Dioxin, 2,3,7,8-tetrachlorodibenzo-p[ara]-dioxin (TCDD), is the
nongenotoxic (it does not directly affect DNA) cancer promoting
chemical in Agent Orange. It acts by binding to aromatic hydrocarbon
receptors (AHr) in the body, which, at a certain level of saturation,
cause other chemical reactions to take place that induce cancers.
Kidney cancer cells (renal carcinomas) have been shown experimentally
to behave in the same manner as other cancers with respect to dioxin
and AHr binding.
A Comparison of Dioxin Risk Characterizations
The Chlorine Chemistry Council
May 2002
http://www.dioxinfacts.org/dioxin_health/dr.pdf
[cited in the above]
Randerath, K., Putman, K.L., Randerath, E., et al. (1988).
Organ-specific effects of long-term feeding of
2,3,7,8-tetrachlorodibenzo-p-dioxin and
1,2,3,7,8-pentachlorodibenzo-p-dioxin on I-compounds in hepatic and
renal DNA of female Sprague-Dawley rats. Carcinogenesis 9, p. 2285-89.
DISCUSSION OF AHr-DIOXIN BINDING
9. TOXIC EQUIVALENCY FACTORS (TEFs) FOR DIOXIN AND RELATED COMPOUNDS
[DRAFT]
http://www.epa.gov/nceawww1/pdfs/dioxin/part2/drich9.pdf
"9.3.2. The Role of the AhR in the Toxicity of Dioxin-Like Compounds
The general basis for the TEF scheme is the observation that the AhR
mediates most if not all of the dioxin-like biological and toxic
effects induced by compounds included in the TEF scheme (Safe, 1990;
Okey et al., 1994; Birnbaum, 1994; Hankinson, 1995). Binding to the
receptor is necessary, but not sufficient, to generate the wide
variety of toxic effects caused by dioxin-like HAHs (Sewall and
Lucier, 1995; De Vito and Birnbaum, 1995) (for additional review
references, see Part II, Chapter 2). There are several lines of
evidence that the Ah receptor is important in the toxicity of the
dioxin-like compounds."
[...]
"There are several lines of evidence suggesting that the AhR is an
important factor in developmental and homoeostatic processes. The AhR
is a ligand-activated transcription factor that is a member of the
basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily. The
bHLH-PAS superfamily consists of a growing list of at least 32
proteins found in diverse organisms such as Drosophila, C. elegans,
and humans. Many of these proteins are transcription factors that
require either hetero- or homodimerization for functionality. These
proteins regulate circadian rhythms (per and clock) and steroid
receptor signaling (SRC-1, TIF2, RAC3) and are involved in sensing
oxygen tension (Hif-1, EPAS-1/HLF) (Hahn, 1998). The AhR is also a
highly conserved protein that is present in all vertebrate classes
examined, including modern representatives of early vertebrates such
as cartilaginous and jawless fish (Hahn, 1998). In addition, an AhR
homologue has been identified in C. elegans (Powell-Coffman et al.,
1998). The classification of the AhR as part of the bHLH-PAS
superfamily and its evolutionary conservation imply that this protein
may play an important role in normal physiological function. It has
been proposed that understanding the function of the bHLH-PAS family
of proteins and the phylogenetic evolution of the AhR may lead to an
understanding of the role of this protein in normal processes (Hahn,
1998)."
J Steroid Biochem Mol Biol 1997 Jun;62(2-3):223-32
Induction of cytochrome P450 1B1 and catechol estrogen metabolism in
ACHN human renal adenocarcinoma cells.
Spink DC, Spink BC, Cao JQ, Gierthy JF, Hayes CL, Li Y, Sutter TR.
Wadsworth Center, New York State Department of Health, Albany, NY
12201-0509, U.S.A.
The catechol estrogen metabolites of 17beta-estradiol (E2),
2-hydroxyestradiol (OHE2) and 4-OHE2, differ in hormonal properties
and carcinogenic potential. In Syrian hamster kidney, 4-OHE2 induces
clear-cell carcinoma whereas 2-OHE2 does not, and an E2 4-hydroxylase
appears to be involved in E2-induced carcinogenesis in these animals.
Specific E2 4-hydroxylase activity has been observed in extrahepatic
tissues from several species. In humans, cytochrome P450 1B1 (CYP1B1)
appears to be an extrahepatic E2 4-hydroxylase under the regulatory
control of the aromatic hydrocarbon receptor (AhR). As an initial
approach to investigating CYP1B1 expression and E2 4-hydroxylase
activity in human kidney, we used the ACHN cell line, derived from a
human renal adenocarcinoma. In untreated ACHN cells, a very low level
of CYP1B1 mRNA expression was observed and CYP1B1 protein could not be
detected; however, in ACHN cells exposed to the high-affinity AhR
ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), CYP1B1 mRNA levels
were elevated 28-fold, and the CYP1B1 protein was detected by
immunoblot analysis. Exposure of ACHN cells to TCDD resulted in
minimal induction of the CYP1A1 mRNA, and the CYP1A1 protein was not
detectable prior to or after exposure to TCDD. E2 hydroxylase activity
could not be detected with microsomes from untreated ACHN cells,
although activities at C-4 and, to a lesser extent, at C-2 of E2 were
observed with microsomes from TCDD-treated ACHN cells. In experiments
with intact ACHN cells, elevated rates of formation of
4-methoxyestradiol (MeOE2) and 2-MeOE2 were observed in response to
treatment with TCDD. The EC50 for induction of the CYP1B1 mRNA was 1.5
nM TCDD; EC50s for the stimulation of 2- and 4-MeOE2 formation were
0.68 and 1.1 nM TCDD. These results indicate that the ACHN cell line
may be a useful in vitro model system to study the regulation of
CYP1B1 expression and the cytotoxic effects associated with E2
4-hydroxylation.
PMID: 9393958 [PubMed - indexed for MEDLINE]
Environ Health Perspect 1996 Mar;104 Suppl 1:123-34
Implications for risk assessment of suggested nongenotoxic mechanisms
of chemical carcinogenesis.
Melnick RL, Kohn MC, Portier CJ.
Laboratory of Quantitative and Computational Biology, National
Institute of Environmental Health Sciences, Research Triangle Park,
North Carolina 27709, USA.
Nongenotoxic carcinogens are chemicals that induce neoplasia without
it or its metabolites reacting directly with DNA. Chemicals classified
as nongenotoxic carcinogens have been assumed to act as tumor
promoters and exhibit threshold tumor dose-responses. This is in
contrast to genotoxic carcinogens that are DNA reactive, act as tumor
initiators, and are assumed to exhibit proportional responses at low
doses. In this perspective, we examine the basic tenets and utility of
this classification for evaluating human cancer risk. Two classes of
so-called nongenotoxic chemical carcinogens selected for review
include cytotoxic agents that induce regenerative hyperplasia
(trihalomethanes and inducers of alpha 2-microglobulin nephropathy)
and agents that act via receptor-mediated mechanisms (peroxisome
proliferators and dioxin). Major conclusions of this review include:
a) many chemicals considered to be nongenotoxic carcinogens actually
possess certain genotoxic activities, and limiting evaluations of
carcinogenicity to their nongenotoxic effects can be misleading; b)
some nongenotoxic activities may cause oxidative DNA damage and
thereby initiate carcinogenesis; c) although cell replication is
involved in tumor development, cytotoxicity and mitogenesis do not
reliably predict carcinogenesis; d) a threshold tumor response is not
an inevitable result of a receptor-mediated mechanism. There are
insufficient data on the chemicals reviewed here to justify treating
their carcinogenic effects in animals as irrelevant for evaluating
human risk. Research findings that characterize the multiple
mechanisms of chemical carcinogenesis should be used quantitatively to
clarify human dose-response relationships, leading to improved
scientifically based public health decisions. Excessive reliance on
oversimplified classification schemes that do not consider all
potential contributing effects of a toxicant can obscure the actual
causal relationships between exposure and cancer outcome.
Publication Types: Review
Review, Tutorial PMID: 8722116 [PubMed - indexed for MEDLINE]
Arch Toxicol 2002 Jun;76(5-6):287-98
Induction of CYP1A1, CYP1A2, and CYP1B1 mRNAs by nitropolycyclic
aromatic hydrocarbons in various human tissue-derived cells:
chemical-, cytochrome P450 isoform-, and cell-specific differences.
Iwanari M, Nakajima M, Kizu R, Hayakawa K, Yokoi T.
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences,
Kanazawa University, Takara-machi 13-1, Kanazawa 920-0934, Japan.
Nitropolycyclic aromatic hydrocarbons (NPAHs) are found in diesel
exhaust and ambient air. NPAHs as well as polycyclic aromatic
hydrocarbons (PAHs) are known to have mutagenicity, carcinogenicity,
and endocrine-disruptive effects. In the present study, the
inducibility of the human cytochrome P450-1 (CYP1) family by NPAHs was
compared with those produced by their parent PAHs and some reductive
metabolites, amino-PAHs. Furthermore, to investigate the differences
in the inducibility of the CYP1 family in human tissues, various human
tissue-derived cell lines, namely HepG2 (hepatocellular carcinoma),
ACHN (renal carcinoma), A549 (lung carcinoma), MCF-7 (breast
carcinoma), LS-180 (colon carcinoma), HT-1197 (bladder carcinoma),
HeLa (cervix of uterus adenocarcinoma), OMC-3 (ovarian carcinoma), and
NEC14 (testis embryonal carcinoma), were treated with NPAHs, PAHs, or
amino-PAHs. The mRNA levels of CYP1A1, CYP1A2, and CYP1B1 were
determined with reverse transcription-polymerase chain reaction
(RT-PCR). The cell lines were classified into two groups: CYP1
inducible cell lines, comprising HepG2, MCF-7, LS-180, and OMC-3
cells, and CYP1 non-inducible cell lines, comprising ACHN, A549,
HT-1197, HeLa, and NEC14 cells. In inducible cell lines, the induction
profile of chemical specificity was similar for CYP1A1, CYP1A2, and
CYP1B1, although the extent of induction differed among the cell lines
and for the CYP isoforms. Pyrene, 1-nitropyrene, 1-aminopyrene, 1,3-,
1,6-, and 1,8-dinitropyrenes slightly induced CYP1 mRNAs, but
1,3-dinitropyrene produced a 6-fold induction of CYP1A1 mRNA in MCF-7
cells. 2-Nitrofluoranthene and 3-nitrofluoranthene exhibited stronger
inducibility than fluoranthene in the inducible cell lines.
6-Nitrochrysene induced CYP1 mRNAs to the same extent or more potently
than chrysene. The induction potencies of 6-nitrobenzo[ a]pyrene and
7-nitrobenz[ a]anthracene were weaker than those of their parents
benzo[ a]pyrene and benz[ a]anthracene, respectively. This study
demonstrated that NPAHs as well as PAHs induced human CYP1A1, CYP1A2,
and CYP1B1 in a chemical-, CYP isoform-, and cell-specific manner.
Furthermore, the cell-specific induction of the CYP1 family was not
related to the expression levels of aryl hydrocarbon receptor, aryl
hydrocarbon nuclear translocator, or estrogen receptors alpha and
beta.
PMID: 12107646 [PubMed - indexed for MEDLINE]
Biochem Pharmacol 1985 Aug 1;34(15):2721-31
Comparison of aryl hydrocarbon hydroxylase and acetanilide
4-hydroxylase induction by polycyclic aromatic compounds in human and
mouse cell lines.
Jaiswal AK, Nebert DW, Eisen HW.
The human MCF-7 and the mouse Hepa-1 cell culture lines were compared
for aryl hydrocarbon hydroxylase and acetanilide 4-hydroxylase
inducibility by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and
benzo[a]anthracene (BA) and TCDD- and BA-specific binding in the
cytosol and nucleus. The effective concentration of BA in the growth
medium required to induce either enzyme to 50% of its maximally
inducible activity (EC50) was the same (5-11 microM) in both MCF-7 and
Hepa-1 cells. On the other hand, the EC50 for TCDD in MCF-7 cells
(5-25 nM) was more than 40-fold greater than that in Hepa-1 cells (0.4
to 0.6 nM). P1-450- and P3-450-specific mouse cDNA probes were used to
quantitate mRNA induction in the Hepa-1 cell line. P1-450 mRNA was
induced markedly by TCDD and benzo[a] anthracene, whereas P3-450 mRNA
was induced negligibly. A P1-450-specific human cDNA probe was used to
quantitate P1-450 mRNA induction in the MCF-7 cell line. Aryl
hydrocarbon hydroxylase inducibility by TCDD or BA always paralleled
P1-450 mRNA inducibility in either the mouse or human line. Although
the cytosolic Ah receptor in Hepa-1 cells was easily detected by
sucrose density gradient centrifugation, gel permeation
chromatography, and anion-exchange high-performance liquid
chromatography, the cytosolic receptor cannot be detected in MCF-7
cells. Following in vivo exposure of cultures to radiolabeled TCDD,
the intranuclear concentration of inducer-receptor complex was at
least fifty times greater in Hepa-1 than MCF-7 cultures. The complete
lack of measurable cytosolic receptor and almost totally absent
inducer-receptor complex in the nucleus of MCF-7 cells was, therefore,
out of proportion to its capacity for aryl hydrocarbon hydroxylase and
acetanilide 4-hydroxylase inducibility. This MCF-7 line should provide
an interesting model for a better understanding of the mechanisms of
drug-metabolizing enzyme induction by polycyclic aromatic compounds,
including the Ah receptor-mediated mechanism.
PMID: 2990496 [PubMed - indexed for MEDLINE]
J Biol Chem 2002 Mar 1;277(9):6949-59 (See below for link to full
article.)
Regulatory interactions among three members of the vertebrate aryl
hydrocarbon receptor family: AHR repressor, AHR1, and AHR2.
Karchner SI, Franks DG, Powell WH, Hahn ME.
Biology Department, Woods Hole Oceanographic Institution, Woods Hole,
MA 02543, USA.
The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related
compounds occur via the aryl hydrocarbon receptor (AHR), a member of
the basic helix-loop-helix-Per-ARNT-Sim homology (bHLH-PAS) protein
superfamily. A single AHR gene has been identified in mammals, whereas
many fish species, including the Atlantic killifish (Fundulus
heteroclitus) possess two distinct AHR genes (AHR1 and a novel form,
AHR2). A mouse bHLH-PAS protein closely related to AHR and designated
AHR repressor (AHRR) is induced by 3-methylcholanthrene and represses
the transcriptional activity of the AHR. To determine whether AHRR is
the mammalian ortholog of fish AHR2 and to investigate the mechanisms
by which AHRR regulates AHR function, we cloned an AHRR ortholog in F.
heteroclitus with high sequence identity to the mouse and human AHRRs.
Killifish AHRR encodes a 680-residue protein with a predicted
molecular mass of 75.2 kDa. We show that in vitro expressed AHRR
proteins from human, mouse, and killifish all fail to bind [(3)H]TCDD
or [(3)H]beta-naphthoflavone. In transient transfection experiments
using a luciferase reporter gene under control of AHR response
elements, killifish AHRR inhibited the TCDD-dependent transactivation
function of both AHR1 and AHR2. AHRR mRNA is widely expressed in
killifish tissues and is inducible by TCDD or polychlorinated
biphenyls, but its expression is not altered in a population of fish
exhibiting genetic resistance to these compounds. The F. heteroclitus
AHRR promoter contains three putative AHR response elements. Both AHR1
and AHR2 activated transcription of luciferase driven by the AHRR
promoter, and AHRR could repress its own promoter. Thus, AHRR is an
evolutionarily conserved, TCDD-inducible repressor of AHR1 and AHR2
function. Phylogenetic analysis shows that AHRR, AHR1, and AHR2 are
distinct genes, members of an AHR gene family; these three vertebrate
AHR-like genes descended from a single invertebrate AHR.
PMID: 11742002 [PubMed - indexed for MEDLINE]
Arch Biochem Biophys 1987 Feb 15;253(1):233-40
Transcriptional control of human cytochrome P1-450 gene expression by
2,3,7,8-tetrachlorodibenzo-p-dioxin in human tissue culture cell
lines.
Cresteil T, Jaiswal AK, Eisen HJ.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces aryl hydrocarbon
hydroxylase (AHH) activity and human cytochrome P1-450 mRNA in the
human breast carcinoma MCF-7 and hepatoblastoma HepG2 tissue culture
cell lines. Although AHH activities induced by 100 nM TCDD are
comparable in these cell lines, the EC50 values for TCDD differ: EC50
approximately equal to 1 nM for HepG2; EC50 greater than 20 nM for
MCF-7. In order to determine the mechanism responsible for this
difference in EC50, we have examined putative regulatory factors such
as the intracellular TCDD receptor as well as the kinetics of mRNA
transcription and accumulation in these cells. TCDD increases
transcription of hP(1)450 mRNA in both MCF-7 and HepG2 cells; however,
MCF-7 cells require higher concentrations of TCDD to produce
transcriptional activation comparable to that observed for HepG2
cells. These data indicate that the difference in EC50 is determined
at an early step in the induction of hP(1)450 mRNA. With the use of a
sensitive assay based on high-performance anion-exchange liquid
chromatography, an intracellular protein which binds TCDD with high
affinity was detected in HepG2 cytosolic fractions but not in MCF-7
cells. Thus, the difference in EC50 for TCDD can be correlated to the
differences in TCDD binding. We postulate that MCF-7 cells contain a
"defective" receptor with decreased affinity for TCDD.
PMID: 3813564 [PubMed - indexed for MEDLINE]
Biochem Biophys Res Commun 1997 Dec 8;241(1):86-91
Transforming growth factor-beta1 coregulates mRNA expression of aryl
hydrocarbon receptor and cell-cycle-regulating genes in human cancer
cell lines.
Dohr O, Abel J.
Department of Toxicology, Heinrich-Heine-University of Dusseldorf,
Auf'm Hennekamp 50, Dusseldorf, 40225, Germany.
Transforming growth factor (TGF)-beta1 down-regulates mRNA expression
of the aryl hydrocarbon receptor (AhR) and of AhR-inducible genes in
A549 cells. Here, we describe a dose-dependent inhibition of
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cytochrome P450
(CYP) 1A1, CYP1B1 and NADPH-quinone-oxidoreductase (NMO-1) mRNA
expression as well as TCDD-induced 7-ethoxyresorufin-O-deethylase
(EROD) activity in MDA-MB 231 cells. The AhR mRNA expression was not
affected by TGF-beta1. TGF-beta-responsiveness was investigated by
examining the effect on the expression of responsive genes. While
TGF-beta1 up-regulates mRNA expression of TGF-beta1 and TIEG
(TGF-beta-inducible early gene) as well as luciferase activity of a
responsive reporter plasmid in both cell lines, a down-regulation of
c-myc and cyclin A mRNA expression was only found in A549 cells.
Furthermore, TGF-beta1 inhibits only cell proliferation of A549 but
not of MDA-MB 231 cells. The results show a coregulation of mRNA
expression of AhR and cell-cycle regulating genes, and further
indicate that the AhR may be involved in regulation of cell
proliferation. Copyright 1997 Academic Press.
PMID: 9405238 [PubMed - indexed for MEDLINE]
Toxicol Sci 2003 Apr;72(2):253-9
Expression of aryl hydrocarbon receptor repressor in normal human
tissues and inducibility by polycyclic aromatic hydrocarbons in human
tumor-derived cell lines.
Tsuchiya Y, Nakajima M, Itoh S, Iwanari M, Yokoi T.
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences,
Kanazawa University, Takara-machi 13-1, Kanazawa 920-0934, Japan.
Aryl hydrocarbon receptor repressor (AhRR) has been recently
identified as a negative factor that suppresses aryl hydrocarbon
receptor (AhR)-mediated transcriptional gene expression. In the
present study, the expression level of AhRR in normal human tissues
was determined. AhRR mRNA was detected in liver, breast, colon,
kidney, lung, bladder, uterus, testis, ovary, and adrenal gland. The
expression level in the testis was prominently high. AhRR mRNA was
also detected in various human tissue-derived cell lines, HepG2
(hepatocellular carcinoma), MCF-7 (breast carcinoma), LS-180 (colon
carcinoma), ACHN (renal carcinoma), A549 (lung carcinoma), HT-1197
(bladder carcinoma), HeLa (cervix of uterus adenocarcinoma), NEC14
(testis embryonal carcinoma), and OMC-3 (ovarian carcinoma). Since the
expression level of AhRR mRNA was prominently high in HeLa cells, it
is suggested that the high expression level of AhRR might work as a
negative factor for the low inducibility of the CYP1 family in HeLa
cells. The expression of AhRR mRNA was induced by
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3-methylchoranthrene
(3-MC) in HepG2, MCF-7, LS-180, and OMC-3 cells, but not in ACHN,
A549, HT-1197, HeLa, and NEC14 cells. The responsiveness was similar
to the cell-specific inducibility of the CYP1 family. The inducibility
of AhRR mRNA by nitropolycyclic aromatic hydrocarbons (NPAHs) as well
as their parent PAHs was compared in HepG2 and OMC-3 cells. The
chemical-specific inducibility of AhRR was also similar to that of the
CYP1 family determined in our previous study. These results indicated
that AhRR is also induced in chemical- and cell-specific manners.
PMID: 12655030 [PubMed - in process]
J. Biol. Chem., Vol. 277, Issue 9, 6949-6959, March 1, 2002
Regulatory Interactions among Three Members of the Vertebrate Aryl
Hydrocarbon Receptor Family: AHR Repressor, AHR1, and AHR2*
Sibel I. Karchner, Diana G. Franks, Wade H. Powell[Dagger],
and Mark E. Hahn§
From the Biology Department, Woods Hole Oceanographic Institution,
Woods Hole, Massachusetts 02543
http://www.jbc.org/cgi/content/full/277/9/6949
"ABSTRACT
The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related
compounds occur via the aryl hydrocarbon receptor (AHR), a member of
the basic helix-loop-helix-Per-ARNT-Sim homology (bHLH-PAS) protein
superfamily. A single AHR gene has been identified in mammals, whereas
many fish species, including the Atlantic killifish (Fundulus
heteroclitus) possess two distinct AHR genes (AHR1 and a novel form,
AHR2). A mouse bHLH-PAS protein closely related to AHR and designated
AHR repressor (AHRR) is induced by 3-methylcholanthrene and represses
the transcriptional activity of the AHR. To determine whether AHRR is
the mammalian ortholog of fish AHR2 and to investigate the mechanisms
by which AHRR regulates AHR function, we cloned an AHRR ortholog in F.
heteroclitus with high sequence identity to the mouse and human AHRRs.
Killifish AHRR encodes a 680-residue protein with a predicted
molecular mass of 75.2 kDa. We show that in vitro expressed AHRR
proteins from human, mouse, and killifish all fail to bind [3H]TCDD or
[3H] [beta ]-naphthoflavone. In transient transfection experiments
using a luciferase reporter gene under control of AHR response
elements, killifish AHRR inhibited the TCDD-dependent transactivation
function of both AHR1 and AHR2. AHRR mRNA is widely expressed in
killifish tissues and is inducible by TCDD or polychlorinated
biphenyls, but its expression is not altered in a population of fish
exhibiting genetic resistance to these compounds. The F. heteroclitus
AHRR promoter contains three putative AHR response elements. Both AHR1
and AHR2 activated transcription of luciferase driven by the AHRR
promoter, and AHRR could repress its own promoter. Thus, AHRR is an
evolutionarily conserved, TCDD-inducible repressor of AHR1 and AHR2
function. Phylogenetic analysis shows that AHRR, AHR1, and AHR2 are
distinct genes, members of an AHR gene family; these three vertebrate
AHR-like genes descended from a single invertebrate AHR.
INTRODUCTION
The AHR1 is a ligand-activated transcription factor through which TCDD
and other polyhalogenated and polycyclic aromatic hydrocarbons cause
altered gene expression and toxicity (1-3). When activated by ligand
binding, the AHR forms a complex with ARNT that regulates the
expression of target genes by interacting with AHR response elements
(AHREs; also known as xenobiotic response elements or dioxin response
elements)2 (4). The AHR may also possess physiological functions that
are independent of exogenous chemical exposure (5-7)."
[...]
"Fig. 9. AHRR tissue-specific expression pattern in dioxin-sensitive
and dioxin-resistant populations of F. heteroclitus. Shown are (38K):
ethidium bromide-stained gels of RT-PCR products for AHRR and actin
from the indicated tissues of adult killifish from Scorton Creek
(dioxin-sensitive) or New Bedford Harbor (dioxin-resistant). PCRs were
performed under conditions in which formation of product was linearly
related to cycle number and amount of input cDNA. The abbreviations
indicate tissue source of RNA: B, brain; Gi, gill; K, kidney; O,
ovary; S, spleen; Gu, gut; L, liver; H, heart. Additional details
concerning these fish, including expression of AHR1, AHR2, ARNT2, and
CYP1A, can be found elsewhere (28, 29)."
EPIDEMIOLOGICAL STUDY
Environmental Health Monthly
Vol. 10 No. 8-9 May-June, 1998
http://www.chej.org/EHM/MayJun98.htm
"One of the key studies relied upon by IARC was an international
cohort of workers exposed to phenoxy herbicides and chlorophenols that
was set up by IARC in association with the U.S.’s National Institute
for Environmental Health Sciences (NIEHS). This study included 21,863
workers in 36 cohorts from 12 countries who were followed from 1939 to
1992. Each worker was placed in one of three exposure groups relative
to TCDD or higher PCDDs: 1) exposed; 2) not exposed or 3) unknown
exposure. This study found that for workers exposed to TCDD or higher
PCDDs, cancer mortality was elevated for soft-tissue sarcoma and that
mortality from all cancers combined, lung cancer, and non-Hodgkin’s
lymphoma was slightly increased. Risk for all cancers, for sacomas and
for lymphomas increased with time since first exposure to herbicides
contaminated with dioxins. Kidney cancer was among the cancers showing
an overall statistically significant increase in mortality."
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