
B6.129-Ahrtm1Bra/J (AhR–/–) mice were purchased from
The Jackson Laboratory (Bar Harbor, MA, U.S.A.) and
were allowed 2 weeks for acclimatization. The mice were
housed in polyethylene cages containing wood shavings and
were given rodent chow and water ad libitum. Mice were
housed in rooms maintaining temperature of 21 ± 1°C,
humidity of 55 ± 5%, and a 12-hr light/dark cycle. The
experimental protocols were conducted in accordance with
internationally accepted principles for laboratory animal use
and care as found in the Korea Food and Drug Administra-
tion guidelines.
TCDD treatment and sample collection: Three mice of
each treatment group were injected i.p. with TCDD at the
dose of 100 µg/kg body weight. Control mice received the
vehicle alone. At 72 hr after TCDD treatment, blood sam-
ples were drawn from the animals at necropsy and activities
of alanine aminotransferase (ALT) and aspartate amino
transferase (AST) were measured using a clinical chemistry
analyzer (Bayer ADIVIA-120 hematology system, Tarry-
town, NY, U.S.A.). The terminal body weights and liver
weights were recorded. The left lateral lobe of the liver was
processed for histopathologic evaluation with H&E stain-
ing. Three small pieces of liver (approximately 20 mg) from
each mouse were stored at –20°C until use of RNA extrac-
tion (Ambion Inc, Austin TX, U.S.A.).
Extraction of total RNA: Each sample was placed into 1
ml of Trizol solution (Invitrogen, Carlsbad, CA, U.S.A.) and
homogenized with a polytron homogenizer (Wheaton,
Millville, NJ, U.S.A.). Total RNA was separated with
Qiagen RNeasy mini kit, according to the protocol
described by the manufacturer (Qiagen, Valencia, CA,
U.S.A.). The RNA quality was assessed by analyzing the
A260/A280 ratio (1.8 or above) and by evaluating the integ-
rity of the 28S and 18S RNA bands using an Agilent 2100
Bioanalyzer (Agilent Technology, Palo Alto, CA, U.S.A.).
Microarray analysis: First- and second-strand cDNA
synthesis, biotin-labeled cRNA synthesis, fragmentation of
cRNA and hybridization reactions were performed as a cus-
tomer service by Affymetrix Inc. (Santa Clara, CA, U.S.A.)
and detailed descriptions were found at the Web site, http://
www.affymetrix.com. Briefly, cDNA was synthesized
using an one-cycle cDNA synthesis kit from 10 µg of each
RNA sample. Labeled cRNA was synthesized from cDNA
using a GeneChip IVT labeling kit according to the manu-
facturer’s instructions. Approximately 20 µg cRNA was
then fragmented in a solution of 5 × fragmentation buffer
and RNase-free water at 94°C for 35 min. Labeled cRNA
was hybridized to the GeneChip Test 3 array (Cat. No.
Affymetrix 900341) to verify the quality of labeled cRNA.
Then cRNA was hybridized by filling with appropriate vol-
ume of the clarified hybridization cocktail to the Mouse
genome 430A 2.0 array (Cat. No. Affymetrix 900499). The
cRNA was hybridized for 16 hr at 45°C in the hybridization
oven 640 set to 60 rpm. After hybridization, the cocktail
from the probe array was removed. Then, the probe array
was completely washed with the appropriate volume of non-
stringent wash buffer and stained with streptavidin phyco-
erythrin (SAPE) using GeneChip fluidics station 450. The
probe array was scanned after the wash and staining proto-
cols with GeneChip Scanner 3,000.
Data analysis and clustering algorithm: For each of the
approximately 39,000 genes on the Affymetrix Mouse
genome 430A 2.0 array, the data of induction or repression
values were analyzed using Affymetrix software analysis
(GCOS and DMT). Cluster analysis for gene expression
was performed using Cluster 2.1.1 and ‘TreeView’ version
1.60 software supplied by Stanford University. The cluster-
ing was hierarchical using correlation distance as the mea-
surement.
RESULTS
TCDD-induced liver damage: In wild type AhR+/+ mice,
hepatomegaly was reflected by statistically significant
increases in relative liver weights at 100 µg/kg body weight
(Fig. 1). The relative liver weight in AhR+/+ mice was
increased by about 12.0% compared with the control. How-
ever, the relative liver weight in AhR –/– mice was appar-
ently unaffected. As compared with the control, the activity
of ALT in AhR–/– mice was significantly (p<0.05)
increased but that of AST was not significantly changed in
both AhR+/+ and AhR–/– mice (Fig. 2). The treatment of
TCDD at the dose of 100 µg/kg body weight caused little
change in histological examination after 72 hr in the liver of
both AhR+/+ and AhR–/– mice (figure not shown).
TCDD-induced gene expression changes in liver:
Microarray analysis was done to determine the hepatic gene
expression 72 hr after treatment with TCDD at the dose of
100 µg/kg body weight in AhR+/+ and AhR–/– mice. As
Fig. 1. Effects of TCDD on the relative liver weight in AhR+/+
and AhR–/– mice. Relative liver weight (%) was reported as a
proportion of total body weight at 72 hr after TCDD treatment at
the dose of 100 µg/kg body weight. Bars represent mean ± SD
(n=3). *Significantly different from the control at p<0.05.

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665
GENE EXPRESSION BY TCDD IN MOUSE LIVER
compared with AhR–/– mice, the expression of 51 genes
(>3-fold) was changed in AhR+/+ mice (Table 1); 28 genes
were induced, while 23 genes were repressed (Table 2). The
genes intensively up-regulated in only AhR+/+ mice com-
pared with AhR–/– knockout mice were Mcsp, Myc, Hspa2,
Atf3, Plcb2, S100a8, Ngp, Saa2, S100a8, S100a9, Cyp4f16,
Tnfrsf1b, Csf2rb2, Plcb2,Saa2, Adamdec1,Csf2rb2, Cdgap,
H2-D1, Cml5, Kcnq2, and Meig1 (Table 1). Meanwhile,
the genes intensively down-regulated in only AhR+/+ mice
as compared with AhR–/– mice were Slc13a2, Afmid, Csad,
1810073K19Rik, E130112L23Rik, Upk3b, Vamp1, Tieg1,
Erbb2ip, Ngfa, Cdc20, Cabyr, and Lect1 (Table 2).
DISCUSSION
To identify the specific genes related with AhR-mediated
TCDD hepatotoxicity we analyzed the differences of liver
gene expression induced by TCDD at the dose of 100 µg/kg
body weight in AhR+/+ and AhR–/– mice. We selected a 72
hr time-point for a variety of reasons. This time point would
provide for a complete gene induction response within the
liver without the complication of a significant secondary
inflammatory response (cellular infiltration) or fibrosis
likely to be encountered at later time points [38]. Although
histopathological evaluation was performed in our study,
apparent lesions in the liver were not observed. Meanwhile,
in our preliminary study the treatment of TCDD at the dose
of 150 µg/kg body weight caused an increase in the number
of apoptotic cells and inflammatory infiltrates in the liver of
C57BL/6 mice. In this study, TCDD treatment with 100 µg/
kg body weight resulted in a significant increase in the rela-
tive liver weight at 72 hr but no histopathological changes
were observed. These results are consistent with a recent
study that reported increases in liver weights but no alter-
ations in body weight after a single oral dose of TCDD at the
concentration up to 100–300 µg/kg [4].
In our study, the levels of enzymes decreased at 72 hr
after TCDD treatment in AhR+/+ mice, while increased in
AhR–/– mice. Fletcher et al. [9] also reported that TCDD
treatment caused a decrease in ALT at day 7 in male Spra-
gue-Dawley rats. Meanwhile, Boverhof et al. [4] reported
that a significant treatment related alteration were noted in
ALT and the levels increased steadily after 24 hr to a maxi-
mum of 2.6-fold at 168 hr, indicative of mild liver injury in
TCDD-treated immature ovarectomized female mice.
In our study, despite the absence of apparent histopatho-
logical lesions after treatment with TCDD, changes of gene
expression that might be indicative of changes in cellular
function were observed. Because of the placement of chlo-
rine atoms on the molecule, TCDD resists metabolic pro-
cessing and it persists within the cell and produces sustained
alterations in gene expression [28, 40]. We suspect that per-
sistence of TCDD is an important factor in producing
adverse effects. In our study, we compared the differences
of liver gene expression induced or repressed by TCDD
treatment between AhR+/+ and AhR–/– mice. The func-
tions of 28 genes intensively up-regulated (>3-fold) in only
AhR+/+ mice compared with AhR–/– knockout mice were
associated with maintenance and stabilization of spermato-
zoa mitochondria (Mcsp) [1], cell proliferation and transfor-
mation related with carcinogenesis (Myc) [14, 17], stress
response (Hspa2, Atf3, Plcb2) [2, 11], chemotaxis (S100a8)
[35], inflammatory response (Ngp, Saa2, S100a8, S100a9,
Cyp4f16, Tnfrsf1b, Csf2rb2, Plcb2) [6, 34, 35], acute-phase
response (Saa2) [34] and immune response
(Adamdec1,Csf2rb2, Cdgap, H2-D1) [3, 41], cell adhesion
(Cml5) [25], neuronal excitation (Kcnq2) [8], cell division
(Meig1) [33]. Meanwhile, the functions of 23 genes inten-
sively down-regulated (>3-fold) in only AhR+/+ mice were
associated with cell metabolism (Slc13a2, Afmid, Csad,
1810073K19Rik, E130112L23Rik, Upk3b) [16, 19, 23, 30],
nerve regeneration (Vamp1) [5], cell growth (Tieg1,
Erbb2ip, Ngfa) [21, 22], cell cycle (Cdc20) [32], testis-spe-
cific Ca2+-binding protein (Cabyr) [29] and inhibition of
Fig. 2. Effects of TCDD on aspatate aminotransferase (AST) and
alanine aminotransferase (ALT) levels in the serum of AhR+/+
and AhR–/– mice. Blood of mice was collected via retroorbital
sinus at 72 hr after TCDD treatment at the dose of 100 µg/kg
body weight. Bars represent mean ± SD (n=3). *Significantly
different from the control at p<0.05.

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C. Y. YOON ET AL.
666
tumor growth (Lect1) [12].
The results reported here suggest that toxicity may reflect
sustained alterations in the expression of many genes and
that the changes reflect both direct and indirect effects of
Table 1.
AhR+/+ mice in comparison with AhR–/– mice
Major genes induced at 72 hr after treatment of TCDD at the dose of 100 µg/kg body weight in
Probe Set ID Gene Title Gene SymbolFold change
1417101_at
1417944_at
1418358_at
1418722_at
1419075_s_at
1419203_at
1419394_s_at
1419476_at
1420800_a_at
1422988_at
1423410_at
1424811_at
1424942_a_at
1426597_s_at
1430172_a_at
1430173_x_at
1441115_at
1448296_x_at
1448756_at
1448951_at
1449233_at
1449360_at
1449363_at
1450162_at
1450255_at
1450412_at
1452481_at
1452544_x_at
heat shock protein 2
guanine nucleotide binding protein, gamma 4 subunit
mitochondrial capsule selenoprotein
neutrophilic granule protein
serum amyloid A 2
gene trap locus F3a
S100 calcium binding protein A8 (calgranulin A)
ADAM-like, decysin 1
potassium voltage-gated channel, subfamily Q, member 2 Kcnq2
N-sulfoglucosamine sulfohydrolase (sulfamidase)
meiosis expressed gene 1
camello-like 5
myelocytomatosis oncogene
expressed sequence C79267
cytochrome P450, family 4, subfamily f, polypeptide 16
cytochrome P450, family 4, subfamily f, polypeptide 16
DNA segment, Chr 18, ERATO Doi 232, expressed
Hspa2
Gng4
Mcsp
Ngp
Saa2
Gtlf3a
S100a8
Adamdec1
3.15
4.38
4.26
3.07
3.39
3.99
5.36
3.1
3.11
3.32
3.53
3.04
4.35
3.34
3.19
3.01
3.09
3.33
6.4
3.93
3.31
3.71
3.87
3.01
3.07
3.24
3.1
3.31
Sgsh
Meig1
Cml5
Myc
C79267
Cyp4f16
Cyp4f16
D18Ertd232e
S100 calcium binding protein A9 (calgranulin B)
tumor necrosis factor receptor superfamily, member 1b
muscle, intestine and stomach expression 1
colony stimulating factor 2 receptor, beta 2, low-affinity
activating transcription factor 3
D4, zinc and double PHD fingers, family 3
Cdc42 GTPase-activating protein
transducin (beta)-like 2
phospholipase C, beta 2
histocompatibility 2, D region locus 1
S100a9
Tnfrsf1b
Mist1
Csf2rb2
Atf3
Dpf3
Cdgap
Tbl2
Plcb2
H2-D1
Table 2.
AhR+/+ mice in comparison with AhR–/– mice
Major genes repressed at 72 hr after treatment of TCDD at the dose of 100 µg/kg body weight in
Probe Set ID Gene TitleGene Symbol Fold change
1416029_at
1417867_at
1418174_at
1418857_at
1419857_at
1420942_s_at
1421862_a_at
1423257_at
1427047_at
1427981_a_at
1424558_a_at
1431722_a_at
1436643_x_at
1436768_x_at
1438211_s_at
1439028_at
1439079_a_at
1439394_x_at
1450222_x_at
1452183_a_at
1454881_s_at
1456624_at
1460258_at
TGFB inducible early growth response 1
adipsin
D site albumin promoter binding protein
solute carrier family 13, member 2
Tieg1
Adn
Dbp
Slc13a2
–3.04
–4
–3.2
–3.15
–3.11
–3.02
–3.09
–7.73
–3.33
–3.1
–3.81
–3.33
–3.03
–3
–3.69
–3.3
–3.08
–3.09
–4.07
–7.17
–3.64
–3.05
–3.88
vesicle-associated membrane protein 1Vamp1
nucleoporin 188
cysteine sulfinic acid decarboxylase
calcium-binding tyrosine-(Y)-phosphorylation regulated
arylformamidase
RIKEN cDNA 1810073K19 gene
RIKEN cDNA E130112L23 gene
D site albumin promoter binding protein
Nup188
Csad
Cabyr
Afmid
1810073K19Rik
E130112L23Rik
Dbp
Erbb2 interacting protein
cell division cycle 20 homolog (S. cerevisiae)
nerve growth factor, alpha
GTL2, imprinted maternally expressed untranslated mRNA Gtl2
uroplakin 3B
DNA segment, Chr 11, ERATO Doi 498, expressed
leukocyte cell derived chemotaxin 1
Erbb2ip
Cdc20
Ngfa
Upk3b
D11Ertd498e
Lect1

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667
GENE EXPRESSION BY TCDD IN MOUSE LIVER
TCDD. Recently, several groups reported gene expression
profiles in vitro and in vivo models exposed to TCDD.
Using cDNA microarray technology, Frueh et al. (2001)
reported that numerous induced genes of human liver
HepG2 cell by TCDD treatment appear to have functions in
cell growth and proliferation, cell adhesion, antioxidative
activity, acute-phase responses, and these results may be
associated with maintaining homeostasis against TCDD
exposure. Using pathway-specific cDNA arrays to detect
the transcriptional signature induced by TCDD in C57BL/6
mice after intraperitoneal injection with 50 µg/kg body
weight of TCDD, TCDD altered the expression of a large
array of genes involved in apoptosis and angiogenesis [42].
The other experiment using serial analysis of gene expres-
sion (SAGE) technique revealed that in C57BL/6 mice the
genes involved in hepatotoxicity and hepatocarcinogenesis
induced by TCDD treatment with a single oral dose of 20
µg/kg body weight were not only the genes encoding drug
metabolizing enzymes and stress response genes but also a
wide variety of genes encoding cytoskeleton related pro-
teins, signal transduction, and plasma proteins [18].
Regarding the liver genes involved in xenobiotics metabo-
lism or stress response, signal transduction, cell cycle and
cell proliferation, the expression profiles of these studies
were mostly consistent with our results obtained by using
the oligonucleotide DNA microarray chip (Affymetrix) in
vivo mouse model.
In our study, the most significant gene changed by TCDD
in both AhR+/+ and AhR–/– knockout mice was Cyp1a1
which was up-regulated over 100-fold by TCDD, although
the change was not shown in our comparative data, indicat-
ing that the difference from change in gene expression by
TCDD between AhR+/+ mice and AhR–/– mice was less
than 3-fold. Most compounds that are known to induce
Cyp1a1 have been shown be the ligand for the AhR [39].
However, there are reports that Cyp1a1 induction can be
seen with compounds that are not apparent AhR ligands
based on their inability to compete with TCDD for receptor
binding [39]. In addition, there are different hypotheses
proposed for how Cyp1a1 could be induced by mechanisms
that do not involve in the AhR [7]. Based on the similarity
of effect of TCDD on Cyp1a1 expression of both AhR+/+
and AhR–/– mice, it is likely that there are other signaling
pathways for Cyp1a1 induction though more studies would
be required to conclusively understand those.
Overall, the results of our study imply that cellular
responses to TCDD is notably complex and is associated
with alterations in the expression of a large array of genes,
and can provide a fingerprint genes that may help to clarify
the mechanism of TCDD effects on hepatic genotoxicity
and carcinogenesis.
ACKNOWLEDGMENT. This work was financially sup-
ported by the Korea Food and Drug Administration Grant
KFDA-04131-EDS-299.
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