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Department of Toxicology, Agricultural University Wageningen (A.G.S., F.M.B., A.B.), Wageningen; and the Department of Internal Medicine III, Erasmus University Medical School (T.J.V.), Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. A. G. Schuur, Department of Toxicology, Agricultural University Wageningen, P.O. Box 8000, 6700 EA Wageningen, The Netherlands. E-mail: Gerlienke.Schuur{at}algemeen.tox.wau.nl
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thyroid hormones influence a variety of metabolic processes in most mammalian tissues and may also have a significant effect on rates of drug metabolism. Studies by Rumbaugh et al. (16) established a dose-dependent stimulating effect of thyroid hormones on hepatic mixed function oxidases. CYP activities were lower in thyroidectomized (Tx) male and female Sprague-Dawley rats compared with those in euthyroid (Eu) controls. Substitution of Tx rats with T4 restored these activities to Eu levels. Müller et al. (17) showed that T3 treatment increases CYP1A activities in rat liver. This suggests that the effects of PHAHs on biotransformation enzymes may be modulated by the altered thyroid status associated with PHAH treatment.
To further elucidate the peripheral mechanisms mediating the effects of PHAHs on thyroid hormone turnover, we investigated the effects of TCDD in Tx rats substituted with T4 or T3. In addition, this model was used to study the role of changes in thyroid hormone status on the induction of hepatic cytochrome P450 isozymes and other biotransformation enzymes by PHAHs. For this purpose we used Tx male Sprague-Dawley rats infused with substitution doses of T3 (Tx+T3) or T4 (Tx+T4) by osmotic minipumps. Here, we describe the validation of this model as well as the effects of TCDD on plasma and tissue thyroid state-dependent parameters in Eu, Tx, Tx+T3, and Tx+T4 rats. The modulating effects of thyroid hormone on the induction of hepatic phase I (CYP) and phase II (UGT and glutathione S-transferase) detoxification enzymes are presented elsewhere (18).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals and treatment
Male Sprague-Dawley rats, surgically Tx or sham-operated by the
supplier at 4 weeks of age, were purchased from Harlan/CPB (Zeist, The
Netherlands). The complete resection of the thyroid in the Tx rats was
confirmed at the end of the experiment by autopsy. The rats were
obtained at 6 weeks of age and allowed to acclimatize for 2 weeks
before the experiment. They were maintained at 50% humidity and 21 C
on bedding in plastic cages with a 12-h light, 12-h dark cycle. Rat
chow (Hope Farms, Woerden, The Netherlands) and tap water with 0.5%
CaCl2 were supplied ad libitum. Model 2002 Alzet
minipumps (Charles River Wiga, Sulzfeld, Germany), delivering 0.4 µg
T3/100 g BW·day (Tx+T3 rats; n = 15) or
1.0 µg T4/100 g BW·day (Tx+T4 rats; n
= 15) in 0.1 M NaOH in 0.9% NaCl were implanted ip on day
0 under ether anesthesia. Five sham-operated rats, 15 nonoperated Eu
rats, and 15 Tx rats received pumps with solvent only. Water and food
consumption was recorded daily, and body weight was recorded twice a
week. On day 7 after osmotic minipump implantation, 5 rats from each
group (Eu, Tx, Tx+T3, and Tx+T4) were given an
ip injection of 10 µg TCDD/kg BW in corn oil (5 ml/kg). Of each
group, 5 control and 5 pairfed control rats were given an ip injection
of corn oil only. On the day before pump implantation (day -1), day 3,
day 7, and day 10, blood (
1 ml) was collected by orbital puncture in
heparinized tubes and stored on ice until separation of plasma. On day
10, all rats were killed under ether anesthesia. Livers were perfused
with saline, dissected, weighed, and frozen in 3 portions. Kidneys,
thymuses, and brains were removed, weighed, and frozen on dry ice. All
tissues were stored at -80 C, and plasma was stored at -20 C until
analysis. All procedures were approved by the animal welfare committee
of the Agricultural University Wageningen.
Tissue preparation
Whole brains were homogenized in 8 vol ice-cold 0.1
M Tris-HCl buffer, pH 7.5, containing 1 mM DTT
using a Potter tube and stored at -80 C until analysis. Livers were
homogenized on ice in 3 vol ice-cold 0.1 M Tris-HCl buffer,
pH 7.5, containing 0.25 M sucrose using a Potter tube, and
the homogenate was centrifuged for 30 min at 9,000 x g
at 0–4 C. The resulting supernatant was centrifuged for 90 min at
105,000 x g at 0–4 C, and the microsomal pellet was
resuspended in ice-cold 0.1 M phosphate buffer, pH 7.5.
Microsomes and cytosol were stored in aliquots at -80 C until further
analysis. Protein levels of tissue fractions were determined using the
Bio-Rad protein reagent (20) and BSA as a standard.
Thyroid hormone analysis
Plasma T4, FT4, and T3 were
analyzed in duplicate using the Amerlite chemiluminescence kits
(Amersham) according to the protocol of the supplier with the following
modifications: the T4 and T3 assay buffer was
diluted five times with demineralized water, and the standard curve for
T4 ranged from 0–120 nmol T4/liter. It was
ascertained that TCDD does not interfere in the Amerlite assays. Plasma
TSH was determined by RIA with the materials and protocols from the
NIDDK, NIH, using TSH RP-2 as a standard.
Enzyme assays
Type I iodothyronine deiodinase (D1).
Hepatic D1 activity
was determined as previously described (21). In short, microsomes (20
µg protein/ml) were incubated for 30 min at 37 C with 1
µM rT3 and about 100,000 cpm
[125I]rT3 in 0.1 M phosphate
buffer (pH 7.2), 2 mM EDTA, and 5 mM DTT. The
reaction was stopped on ice by the addition of 750 µl 0.1
M HCl. The tubes were centrifuged, and radioiodide was
determined in the supernatant by Sephadex LH-20 chromatography as
described previously (19).
Type II iodothyronine deiodinase (D2).
Brain D2 activity was
analyzed essentially as described by Visser et al. (22) with
slight modifications as described by Morse et al. (23). The
final incubation conditions were 0.8 mg brain homogenate protein/ml, 2
nM T4 with about 50,000 cpm
[125I]T4, 1 mM
propyl-2-thiouracil, 0.5 µM T3, 25
mM DTT, and 1 mM EDTA in 200 µl 0.1
M phosphate buffer, pH 7.2. After incubation for 60 min at
37 C, the reaction was stopped on ice by the addition of 100 µl 7%
(wt/vol) BSA, followed by 500 µl 10% (wt/vol) trichloroacetic acid.
The tubes were centrifuged, and the radioiodide released was further
isolated from the supernatant by Sephadex LH-20 chromatography as
described previously (21).
UGTs.
Hepatic T4 and T3 UGT
activities were determined essentially according to the method of
Beetstra et al. (5). Microsomes (1 mg protein/ml) were
incubated for 30 min at 37 C with 1 µM T4 or
T3 (plus 50,000 cpm of the 125I-labeled
compound), 3.75 mM MgCl2, and 0.125% BSA in
the presence or absence (blank) of 5 mM uridine
diphosphoglucuronic acid in 200 µl 75 mM Tris-HCl, pH 7.8
(24). Reactions were stopped by the addition of 0.2 ml ice-cold
methanol. After centrifugation, 0.2 ml supernatant was mixed with 0.8
ml 0.1 M HCl and analyzed for glucuronide formation on
Sephadex LH-20 minicolumns (5).
Malic enzyme.
Hepatic malic enzyme activity was determined
according to the method of Hsu and Lardy (25) by incubating 0.33 mg
cytosolic protein/ml for 10 min at 25 C with 2 mM malic
acid, 1.13 mM NADP, and 16 mM MnCl2
in 0.13 M triethanolamine buffer, pH 7.4, and the formation
of NADPH was determined at 340 nm using a 96-well plate
spectrophotometer (Molecular Devices Corp., Menlo Park, CA).
Statistics
Treatment-related effects were first evaluated with a one-way
ANOVA followed by a least significant difference test
(P < 0.05) using the statistical software package
SPSS/PC+ (SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thyroidectomy performed 4 weeks earlier, i.e. at 4 weeks of
age, caused an approximately 29% decrease (P < 0.05)
in body weight at the start of the infusion period. The increase in
body weight of Tx rats infused with replacement doses of T3
(Tx+T3) or T4 (Tx+T4) during the
7-day period was greater than that of Tx or Eu rats (P
< 0.05). Body weights of Tx+T3 and Tx+T4 rats
after 10 days of infusion were in between those of Tx and Eu rats.
During the entire period, the daily food intake of Tx rats was about
70% that of Eu, Tx+T3, and Tx+T4 animals. No
differences were found in water intake between the different
groups.
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. Eu rats maintained
constant levels of plasma T4 (50 nM),
T3 (1.3 nM), FT4 (20
pM), and TSH (2.3 ng/ml) over the 7-day period following
osmotic minipump implantation. In the Tx rats, strongly reduced plasma
T4 (to 30% of that in Eu rats) and FT4 (to
20% of that in Eu rats) levels were observed. Plasma T3
levels were less affected in Tx rats and were maintained at about 50%
of Eu values throughout the 7-day period preceding TCDD treatment.
Plasma TSH levels were increased approximately 9-fold in Tx
vs. Eu rats throughout this period, indicating a strongly
decreased negative feedback on hypophyseal TSH secretion.
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No differences were found between pairfed and ad libitum-fed, corn oil-treated controls in all groups. Therefore, only data derived from pairfed controls are presented. Treatment with TCDD had no significant effect on food intake, body weight, or body weight gain compared with those in control rats in any of the groups. Thymus weight was decreased significantly by 6–20%, and liver weight was increased significantly by 30–50% after TCDD treatment in the different groups (not shown). Results are presented as enzyme activities per mg protein. The significance of the effects of thyroid state and TCDD treatment were similar if results were expressed per g liver or per whole liver. No significant differences were found for brain and kidney weights between TCDD-treated rats and controls.
The effects of TCDD on plasma thyroid hormone levels are presented in
Fig. 2. In the Eu and Tx+T4
groups, TCDD significantly reduced plasma T4 levels by 38%
and 52%, respectively, compared with their respective control values.
No significant effect of TCDD treatment was found on the low plasma
T4 levels in the Tx and Tx+T3 groups (Fig. 2A).
TCDD treatment caused a significant 28% decrease and an insignificant
38% decrease in plasma FT4 levels in Eu and
Tx+T4 animals, respectively, compared with levels in the
corresponding controls (Fig. 2B), whereas no effect was observed in the
Tx and Tx+T3 groups. TCDD exposure resulted in a decrease
in plasma T3 concentrations in the Tx, Tx+T3,
and Tx+T4 rats, which was significant only for the
Tx+T3 group (51% of control Tx+T3 rats; Fig. 2C). TCDD tended to increase plasma T3 in Eu rats, but this
was not significant. No TCDD-related changes were observed in plasma
TSH in any of the groups (Fig. 2D).
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). In control Tx+T3 and
Tx+T4 rats, hepatic D1 activity was the same as that in Eu
rats. TCDD treatment resulted in a further insignificant decrease in D1
activity in Tx rats. No effects of TCDD on D1 activity were observed in
Eu, Tx+T3, and Tx+T4 rats.
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). T4 replacement
resulted in a return of D2 activity to control Eu levels. TCDD
treatment tended to increase brain D2 activity in the Tx,
Tx+T3, and Tx+T4 rats, although the differences
from the respective control values were not significant.
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).
With either substrate, UGT activities were similar in control Eu and Tx
rats. T4 UGT activity was increased about 5-fold in all
groups treated with TCDD. In contrast, T3 UGT activity was
slightly, but not significantly, increased by TCDD treatment
independent of thyroid state.
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). Malic enzyme
activity was decreased by 67% in control Tx rats vs. that
in control Eu rats. Malic enzyme activity was partially restored in
control Tx+T3 and Tx+T4 rats, with values in
between those in control Tx and Eu rats. TCDD treatment increased malic
enzyme activity significantly in Eu, Tx+T3, and
Tx+T4 rats to 148%, 244%, and 162%, respectively, of the
corresponding control values. However, no effect of TCDD treatment on
malic enzyme activity was found in the Tx group.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Tissue thyroid state was assessed by measuring hepatic malic enzyme and D1 activities, which are under the positive control of thyroid hormone (27, 28), as well as brain D2 activity, which is down-regulated by thyroid hormone, in particular T4 (29). Hepatic malic enzyme activity was very low in Tx rats, indicating functional hypothyroidism. In Tx+T3 and Tx+T4 rats, malic enzyme activity was partially restored back to Eu levels. Smaller, insignificant changes were observed in hepatic D1 activity, suggesting that malic enzyme activity is a more sensitive parameter of the hepatic thyroid state. Brain D2 activity was highly elevated in the Tx group, whereas T4, but not T3, replacement resulted in a decrease in D2 activity back to Eu values.
As thyroidal secretion of T4 and T3 in the hormone-replaced rats is negligible, these rats are a suitable model for study of the extrathyroidal effects of xenobiotics on thyroid hormone status and metabolism. T4 and FT4 levels were reduced to a greater extent by TCDD in Tx+T4 rats than in Eu rats, indicating that the TCDD-induced plasma T4 reduction is mainly due to an extrathyroidal mechanism. This is in agreement with findings reported by Barter and Klaassen (8) in Tx+T3/T4 rats after treatment with Aroclor, a PCB mixture. No effect of TCDD was found on plasma T3 levels in Eu rats, which is in agreement with the results of other studies (1, 5, 30, 31, 32), although plasma T3 has also been reported to decrease (33, 34) or increase (2, 4) after TCDD treatment. In contrast to Eu rats, Tx+T3 rats showed a marked decrease in plasma T3 after treatment with TCDD in this study, which may be explained by a TCDD-induced increase in the clearance of plasma T3. The variable effects of TCDD on plasma T3 in Eu rats reported in the different studies may be explained by the varying extents of the inhibition of hepatic D1 activity, the decrease in plasma T4 substrate levels, and the increase in plasma TSH and, hence, the stimulation of thyroidal T3 secretion. No significant effects of TCDD were observed on plasma TSH levels regardless of thyroid state, which has also been shown previously (31). It is not known why the TCDD-induced decrease in plasma T4 and FT4 levels does not provoke an increase in TSH secretion. One explanation is a possible damaging effect of TCDD and PCBs on the hypothalamus and/or pituitary (35, 36, 37, 38). However, chronic administration of TCDD has been shown to increase plasma TSH, which may even be associated with the development of thyroid tumors in rats (39).
T4 is glucuronidated in rat liver by at least two different UGT isozymes: bilirubin UGT and phenol UGT. Phenol UGT activity is inhibited in vitro in the presence of Brij 56, whereas bilirubin UGT activity is stimulated in vitro by this detergent (9, 24). T4 UGT activity was measured in this study in the absence of Brij 56 and, thus, largely reflect glucuronidation of T4 by phenol UGT. The results showed that TCDD treatment induced an approximately 5-fold increase in T4 UGT activity in Eu, Tx, and Tx+T3 or Tx+T4 rats. These results are in agreement with previous studies, showing that hepatic phenol UGT activity is potently induced by 3-methylcholanthrene-like inducers, such as TCDD and PCBs (5, 7, 8, 9, 40), which probably represents an increase in UGT gene expression (41). This marked increase in hepatic T4 UGT activity is most likely responsible for the reduction of plasma T4 and FT4 levels, as suggested previously (5, 8). This is further supported by the significant negative correlation between T4 UGT and plasma T4 levels found in this study (not shown) and in a previous study (38) employing different hepatic enzyme inducers. However, TCDD treatment does not decrease residual serum T4 levels in Tx and Tx+T3 rats. In this respect it should be realized that glucuronidation is not an irreversible pathway of T4 disposal, as T4 glucuronide is hydrolyzed in the intestine and at least part of the liberated T4 is resorbed (enterohepatic cycle) (42). A possible explanation for the lack of a TCDD-induced decrease in serum T4 in the Tx and Tx+T3 rats is a more efficient recovery of biliary excreted T4 glucuronide in these animals.
Perhaps the most remarkable result of our study is the decrease in plasma T3 levels after TCDD treatment of Tx+T3 rats. As mentioned above, this may be explained by a TCDD-induced increase in plasma T3 clearance. In contrast to the strong increase in T4 UGT activity, TCDD produced only a small and insignificant increase in hepatic T3 UGT activity. Even if the approximately 30% increase in liver weight is taken into account, TCDD induces only about a 50% increase in hepatic T3 UGT capacity in contrast to a more than 5-fold increase in T4 UGT capacity. The TCDD-induced increase in plasma T3 clearance may, therefore, be due to an increase in alternative pathways of T3 metabolism.
TCDD did not affect hepatic D1 activity in this study, although in Tx rats an insignificant decrease was observed. In other studies TCDD treatment resulted in a significant decrease in liver D1 activity in rats (9, 43). Such a decrease in D1 activity has also been found after TCDD treatment of Tx and Tx+T3 rats (44). A possible explanation for this discrepancy is the difference in dose and duration of TCDD exposure between the different studies. If it occurs, the decrease in hepatic D1 activity may be an indirect effect mediated by a TCDD-induced decrease in thyroid hormone bioactivity (28). In our study the lowest D1 activity was observed in TCDD-treated Tx rats, which also had the lowest serum T3 levels. However, direct inhibition of D1 activity by TCDD-like compounds in vitro has also been reported (45).
In this study no statistically significant effects of TCDD were found on brain D2 activity in Eu rats, although in Tx, Tx+T3, and Tx+T4 rats TCDD increased D2 activity to 122–286% of the control value. Increased brain D2 activity after treatment of rats with TCDD or PCB mixture has been demonstrated by Lans (43) and Morse et al. (46). This increase in brain D2 activity suggests a physiological response to decreased plasma T4 levels to maintain constant T3 levels in the brain (47). A possible explanation for the relatively small TCDD-induced increases in brain D2 activity in the present study is the relatively small decrease in plasma T4 compared with the findings of Lans (43), who used a higher dose of TCDD and a longer exposure time.
Another important finding of the present study is the increased hepatic malic enzyme activity observed after TCDD treatment in all groups, except Tx rats. Kelling et al. (48) and Roth et al. (3) also reported an increase in malic enzyme activity after treatment with TCDD, but also only in the presence of thyroid hormone. Thyroid hormone is, therefore, a permissive factor for the induction of malic enzyme by TCDD. As malic enzyme is also controlled by the peroxisome proliferator-activated receptor (PPAR) (49), it appears that malic enzyme expression is regulated by multiple nuclear receptors, including the T3 receptor, PPAR, and the aryl hydrocarbon receptor. Both the aryl hydrocarbon receptor and PPAR mediate the induction of different hepatic CYP isoenzyme by their ligands. The induction of malic enzyme by both receptor-ligand systems may serve the purpose of providing the necessary NADPH required for the induced CYP activities (48).
In conclusion, T4 or T3 was infused by osmotic minipumps into Tx rats, restoring plasma T3 and T4 to near-euthyroid levels; this provided a model in which the peripheral effects of TCDD on thyroid hormone turnover can be investigated without confounding effects on thyroid function. TCDD induced greater decreases in plasma T4 levels in Tx+T4 rats than in Eu rats, indicating that these changes are caused by an extrathyroidal mechanism in which increased hepatic T4 glucuronidation by induction of phenol UGT activity plays an important role.
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Acknowledgments |
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Footnotes |
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Received February 4, 1997.
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References |
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-glycerophosphate dehydrogenase
and malic enzyme by L-triiodothyronine. Characteristics of
the response with specific nuclear thyroid hormone binding sites fully
saturated. J Clin Invest 59:517–427
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),
Tx+T3 (
), and Tx+T4 (
) rats. The levels
were measured before and 3 and 7 days after osmotic minipump
implantation (day -1). Results represent the mean ±
SEM of five rats per group. *, Significantly different from
Eu rats (P < 0.05). #, Significantly different
from Tx rats (P < 0.05).
