Mechanisms of Exocrine Pancreatic Toxicity Induced by Oral
Treatment with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin in Female Harlan
Katsuhiko Yoshizawa,* Tiwanda Marsh,* Julie F. Foley,* Bo Cai,† Shyamal Peddada,† Nigel J. Walker,‡
and Abraham Nyska*,1
*Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709;
†Biostatistics Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709; ‡Laboratory of Computational
Biology and Risk Analysis, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709
Received December 7, 2004; accepted February 12, 2005
In previous 2-year studies of 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) conducted by the National Toxicology Program
on female Harlan Sprague-Dawley rats, acinar-cell vacuolation,
atrophy, inflammation, and arteritis developed at high incidence,
and a rare occurrence of pancreatic acinar-cell adenomas and
carcinomas was noted. In this investigation, we sought to identify
the mechanism involved in the early formative stages of acinar-
cell lesions. Pancreas from animals treated for 14 and 31 weeks
with 100 ng TCDD/kg body weight or corn oil vehicle was exam-
ined immunohistochemically and/or morphometrically. Acinar-
cell kinetics were analyzed using staining with hematoxylin and
eosin and proliferating cell nuclear antigen. Expressions of
cytochrome P450 (CYP) 1A1 and aryl hydrocarbon receptor
(AhR) were evaluated to assess direct effects of TCDD exposure.
The cholecystokinin-A receptor (CCK-A receptor; CCKAR) and
duodenal cholecystokinin 8 (CCK) revealed the associations of
dioxin treatment with hormonal changes. Amylase localization
showed acinar structural changes that could affect enzymatic
production. Increased apoptotic activity in acinar cells occurred in
14- and 31-week-treated animals, with an increase in proliferative
activity in the latter. Also in the latter, in the vacuolated acinar
cells, CYP1A1 was overexpressed, and statistically significant
decreases in expressions of AhR, CCKAR, and amylase occurred.
The intensity of CCKAR expression increased in nonvacuolated
acinar cells; a decrease in the size of CCK-positive epithelial cells
occurred in duodenum. Our findings indicate that dioxin-induced
acinar-cell lesions might be related to a direct effect of TCDD on
the pancreas. Increase in CYP1A1 and decrease in CCKAR
expressions in vacuolated acinar cells may be involved in the
pathogenesis of pancreatic lesions. Changes in the expression of
CYP or CCKAR may have induced the acinar-cell tumors by
Key Words: acinarcells;dioxin;immunohistochemistry;pancreas;
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), commonly
referred to as dioxin, is an environmental contaminant that is
known for its extreme toxic potency. Certain polychlorinated
(PCDFs), and coplanar polychlorinated biphenyls (PCBs)
exhibiting biologic actions similar to those of TCDD have
been commonly designated dioxin-like compounds (DLCs).
They may induce developmental, endocrine, and immunolog-
ical toxicity and multiorgan carcinogenicity in animals and/or
humans (ATSDR, 1998; Bertazzi et al., 2001; Kociba et al.,
1978; Steenland et al., 1999, 2001). Incidences of cancer have
been evaluated in several analyses of human populations
exposed to elevated amounts of dioxin and DLCs. The most
recent studies indicate that exposure is associated with an
increase in all cancers combined and several specific cancers
including rectal cancer, lung cancer, Hodgkin disease, non-
Hodgkin lymphoma, and myeloid leukemia, as well as chronic
(ATSDR, 1998; Bertazzi et al., 2001).
Recently, the National Toxicology Program (NTP) con-
ducted 2-year bioassays in female rats to evaluate the chronic
pathology and carcinogenicity induced by dioxin, DLCs,
structurally related PCBs, and mixtures of these compounds,
including TCDD; 3,3#,4,4#,5-pentachlorobiphenyl (PCB126);
2,3,4,7,8-pentachloro-dibenzifyran (PeCDF); 2,2#,4,4#,5,5#-
hexachlorobiphenyl (PCB153); the toxic equivalency factor
(TEF) tertiary mixture of TCDD, PCB126, and PeCDF; and the
binary mixtures of PCB126 and 153 and PCB126 and
2,3#,4,4#,5-pentachlorobiphenyl (PCB118) (National Toxicol-
ogy Program, 2004a, 2004b, 2004c, 2004d, 2004e, 2004f,
2004g). In these studies, an increase occurred in the incidence
of neoplastic effects, such as cholangiocarcinoma and/or
hepatocellular adenoma of the liver, cystic keratinizing epi-
thelioma of the lung, and gingival squamous-cell carcinoma of
the oral cavity (Brix et al., 2004; Jokinen et al., 2003; National
1To whom correspondence should be addressed at NIEHS, P.O. Box 12233,
Mail Drop B3-06, 111 T. W. Alexander Drive, Research Triangle Park, NC
27709. Fax: (919) 541-7666. E-mail: firstname.lastname@example.org.
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TOXICOLOGICAL SCIENCES 85, 594–606 (2005)
Advance Access publication February 16, 2005
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Toxicology Program, 2004a, 2004b, 2004c, 2004d, 2004e,
2004f, 2004g; Tani et al., 2004; Walker et al., 2004; Yoshizawa
et al., 2005). Pancreatic toxicities, such as acinar cytoplasmic
vacuolation, atrophy, inflammation, and arteritis have been
seen at high incidence combined with a rare occurrence of
acinar-cell adenomas and carcinomas (Nyska et al., 2004).
Aryl hydrocarbon receptor (AhR) is a ligand-activated
transcription factor that mediates the biological and toxicolog-
ical effects of TCDD and related DLCs (Denison and Nagy,
2003; Poland and Knutson, 1982; Schmidt and Bradfield,
1996). It is expressed ubiquitously in human and rodent
systemic organs, particularly in the pancreas (Dolwick et al.,
1993; Yamamoto et al., 2004). That most organs with AhR
expression are thought to be more susceptible to TCDD-
induced toxicity is evidenced by AhR-deficient mice that are
resistant to some kinds of TCDD-induced toxicity (Fernandez-
Salguero et al., 1996; Gonzalez and Fernandez-Salguero,
1998). No reports are available regarding the relationship of
exocrine pancreatic toxicity and change in AhR expression
after TCDD treatment in rats. The most well-studied response
to TCDD is induction of the CYP 1A1 and 1B1 classes of
cytochrome P450 (Denison and Nagy, 2003; Schmidt and
Bradfield, 1996; Toyoshiba et al., 2004) regulated by the AhR
(Nebert et al., 2004); their inductions, especially that of
CYP1A1, are sensitive to TCDD and thus serve as useful
markers for exposure to TCDD. These enzymes play a major
role in the activation and deactivation of toxins and carcino-
gens. The susceptibility to pancreatic disease seems to depend
on the integrity of the cellular detoxification process governed
by these drug-metabolizing enzymes (Standop et al., 2002,
2003; Ulrich et al., 2002). Differences in immunohistochem-
ical expression of CYPs, such as 1A1, 1A2, 2B6, 2D6, and/or
3A1 among normal pancreas, chronic pancreatitis, and pan-
creatic tumors have been reported (Foster et al., 1993; Standop
et al., 2003); the possibility of an etiological relationship
between elevated levels of CYPs and the subsequent de-
velopment of human pancreatic diseases has been highlighted.
In tissues derived from the previous NTP oral-treatment
studies of TCDD; PCB 126; PeCDF; a tertiary mixture of
TCDD, PCB126, and PeCDF and a binary mixture of PCB126
and PCB153, duodenal levels of stored cholecystokinin (CCK)
peptide decreased prominently (Lee et al., 2000). Cholecysto-
kinin, regarded as the major hormonal mediator of pancreatic
enzymatic production, assessed chiefly by levels of amylase, is
secreted by the proximal small intestine under the control of
a negative feedback loop (Bourassa et al., 1999; Furukawa
et al., 2001; Haschek and Rousseaux, 1998; Wank, 1995). The
peripheral receptors can be classified pharmacologically as
CCKA receptor (CCKAR), expressed predominately in pan-
creas, and as CCKB receptor (CCKBR), localized chiefly in the
central nervous system (Monstein et al., 1996; Tang et al.,
1996; Wank, 1995). Cholecystokinin induces secretion of
pancreatic enzymes and synthesis of protein and DNA in the
rat acinar cell through its CCKAR (Varga et al., 1998; Wank,
1995). Continuous blocking of this receptor by CCK inhibitors
causes atrophic changes (Biederbick and Elsa ¨sser, 1998;
Ohlsson et al., 1995). The close relationship between the
expression of the CCKAR and pancreatic disease has been
shown experimentally in several models, such as azaserine- or
caerulein-induced pancreatitis and cancer (Bourassa et al.,
1999; Gebhardt et al., 2004; Meijers et al., 1992; Roebuck
et al., 1987). The pathogenesis of exocrine pancreatic toxicity
induced by TCDD has not been clarified.
Taking this information into consideration, we investigated
the potential pathways involved in the TCDD-induced acinar
pancreatic pathology. Hypothesizing that the early changes in
AhR, CYP1A1, and CCK-related proteins in acinar cells after
treatment with TCDD might be related to induction of toxicity
in exocrine pancreas and attempting to elucidate the mecha-
nism in rats, we conducted this retrospective immunohisto-
chemical study of pancreas and duodenum in rats treated with
TCDD for 14 and 31 weeks.
MATERIALS AND METHODS
Study design. This investigation originated from a series of studies
undertaken by the NTP to determine the suitability of the Toxic Equivalency
Factor (TEF) methodology for predicting chronic toxicity and carcinogenicity
induced by TCDD and DLCs (National Toxicology Program, 2004a, 2004b,
2004c, 2004d, 2004e, 2004f, 2004g). Female Harlan Sprague-Dawley rats were
used, because they showed more sensitivity to the effects of TCDD than the
malein previousstudies(Kocibaet al.,1978).Approximately 10 animals/group
were administered 0, 3, 10, 22, 46, and 100 ng/kg TCDD for 14, 31, and 53
weeks (10 rats for 14 and 31 weeks, 8 rats for 53 weeks); in the 2-year study, 49
to 54 animalsweregiventhe same doses by daily gavage for 5 days per weekup
to 2 years. In addition, rats treated with 100 ng/kg for 30 weeks followed by
vehicle treatment through the termination of the 2-year study were designated
the 100 ng/kg stop group. Control animals received corn oil: acetone vehicle
Chemical. 2,3,7.8,-Tetrachlorodibenzo-p-dioxin (lot no. CR82-2–2, purity
approximately 98%, with no change in purity throughout the study) was
supplied by IIT Research Institute (Chicago, IL). Purity of the chemical was
analyzed with a gas chromatography/high resolution/mass spectrometry system
(GC/HR/MS). Acetone and corn oil were obtained from Spectrum Quality
Products (Gardena, CA). Specific amounts of TCDD dissolved in acetone were
added to corn oil to yield concentrations of 0, 1.2, 4, 8.8, 18.4, or 40 ng
TCDD/ml of vehicle determined by GC/HR/MS to be within 10% of target
concentrations. Studies of the dose formulations indicated that the chemical
could maintain an acceptable homogeneity for dosing and stability for 35 days
when stored at room temperature.
and Accreditation of Laboratory Animal Care International (AAALAC)-
accredited facility of Battelle-Columbus Laboratories (Columbus, OH) for
the duration of the study. Animal handling and husbandry were conducted in
accordance with National Institutes of Health (NIH) guidelines (Grossblatt,
1996). Upon receipt, the female Harlan Sprague-Dawley rats were approxi-
mately 6 weeks of age. They were held under quarantine for 15 days for health
screening by a veterinarian and were approximately 8 weeks of age at the start
of the study. Animals were randomly assigned to control or TCDD-treated
groups and permanently identified with tail tattoos. They were housed five to
a cage in solid-bottompolycarbonatecages(Lab Products, Inc., Maywood,NJ).
Filtered room air underwent at least 10 changes per hour. The animal room was
MECHANISM OF TCDD-INDUCED PANCREATIC LESIONS
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