* Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina; and
Experimental Toxicology Division and
Neurotoxicology Division, MD-74B, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received November 28, 2001; accepted April 12, 2002
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ABSTRACT |
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Key Words: polychlorinated biphenyls; PCBs; thyroid hormones; C576J/BL mice; Long-Evans rats.
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INTRODUCTION |
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Induction of uridine diphosphate glucuronosyltransferase (UGT) isozymes is another mechanism by which PCBs interfere with TH (Barter and Klaassen, 1992b; Beetstra et al., 1991
; Hood and Klaassen, 2000a
; Saito et al., 1991
). PCBs induce hepatic UGTs, which conjugate the phenolic hydroxyl group of T4 with glucuronic acid, a metabolic prerequisite for its excretion into the bile (Beetstra et al., 1991
; Saito et al., 1991
; Visser, 1990
). A number of prototypic enzyme inducers, such as 3-methylcholanthrene (3-MC), pregnenolone-16a-carbonitrile (PCN), and phenobarbital (PB), also increase the glucuronidation of TH through this pathway (Barter and Klaassen, 1994
; De Sandro et al., 1992
; Hood and Klaassen, 2000a
; Saito et al., 1991
).
The effects of prototype hepatic enzyme inducers, such as dioxins and PCBs, on circulating concentrations of TH in rats have been well characterized. Dioxins and dioxin-like PCBs decrease TH in rats by activation of the aryl hydrocarbon (Ah) receptor, which results in the induction of UGT and increases the glucuronidation and elimination of T4 (Schuur et al., 1997). Some of the non-dioxin-like PCBs are classified as PB-like because they induce induce phase I and phase II metabolizing enzymes through the PB response unit (PBRU) pathway (Ganem et al., 1999
; Parkinson et al., 1983
; Sueyoshi and Negishi, 2001
). PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) is a PB-like congener that induces UGT (Ganem et al., 1999
; Honkakoski et al., 1998
) and decrease serum T4 concentrations in rats (Desaulniers et al., 1999
; van Birgelen et al., 1994b
).
Numerous studies have demonstrated that PCBs decrease circulating THs in rats (Barter and Klaassen, 1992b; Brouwer et al., 1998
; van Birgelen et al., 1994b
), whereas little work has been done in mice. Many studies of TH-disrupting xenobiotics have focused on the male rat because of its sensitivity to the development of thyroid neoplasias (Contrera et al., 1997
; Hurley, 1998
). Findings in mice treated with PCBs and dioxins are conflicting. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exposure in mice leads to decreases in both T3 and T4 (Weber et al., 1995
). Work comparing the sensitivity of the rat and mouse to TH modulation by xenobiotics suggests that THs in mice are insensitive to a wide variety of chemicals, including the Ah agonist ß-napthoflavone (Viollon-Abadie et al., 1999
). Preliminary work from Kato et al. (2001) suggests that mice and rats show similar suppression of T4 concentrations after exposure to the non-Ah agonist, di-ortho-substituted PCBs.
The current research examined potential species differences in response to TH glucuronidation inducers in C57BL/6J mice and Long-Evans rats. This work tested the hypothesis that species differences in the effects of polyhalogenated aromatic hydrocarbons (PHAHs) on T4 concentrations are due to differences in induction of T4 glucuronidation. Because PCBs are often characterized as dioxin-like and non-dioxin-like, 2 specific PCB congeners were used in this study. PCB126 (3,3',4,4',5-pentachlorobiphenyl) was chosen as the prototypical dioxin-like PCB because its dioxin-like effects are well characterized (van den Berg et al., 1998). The second PCB chosen was the prototypical PB-like congener, PCB153 (Ganem et al., 1999
). Alterations in serum T4 concentrations and metabolism were measured via radioimmunoassay and T4 glucuronidation in liver microsomes. T3 and thyroid-stimulating hormone (TSH) were not measured because work has shown them to be either unaffected or less sensitive than T4 following exposure to PCBs (Barter and Klaassen, 1994
; Desaulniers et al., 1999
; Hallgren et al., 2001
; Hood and Klaassen, 2000a
; van Birgelen et al., 1994a
, 1994b
). Western blot analysis was used to verify induction of UGT protein. Liver microsomal CYP1A1 (using ethoxyresorufin-O-deethylase [EROD] activity) and CYP2B (using pentoxyresorufin-O-deethylase [PROD] activity) were determined as biomarkers for AhR and PB-like activities, respectively.
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MATERIALS AND METHODS |
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Dosing protocol.
Male and female Long-Evans rats (2325 days of age) were obtained from Charles River Laboratory (Raleigh, NC) and male and female C57BL/6J mice (60 days of age) from Jackson Laboratory (Bar Harbor, ME). They were allowed to acclimate for a minimum of 4 days before use. Younger rats were used to save on chemical synthesis costs for the PCB153. Effects on thyroid hormones and constituent expression of UGT, EROD, and PROD are similar in these younger rats compared with adults (Zhou et al., 2002; unpublished data). All animals were housed in standard plastic hanging cages containing sterilized pine shavings (Beta Chips, Northeastern Products, Inc., Warrensburg, NY). Rats were housed 2 per cage, and mice were housed either 3 or 4 per cage. Food (Lab Diet 5001, PMI, Brentwood, MO) and tap water were provided ad libitum. The animal facilities had an ambient temperature of 22°C, a relative humidity of 55 ± 5%, and a 12-h light-dark cycle.
Rats and mice were dosed by oral gavage for 4 consecutive days with PCB126 (0.03100 µg/kg/day for rats and 0.003-300 µg/kg/day for mice), PCB153 (0.3300 mg/kg/day and 0.990 mg/kg/day), or TCDD (0.00310 µg/kg/day and 0.0330 µg/kg/day). Short-term (24 day) dosing regimens are effective in altering THs for a variety of PHAHs (Zhou et al., 2001; Khan et al., 2002
). The dosing volume was 1.0 ml/kg body weight for the rats and 10.0 ml/kg body weight for the mice. Control animals were dosed with the vehicle only. Because some experiments involved a large number of doses, these experiments were done in 2 replicate blocks. On the day after the last dose, animals were randomly killed by decapitation between 0800 and 1000 h. All animal husbandry was done in accordance with AAALAC regulations. All experiments with animals were approved in advance by the Animal Care Committee of the National Health and Environmental Effects Research Laboratory of the U.S. Environmental Protection Agency.
Sample collection and preparation.
Blood was quickly collected from the neck (after decapitation) into clean funnels that drained into serum separator tubes and placed on ice and allowed to clot for up to 2 h. After centrifuging the blood for 30 min at 4°C in a Sorvall refrigerated centrifuge (model no. RT6000B) at 1257 x g (3K rpm), serum aliquots were stored at -80°C. Livers were dissected, weighed, and placed in sample vials and immediately frozen in liquid nitrogen and then later stored at -80°C. Liver microsomes were prepared from thawed samples according to the method described in DeVito et al. (1993).
Thyroxine assay.
Total serum T4 was measured using standard assay kits (Coat-a-Count Kit TKT41, Diagnostic Products, Inc., Los Angeles, CA). The tubes were decanted and counted on a gamma counter (model B5005, Packard Instruments, Downers Grove, IL). T4 concentrations in the samples were determined from a standard curve created using calibration standards included in the kit. All samples were run in duplicate.
EROD and PROD assays.
EROD activity was used as a marker of CYP1A1 activity, using a spectrophotometric assay, according to the method described by DeVito et al. (1993). A similar protocol was used to determine PROD activity as a marker for CYP2B activity. Microsomal protein concentrations were calculated photometrically using a Bio-Rad protein assay kit (Bio-Rad Laboratories, Hercules, CA) with bovine serum albumin as the standard. All samples were run in duplicate. EROD and PROD values were calculated as picomoles of resorufin per milligram of protein per minute.
UGT assay.
UGT activity toward T4 was determined according to the method of Beetstra et al. (1991) as modified by Zhou et al. (2001). 125I-labeled T4 (NEN Life Science Products, Inc., Boston, MA) was purified by rinsing it on a Sephadex LH-20 column (bead volume, 2 ml) with a series of HCl and NH4OH solutions and eluting the purified T4 according to the method of Beetstra et al. (1991). Reaction mixtures contained 0.2 ml 100 mM Tris/HCl (pH 7.8) and 5 mM MgCl2, 0.4 mg protein, 125I-labeled T4 (50,000 cpm), 1 mM cold T4, and 0.1 mM of 6-propyl-2-thiouracil to inhibit outer-ring deiodinase activity. The reaction was initiated with 5 mM uridine-diphosphoglucuronic acid (UDPGA). Sample blanks not containing UDPGA were analyzed concurrently. After 30 min, reactions were stopped with the addition of 200 µl ice-cold methanol. After centrifugation, 200 µl of the supernatent was removed and added to 750 µl of 0.1 M HCl. The samples were then placed on a Sephadex LH-20 column (bead volume, 2 ml), and 1.0 ml water-eluted fractions containing the conjugate were combined and counted on a gamma counter (Model B5005, Packard Instruments, Downers Grove, IL). All samples were run in duplicate.
The effects of detergent (Brij 56) concentrations on T4 glucuronidation activity were determined in control and treated rat and mouse microsomal fractions. Initial studies indicated that in rat microsomes the presence of detergent increased basal activity of T4 glucuronidation by about 4-fold. In the rat, PCB153-treated microsomes showed a 2- to 3-fold induction of UGT activity in the absence of Brij 56; in the presence of Brij 56 there was no induction apparent. TCDD induction of UGT was decreased about 50% in rat microsomes in the presence of Brij 56. Therefore, in subsequent assays, detergents were not used with rat microsomes. In mouse microsomes, Brij 56 also increased basal activity. However, in contrast to rats, the greatest fold induction for both PCB126 and PCB153 in mouse microsomes was observed in the presence of 0.25 mM Brij 56. Therefore, all assays with mouse microsomes included 0.25 mM Brij 56.
Immunoblotting analysis.
Aliquots of liver microsomes from control, low-, and high-dose animals treated with PCB126 were thawed and diluted to 15 mg/ml for the mouse and 5 mg/ml for the rat. These concentrations demonstrated the best linearity in density with respect to protein concentration (data not shown). The samples were loaded onto a precast 10% acrylamide Tris-Glycine gel (Novex, San Diego, CA) at a sample volume of 15 ml and were electrophoresed at 125 V for approximately 90 min. Afterward, proteins on the gel were electrophoretically transferred onto a nitrocellulose membrane (Novex) at 200 mA for 30 min in a 20% methanol transfer buffer containing 25 mM Tris base and 0.2 M glycine. After washing for 1 h with a 5% nonfat dry milk solution, the membrane was incubated with a polyclonal antibody prepared against human UGT-1A (Gentest, catalogue no. 458410, Woburn, MA) at a 1:5000 dilution. This antibody recognizes human UGT1A1, 1A3, 1A4, 1A6, 1A7, 1A9, and 1A10 isoforms. The membrane was washed twice with a Tris buffer (30 mM Tris, 0.3 M NaCl, and 0.2% Tween, pH 7.4) (TBST) and then incubated with a secondary anti-rabbit immunoglobulin G (1:1000 dilution) (Amersham Life Science, Buckinghamshire, England). After 2 washes with TBST, the membrane was incubated with a strepavidin horseradish peroxidase solution (1:1000 dilution) (Amersham Life Science). Membranes were again rinsed with TBST followed by a rinse with Tris-buffered saline (30 mM Tris and 0.2 M NaCl, pH 7.4) and then soaked for 5 min with SuperSignal West Femto Maximum Sensitivity Substrate (Pierce, Rockford, IL) to visualize proteins. Protein band density was quantified from the chemiluminescent images using Fluor-S MultiImager and Quantity One software (Bio-Rad, Hercules, CA) after a 500-s exposure period. A total of 3 to 4 samples were run for each treatment group.
Statistical analysis.
The data for T4 concentrations, EROD, PROD, and UGT-T4 activities were analyzed independently using a one-way analysis of variance (SAS Institute, Cary, NC). Duncans multiple range tests were used to compare differences among treatment groups, with acceptable significance levels set at p < 0.05. For comparative purposes, T4, EROD, and PROD data are presented as percentage of control. UGT data were presented as actual values to demonstrate the difference in basal expression between rats and mice.
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RESULTS |
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Thyroxine concentrations.
Figure 1 illustrates the effects of PCB126 on serum T4 in rats and mice. Actual control T4 values are presented for both species in Table 1
. Both male and female rats demonstrated a 50% decrease in serum T4 concentrations with respect to controls. There were significant main effects of treatment for both male and female rats, F(4, 62) = 22.00, p < 0.0001, and F(8, 71) = 23.50, p < 0.0001, respectively. Group mean contrast tests revealed statistically significant decreases (p < 0.05) beginning at the 3.0 µg/kg dose in female rats and beginning at the 10.0 µg/kg dose in male rats. Serum T4 concentrations were not significantly altered at any PCB126 dose in either the male or female mouse.
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Thyroxine concentrations.
Figure 6 illustrates the similar effects of PCB153 on serum T4 in both rats and mice. Actual T4 control values are presented for both species in Table 1
. Both male and female rats demonstrated dose-related decreases in serum T4 concentrations and achieved an
80% maximal suppression with respect to controls. Statistical decreases were apparent at doses as low as 9.0 mg/kg in female rats and 10.0 mg/kg in male rats, F(4, 27) = 48.66, p < 0.0001, and F(6, 34) = 43.13, p < 0.0001, respectively. Both male and female mice also exhibited a statistically significant decrease in serum T4 at doses as low as 3.0 mg/kg in the female and 20.0 mg/kg in the male, F(4, 24) = 55.51, p < 0.0001, and F(5, 84) = 48.21, p < 0.0001, respectively.
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DISCUSSION |
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The decreases in serum T4 in the rat after PCB126 or TCDD exposure are consistent with findings from other studies (Henry and Gasiewicz, 1987; Saito et al., 1991
; Schuur et al., 1997
; van Birgelen et al., 1994b
). PCB126 and TCDD exposure in female Sprague-Dawley rats caused a 50% decrease in serum T4 concentrations compared with controls, and this decrease was associated with increased hepatic T4 glucuronidation activity (van Birgelen et al., 1994a
). The present data showing no effects of PCB126 and TCDD on serum T4 concentrations in mice are consistent with Viollon-Abadie et al. (1999), who failed to alter T4 concentrations in OF-1 mice treated with the AhR agonist ß-napthoflavone. In contrast, decreased T4 was reported in C57 mice after TCDD exposure (Weber et al., 1995
). The reasons for this discrepancy remain to be determined.
There are a number of possible explanations why, in the present study, PCB126 and TCDD would decrease T4 in rats and not in mice. First, mice may be insensitive to the effects of dioxins. This is unlikely to be the case, however, because in this study EROD activity, a marker for CYP1A1 and responsiveness to Ah receptor agonists, was clearly induced. This is consistent with numerous studies demonstrating that mice are responsive to PCB126 and TCDD (DeVito et al., 2000; Pohjanvirta and Tuomisto, 1994
; Safe, 1994
). Another explanation for the lack of effect on T4 concentrations in mice is that T4 UGT activity may not be inducible in mice exposed to PCB126 and other dioxin-like chemicals. There is ample evidence that UGT activity toward many substrates other than T4 (e.g., p-nitrophenol) are induced in mice exposed to Ah receptor agonists (e.g., Nemoto and Takayama, 1980
; Owens, 1977
; Shen et al., 1989
). In the current study, a very small increase of UGT1A proteins, as demonstrated by Western blot analysis, was observed at the highest dose examined. Consistent with this small induction of protein was the small, approximately 20%, increase of T4 glucuronidation in mice. This small induction of UGTs in mice would not result in changes in serum TH. Although higher doses of PCB126 may have resulted in greater elevation of UGT, it should be noted that the dose administered was 300 µg/kg/d for a total of 1.2 mg/kg, which is approximately the LD50 for this chemical in mice (Pohjanvirta and Tuomisto, 1994
). The human UGT1A antibody is capable of detecting increases in mouse UGT proteins; there is an 8- to 10-fold increase in the density of the
52-kD band in mice exposed to PCB153 at 300 mg/kg/day (unpublished data). Thus, the effects of Ah-agonists on T4 glucuronidation activity appear to be species dependent.
PCB153 dramatically decreased serum T4 concentrations and increased hepatic T4 glucuronidation in both rats and mice. These effects are consistent with other reports examining the effects of either non-coplanar PCBs or A1254 in rats (Desaulniers et al., 1999; Hood et al., 1999
; Hood and Klaassen, 2000a
; Kato et al., 2001
; Khan et al., 2002
; van Birgelen et al., 1994b
). Viollon-Abadie et al. (1999) suggested that THs in mice are insensitive to the effects of hepatic enzyme inducers. The present study indicates that the insensitivity in mice may be chemical specific. Other PHAHs decrease T4 in mice, including polybromominated diphenyl ethers, di-ortho-substituted PCBs, and PHAH contaminated fish (Cleland et al., 1987
; Hallgren et al., 2001
; Kato et al., 2001
). The presence of Ah agonists (dioxins and coplanar PCBs) and other contaminants in the fish examined in the Cleland study makes it difficult to ascribe the T4 decrease to any one type of contaminant. The present data suggest that the nondioxin-like PCBs could be responsible for the effects on serum T4 in the studies by Cleland et al.(1987).
The magnitude of induction of UGT enzymes was not well correlated with the magnitude of decrease in circulating concentrations of serum total T4. The present data show an 80% maximum reduction in T4 concentrations and a 2- to 3-fold induction of UGT activity in both rats and mice exposed to PCB153. Maximal decreases in serum T4 concentrations of only 50% were found in rats exposed to PCB126, yet these animals had up to a 13-fold induction of UGT activity. Consistent with this observation, both De Sandro et al. (1992) and Hood and Klaassen (2000a) found no clear relationship between UGT induction and T4 concentrations. One possible reason for the discrepancy between levels of induction of UGT activity and serum concentrations of T4 is that the UGT assay may not accurately measure the true changes in hepatic glucuronidation of T4. There are a number of different isoforms of UGT, and they require different ex vivo assay conditions to produce maximal activity (De Sandro et al., 1992; Hood and Klaassen, 2000a
; Mackenzie et al., 1984
; Visser et al., 1993
). In the present study, rat hepatic microsomal T4 glucuronidation activity was assayed without Brij 56 because this detergent completely masked the induction of UGT activity in microsomes from PCB153 rats. In contrast, mouse hepatic microsomal T4 glucuronidation activity was assayed in the presence of Brij 56 to observe the greatest fold induction. Presently, the relationship between ex vivo measurement of UGT enzyme activity and the in vivo effects on T4 concentrations is not well understood. It is possible that the enzyme assays used in this report underestimate induction by PCB153 compared with PCB126.
There are other possible explanations as to why serum T4 concentrations are not directly associated with hepatic T4 glucuronidation. TH homeostasis is regulated through a variety of mechanisms. Exposure to A1254 has been shown to upregulate type 2 deiodinase in rat brain during development (Morse et al., 1996). Deiodinases convert T4 to T3 in tissues, and this could lead to decreases in circulating T4 concentrations. However, Hood and Klaassen (2000b) demonstrated that a number of microsomal enzyme inducers, including A1254, had only a minimal impact on overall outer ring deiodination activity. That alterations in deiodinase activity impact circulating T4 concentrations in the present animal model is currently speculation. Another explanation is that PCB congeners and hydroxy-metabolites of PCBs displace T4 from serum binding proteins in vitro (Brouwer, 1989
; Chauhan et al., 2000
). Although the exact role of this mechanism in the regulation of serum hormone concentrations in vivo is unknown, displacement from serum binding proteins could lead to greater availability of the hormones for glucuronidation and elimination, resulting in lowered serum concentrations. A combination of the just-mentioned mechanisms may be ultimately responsible for the difference between measured increases in UGT activity and serum T4 concentrations between chemicals.
In the present study exposure to the di-ortho-substituted congener PCB153 led to significantly increased PROD activity in both species. This data is consistent with the literature on PCB153 exposure in rats and mice (Parkinson et al., 1983; Ganem et al., 1999
; Ikegwuonu et al., 1996
). The similarity in effects of PCB153 in mice and rats is in contrast to the species-specific effects of PCB126.
Most toxicity studies examining the effects of xenobiotics on TH homeostasis have been completed in the rat. This report demonstrates that there are important species differences in the effects of some environmental contaminants on thyroid hormone homeostasis. Data illustrate the differences in the regulation of thyroid hormone glucuronidation in Long-Evans rats and C57BL/6J mice following exposure to the AhR agonist PCB126. This report also highlights striking similarities in response to PCB153 in these same species. Until more reliable data on endocrine disrupting chemicals is collected in multiple species, any comparison to possible consequences of these xenobiotics on humans should be viewed with caution, as evidenced by the species comparison data presented here.
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NOTES |
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This article has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
2 To whom correspondence should be addressed at Neurotoxicology Division, MD-74B, NHEERL, U.S. EPA, Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: crofton.kevin{at}epa.gov.
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