Effects of Polychlorinated Biphenyls, Kanechlor-500, on Serum Thyroid Hormone Levels in Rats and Mice

Yoshihisa Kato*,1, Koichi Haraguchi{dagger}, Tomoaki Yamazaki*, Yuriko Ito*, Shoji Miyajima*, Kiyomitsu Nemoto*, Nobuyuki Koga§, Ryohei Kimura* and Masakuni Degawa*

* School of Pharmaceutical Sciences, University of Shizuoka, 52–1, Yada, Shizuoka 422-8526, Japan; {dagger} Daiichi College of Pharmaceutical Sciences, 22–1, Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan; and § Faculty of Nutritional Sciences, Nakamura Gakuen University, 5–7–1 Befu, Johnan-ku, Fukuoka 814-0198, Japan

Received September 30, 2002; accepted December 17, 2002


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Effects of a commercial polychlorinated biphenyls mixture, Kanechlor-500 (KC500), on the levels of serum thyroid hormones such as total thyroxine (T4) and triiodothyronine (T3) were examined comparatively in male Wistar rats and ddy mice. Serum T4 levels were significantly decreased in both rats and mice 4 days after a single ip injection of KC500 (100 mg/kg body weight), whereas decreased levels of T3 were observed in mice but not in rats. In addition, no significant change in the level of serum thyroid stimulating hormone was observed in either rats or mice. Hepatic UDP-glucuronosyltransferases (UDP-GTs) UGT1A1 and UGT1A6, which efficiently mediate glucuronidation of T4 and promote the excretion of the hormones, were induced by KC500 in rats but not in mice. Hepatic microsomal cytochrome P450 (P450) content and the microsomal activity for 7-ethoxy-, 7-pentoxy-, and 7-benzoyloxy-resorufin dealkylations were significantly increased by KC500 in both rats and mice, although the magnitude of increase in the enzyme activities was higher in rats than in mice. The difference in the increase in the activity of microsomal enzymes, including UDP-GT and P450, between KC500-treated rats and mice was not correlated with that in the level of hepatic methylsulfonyl-PCB metabolites. In the present study, we found for the first time that the decrease in serum T4 levels by KC-500 in mice occurred without increase in hepatic UDP-GTs, UGT1A1 and UGT1A6, responsible for T4 glucuronidation. The present findings further suggested that although the decrease in serum T4 levels in KC500-treated rats would occur at least in part through the induction of the UDP-GTs, it might not be dependent on only the increase in the enzymes.

Key Words: polychlorinated biphenyls; Kanechlor-500; thyroid hormones; UDP-glucuronosyltransferases; Wistar rats; ddy mice.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In 1968, an outbreak of accidental food poisoning caused by ingestion of Kanemi rice oil contaminated with commercial polychlorinated biphenyls (PCBs) occurred in western Japan, and the human toxicity of PCBs was confirmed. Some victims, called Yusho patients, continued to show various symptoms such as acneform eruptions, the hypersecretion of Meibomian glands, the hyperpigmentation of face, eyelids, and gingiva, and others (Kuratsune et al., 1972Go), and 30 years later, Yusho patients still manifested the toxicity.

The worldwide commercial production of PCBs was banned in 1979, and yet, more than 70% of the global production of PCBs is estimated to be still in use or in stock (Hileman, 1993Go). Humans are continuously exposed to PCBs because of their presence in their accidental release from disposal sites (Phaneuf et al., 1995Go) and in our diet, due in part to the accumulation of PCBs in certain species of fish and seafood collected in contaminated areas (Li and Hansen, 1997Go). Despite their gradual decline, PCBs exist as major contaminants of human tissues (Newsome et al., 1995Go).

Toxicities of PCBs (Safe, 1990Go; Brouwer et al., 1999Go), such as body weight loss, endocrine disruption, impairments of reproductive and immune systems, teratogenicity, and carcinogenicity, have been intensively studied over the last 30 years. Spectra of the toxicities are different between the species of animals (McConnell, 1989Go; Safe, 1994Go), and the species difference is believed to occur through the difference in their metabolism of PCBs (Duignan et al., 1987Go, 1988Go). Decreases in serum thyroid hormones in rats by PCBs such as 3,3',4,4',5-pentachlorobiphenyl (3,3',4,4',5-pentaCB), Aroclor 1254, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (Barter and Klaassen, 1994Go; Schuur et al., 1997Go; Van Birgelen et al., 1995Go) have been reported, and the decrease is thought to occur through PCB-mediated induction of hepatic UDP-glucuronosyltransferases (UDP-GTs), especially UGT1A1 and UGT1A6 (Visser, 1996Go). Likewise, some PCB congeners such as 2,3',4,4',5- and 3,3',4,4',5-pentaCBs and 2,2',4,4',5,5'- and 2,3,3',4,4',5-hexachlorobiphenyls (2,2',4,4',5,5'- and 2,3,3',4,4',5-hexaCBs) are reported to decrease the level of serum thyroid hormones and to increase the activity of hepatic drug-metabolizing enzymes in rats (Ness et al., 1993Go; Van Birgelen et al., 1995Go). We have also reported that nonplanar PCBs such as 2,2',4,5,5'-pentaCB and 2,2',3,3',4,6'-hexaCB decrease the level of serum total thyroxine (T4) in both rats and mice (Kato et al., 2001Go). More recently, Craft et al. (2002)Go have reported that TCDD-like and phenobarbital-like PCB congeners induce hypothyroxinemia in both rats and mice through induction of hepatic UDP-GTs and that there is a species difference in magnitude of decrease in serum thyroid hormone level, and the difference is attributed to that in the increase of hepatic UDP-GTs. To date, however, only limited data are available on the species difference in the altered level of serum thyroid hormone by PCBs.

In the present study, we examined the species differences between rats and mice in altered levels of drug-metabolizing enzyme and serum thyroid hormone by Kanechlor-500, a commercial PCB mixture.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals.
Individual methylsulfonyl-PCBs (MeSO2-PCBs) used as analytical standards were synthesized according to the methods of Haraguchi et al. (1987)Go. 4-Methyl-3-MeSO2-2',3',4',5,5'-pentaCB was used as an internal standard in the analysis of MeSO2-PCBs. Panacete 810 (medium-chain triglycerides) was purchased from Nippon Oils and Fats Co. Ltd. (Tokyo, Japan).

Animal treatments.
Male Wistar rats, weighing 160–200 g, and male ddy mice, weighing 28–36 g, were housed, three or four per cage, with free access to commercial chow and tap water, and maintained on a 12-h dark/light cycle (8:00 A.M.-8:00 P.M. light) in an air-controlled room (temperature: 24.5 ± 1°C, humidity: 55 ± 5%). Rats and mice received a single ip injection of KC500 (100 mg/kg body weight) dissolved in Panacete 810 (5 ml/kg). Control animals were treated with vehicle alone (5 ml/kg).

Analysis of serum hormones.
All animals used were killed by decapitation on day 4 after the dosing, and the thyroid gland and liver were removed and weighed. Blood was collected from each animal between 10:30 and 11:30 A.M. After clotting at room temperature, serum was separated by centrifugation and stored at -50°C until used. Levels of total T4, total triiodothyronine (T3), and thyroid-stimulating hormone (TSH) were measured by radioimmunoassays using Amerlex-MT4, Amerlex-MT3 (Ortho-Clinical Diagnostics Co.; Amersham, UK), and Biotrak rTSH [125I] assay system (Amersham Life Science, Ltd.; Little Chalfont, UK), respectively.

Hepatic microsomal enzyme assays.
Hepatic microsomes were prepared according to the method as described previously (Kato et al., 1995aGo). The protein content was determined by the method of Lowry et al. (1951)Go with bovine serum albumin as a standard. Amount of microsomal cytochrome P450 (P450) was estimated according to the method of Omura and Sato (1964)Go. Microsomal O-dealkylase activities of 7-benzyloxy-, 7-ethoxy-, and 7-pentoxy-resorufins were determined by the method of Burke et al. (1985)Go. The activities of microsomal UDP-GT toward T4, 4-nitrophenol, and chloramphenicol were determined by the methods of Barter and Klaassen (1992), Isselbacher et al. (1962)Go and Ishii et al. (1994)Go, respectively. In addition, all UGP-GT activities were measured after activation of UDP-GT by 0.05% Brij 58.

RT-PCR analysis for gene expression of UGT1A1 and UGT1A6.
Total hepatic RNAs were prepared with ISOGEN (NipponGene, Japan) and used for the determination of the gene expression of UDP-GT isoforms, UGT1A1 and UGT1A6, and ribosomal protein L27a (RPL27), an internal control. A portion (4 µg) of total RNA was converted to cDNA by use of poly d(N)6 primer (Pharmacia Biotech) and Moloney murine leukemia virus reverse transcriptase (GIBCO, BRL) in an RT-reaction mixture (20 µl). PCR was performed in a total reaction mixture (25 µl) containing 0.8 µl of the RT-reaction mixture, 0.5 µl of each primer set and AmpliTaq Gold DNA polymerase (Perkin Elmer). The primer sets used were as follows: rat UGT1A1 (Kasahara et al., 2002Go), 5'-TGGTGTGCCGGAGCTCATGTTCG-3' (forward) and 5'-ACTCCGCCCAAGTTCCACAAAAGCA-3' (reverse); rat UGT1A6 (Kasahara et al., 2002Go), 5'-TGCTCGACTTCCTGCAGGTTTC-3' (forward) and 5'-TTCCTGTACTCTCTTAGAGGAGCCA-3' (reverse); mouse UGT1A1 (Bernard et al., 1999Go), 5'-CAGGTTTCTCCTCGTGTGTC-3' (forward) and 5'-CATACTGGAATCCCTTTTGA-3' (reverse); mouse UTG1A6, 5'-TCAGACACTTCCTGCAGGGTTTC-3' (forward) and 5'-TTCCTGTACTCTCTTAGAGGACCCA-3' (reverse). Amplifications of all cDNA examined were performed with GeneAmp PCR System 9700 (PE Applied Biosystems, Foster, Calif., USA). The PCR program used for the analyses of UGT1A1 and UGT1A6 in rats and mice was as follows: pretreatment, at 94°C for 2 min; denaturation at 94°C for 20 s; annealing, at 57°C for 45 s; extension, at 72°C for 45 s; and chase reaction, at 72°C for 10 min. Each PCR product was separated by electrophoresis on a 2% agarose gel and the separated PCR product was visualized by ethidium bromide staining under ultraviolet light. The predicted size of each PCR product is as follows: rat UGT1A1 and UGT1A6 (Kasahara et al., 2002Go), 290 and 300 base pairs (bp), respectively; mouse UGT1A1 (Bernard et al., 1999Go) and UGT1A6, 442 and 318 bp, respectively. In addition, PCR for the RPL27 in rats and mice (Wool et al., 1990Go), an internal standard, was performed with a primer set: 5'-ATCGGTAAGCACCGCAAGCA-3' (forward) and 5'-GGGAGCAACTCCATTATTGT-3' (reverse) for both rats and mice, and the predicted product size is 234 bp.

Determination of MeSO2 metabolites from KC500 in the liver.
Amounts of MeSO2-PCBs in the liver were determined with GC/MS (Mimura et al., 1999Go). M+ and M+2 for MeSO2-tetraCB (m/z 368 and 370, respectively), MeSO2-pentaCB (m/z 402 and 404, respectively), and MeSO2-hexaCB (m/z 436 and 438, respectively) were monitored as selected ions.

Statistics.
The data obtained were statistically analyzed according to Student’s t-test.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Hepatic drug-metabolizing enzymes.
Maximal induction of hepatic drug-metabolizing enzymes by KC500 (100 mg/kg) in rats were reported to be observed at 4 days after the administration (Shimada et al., 1976Go). Therefore, in the present experiments, relative liver weight, microsomal P450 content and microsomal O-dealkylase activities of 7-pentoxy-, 7-benzyroxy-, and 7-ethoxy-resorufins in rats and mice were measured 4 days after the administration of KC500 at a dose of 100 mg/kg.

In both species of rats and mice, KC500-treatment resulted in significant increase in the liver weight: 1.4- and 1.1-fold, respectively (Table 1Go). Likewise, the treatment resulted in significant increases in hepatic microsomal enzymes in rats and mice; P450 content: 3.2- and 1.2-fold, respectively; benzyloxyresorufin O-dealkylase activity (CYP2B and CYP3A): 86- and 10.2-fold, respectively; pentoxyresorufin O-dealkylase activity (CYP2B): 25- and 7.3-fold, respectively; ethoxyresorufin O-dealkylase activity (CYP1A): 46- and 1.9-fold, respectively (Table 2Go). Furthermore, KC500-treatment led to significant increases in UDP-GT activities toward T4 and 4-nitrophenol in rats but not in mice (Table 3Go). UDP-GT activity toward chloramphenicol was extensively increased in rats and slightly in mice.


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TABLE 1 Relative Tissue Weights after the Administration of KC500 to Rats and Mice
 

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TABLE 2 Effects of KC500 on Hepatic Microsomal P450 and Alkoxyresorufin O-Dealkylases in Rats and Mice
 

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TABLE 3 Effects of KC500 on Hepatic Microsomal UDP-Glucuronosyltransferase Activities in Rats and Mice
 
Changes in hepatic gene expression of UGT1A1 and UGT1A6.
Since the species difference between rats and mice in alteration of UDP-GT activity by KC500 was observed (Table 3Go), we further examined the altered gene expression of the UDP-GTs, UGT1A1 and UGT1A6, responsible for glucuronidation of T4 and/or 4-nitrophenol, in KC500-treated rats and mice. In rats, levels of UGT1A1 and UGT1A6 increased in time-dependent manner at least up to 3 days after KC500-treatment, and the increases were observed even 4 days later, whereas in mice, no increase in the UGT1As was observed at any period examined (Fig. 1Go).



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FIG. 1. Representative profile of the agarose gel-electrophoresis of the RT-PCR product for UGT1A1 and UGT1A6 in rats and mice after KC500-treatment. Total RNAs were prepared from the pooled livers of three rats or five mice in each experiment group and used for the RT-PCR analysis, as described in Materials and Methods. Time 0 means the animals were treated with vehicle alone (control). Numbers shown in parentheses represent the numbers of PCR cycles used.

 
Methyl sulfone metabolites of PCBs.
KC500 (100 mg/kg) was administered to rats and mice, and 4 days after the administration, the MeSO2 metabolites in each liver were analyzed (Table 4Go). 3-MeSO2 or 4-MeSO2 derivatives of 2,3',4',5-tetrachlorobiphenyl (2,3',4',5-tetraCB), 2,2',3',4',5-pentaCB, 2,2',4',5',5-pentaCB, 2,2',3',4',5,6-hexaCB, and 2,2',4',5,5',6-hexaCB were detected as main metabolites in rats and mice. The amount of each MeSO2 metabolite produced was 2–9 times higher in mice than in rats, and the total amount of MeSO2 metabolites detected in liver was 5-fold greater in mice as compared with that in rats.


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TABLE 4 Concentrations of Hepatic MeSO2-PCB Metabolites after the Administration of KC500 to Rats and Mice
 
Serum hormone levels.
Effects of KC500 on the levels of serum thyroid hormones, T4 and T3, in rats and mice were examined. Treatments of rats and mice with KC500 decreased total T4 levels to 17 and 27%, respectively, of the corresponding controls, whereas serum total T3 level was slightly decreased in mice (71% of control) but not in rats (Fig. 2Go). In addition, no significant change in the level of serum TSH (Fig. 3Go) or in thyroid weight (Table 1Go) was observed in either species of animals used.



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FIG. 2. Effects of KC500 on levels of serum total thyroxine and triiodothyronine in rats and mice. Animals were killed 4 days after the administration of KC500 (100 mg/kg, ip), and levels of serum thyroid hormones were measured as described in Materials and Methods. Each column represents the mean ± SE (vertical bars) for four to five rats or six to eight mice; *p < 0.05, significantly different from the species-matched controls.

 


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FIG. 3. Effects of KC500 on the level of serum thyroid stimulating hormone in rats and mice. Animals were killed 4 days after the administration of KC500 (100 mg/kg, ip), and levels of serum thyroid stimulating hormone were measured as described in Materials and Methods. Each column represents the mean ± SE (vertical bars) for four to five rats or seven to eight mice.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In the present study, we found for the first time that KC500 treatment resulted in a significant decrease in serum T4 levels in both rats and mice, whereas a significant increase in activity of the UDP-GT responsible for glucuronidation of T4 (T4-UDP-GT) was observed in rats but not in mice. Such species difference in increase of T4-UDP-GT activity by xenobiotics has been reported: clofibrate, phenobarbital, pregnenolone-16{alpha}-carbonitrile, and ß-naphthoflavone increase hepatic T4-UDP-GT activity in rats but not in mice (Viollon-Abadie et al., 1999Go). The previous report and the present findings suggest that in rats, a reduction of serum total T4 level by KC500 would occur at least in part by an increase in T4 glucuronidation through the induction of hepatic T4-UDP-GTs, especially UGT1A1 and UGT1A6 (Schuur et al., 1997Go; Van Birgelen et al., 1995Go; Visser, 1996Go), while in mice, it may occur through alternate mechanisms. This is further supported by the our findings that after treatment with KC500, gene expression of hepatic UGT1A1 and UGT1A6 in the rat liver was enhanced prior to decrease in serum T4 levels, whereas in the mouse liver, such enhancement did not occur.

In general, the decrease in serum T4 level by PCB congeners such as 3,3',4,4'-tetraCB, 2,3',4,4',5'-pentaCB, 2,3,3',4,4',5- and 2,2',4,4',5,5'-hexaCBs and Aroclor 1254 have been reported to decrease serum thyroid hormone levels in rats (Barter and Klaassen, 1994Go; Liu et al., 1995Go; Ness et al., 1993Go; Van Birgelen et al., 1995Go). This has been thought to occur through induction of T4-UDP-GTs (Schuur et al., 1997Go; Van Birgelen et al., 1995Go; Visser, 1996Go). Our preliminary study (Kato et al., 2002Go), however, indicated that the activity of T4-UDP-GT was significantly increased in Wistar rats, but not in UGT1A-deficient Gunn rats, by KC500 treatment, although serum total T4 levels in both strains of rat were significantly reduced by the treatment. This suggests strongly that the decrease in serum total T4 levels in not only mice but also rats by PCBs would not be induced only through increase in hepatic T4 glucuronidation. PCB congeners (Chauhan et al., 2000Go) and their hydroxylated metabolites (Brouwer et al., 1998Go; Lans et al., 1993Go) show in vitro binding to transthyretin (TTR), a major thyroid hormone transporting protein, which plays an essential role in the homeostasis of T4 (Schreiber et al., 1995Go), suggesting that decrease in the level of serum T4 in KC500-treated mice and rats might occur, at least in part, through a TTR-associated pathway.

To determine the mechanism for decrease in the serum T3 level in KC500-treated mice, we examined KC500-altered levels of hepatic microsomal UGT2B2 enzyme by Western blotting with antirat UGT2B polyclonal antibody, because T3 glucuronidation is efficiently mediated by UGT2B2 enzyme (van Raaij et al., 1993Go; Visser et al., 1993Go). UGT2B2, however, was not detected in any experimental group of rats or mice, although other UGT2B subfamily enzymes (UGT2B3, UGT2B6, and UGT2B12) were detected in all the experimental groups examined (data not shown). Accordingly, the decrease in serum T3 levels in mice by KC500 seems to occur without increase in the UGT2B2.

As a possible mechanism for the decrease in the levels of serum T4 and T3, increase in estrogen sulfotransferase, which efficiently catalyzes the sulfation of iodothyronines T4 and T3 (Kester et al., 1999Go), might be considered. However, since Aroclor 1254 has been reported to show only a minimal impact on overall outer ring deiodination activity (Hood and Klaassen, 2000Go), KC500 seems to hardly induce deiodinases converting T4 to T3. Furthermore, we showed in the present study that serum TSH levels in either rats or mice was not significantly changed by KC500, indicating that TSH is not attributed to a decrease in serum T4 and/or T3 levels by KC500. In addition, it had been reported that serum TSH level was little affected by PCBs (Hallgren et al., 2001Go; Hood et al., 1999Go; Liu et al., 1995Go).

We have previously reported that 3-MeSO2 metabolites of nonplanar PCBs have definite activities for inducing hepatic microsomal drug-metabolizing enzymes, and their activities were much greater than parent PCBs (Kato et al., 1995aGo,bGo, 1999bGo). We further demonstrated that 3-MeSO2-2,3',4',5-tetraCB, 3-MeSO2-2,2',3',4',5-pentaCB, 3-MeSO2-2,2',4',5,5'-pentaCB, 4-MeSO2-2,2',4',5,5'-pentaCB, 3-MeSO2-2,2',3',4',5,6-hexaCB, 3-MeSO2-2,2',4',5,5',6-hexaCB and 4-MeSO2-2,2',4',5,5',6-hexaCB could reduce serum T4 level (Kato et al., 1998Go, 1999aGo). KC500, used in the present study, includes many nonplanar PCBs which were biotransformed to MeSO2 metabolites, thus posing the possibility that MeSO2-PCB metabolites formed are attributed to decrease in the level of serum thyroid hormones in KC500-treated rats and mice. However, species difference between rats and mice in induced levels of hepatic drug-metabolizing enzymes was not necessarily correlated with that in the decreased level of serum thyroid hormones. Although hepatic concentrations of MeSO2-PCB metabolites in KC500-treated mice were much higher than those in KC500-treated rats, the decreased levels in serum T4 in rats and mice were almost the same. Furthermore, the magnitude of the induction of T4-UDP-GT and cytochrome P450 enzymes was greater in rats than in mice, despite hepatic levels of MeSO2 metabolites being greater in mice than in rats. Namely, the difference between rats and mice in the level of MeSO2 metabolites was not correlated with the difference in induction of microsomal drug-metabolizing enzymes or in reduction of serum thyroid hormone.

In conclusion, we demonstrate for the first time that in mice, the decrease in serum T4 level by KC500 occurs without increase in the T4-UDP-GTs, UGT1A1, and UGT1A6 responsible for glucuronidation of T4, and further suggest that the decrease in rats would not be produced only through induction of the T4-UDP-GTs. However, exact mechanisms for KC500-mediated decrease in serum thyroid hormone levels in rats and mice remain unclear, and further studies are necessary for understanding the susceptibility to PCBs in animals including humans.


    ACKNOWLEDGMENTS
 
We express our appreciation to Dr. Shinichi Ikushiro (Himeji Institute of Technology) for the generous gift of antibodies against rat UGT2B isoforms. This work was supported in part by a Grant-in-Aid for Scientific Research (C) (no. 12680549, Y.K.; 12672180, K.H.; 14572119, N.K.) from the Japan Society for the Promotion of Science, and by a Health Sciences Research Grant for Research on Environmental Health (H11-Seikatsu-024, M.D., H13-Seikatsu-013, Y.K.) from the Ministry of Health and Welfare of Japan.


    NOTES
 
1 To whom correspondence should be addressed. Fax: +81 54 264 56 35. E-mail: kato{at}ys7.u-shizuoka-ken.ac.jp. Back


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 DISCUSSION
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