* Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina;
Experimental Toxicology Division and
Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
Received September 7, 2000; accepted January 7, 2001
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ABSTRACT |
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Key Words: polybrominated diphenyl ether; thyroid hormone; hepatic enzyme activity; rat; benchmark dose.
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INTRODUCTION |
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PBDEs are structurally similar to polychlorinated biphenyls (PCBs), dioxins (TCDDs), and thyroid hormones, and therefore may act as endocrine disruptors via interference with thyroid hormone (TH) homeostasis (Brouwer et al., 1998; Hooper and McDonald, 2000
). Chronic exposure to deca-BDE results in an increased incidence of thyroid hyperplasia and tumors in mice, but not rats (NTP, 1986
). Reduction in plasma thyroxine (T4) has been reported in young rodents (both rats and mice) following a 14-day exposure to commercial PBDE mixtures (Bromkal 70 or DE-71) or BDE-47 (Fowles et al., 1994
; Darnerud and Sinjari, 1996
; Hallgren and Darnerud, 1998
). In all cases, however, plasma thyroid stimulating hormone (TSH) concentrations were not affected.
Information on the mechanism by which PBDEs decrease T4 is limited. In vitro data suggest that hydroxylated PBDE congeners will displace T4 from transthyretin, a plasma transport protein (Meerts et al., 2000). Marsh et al. (1998) demonstrated in vitro binding of two hydroxylated PBDE congeners to human TR-
1 and TR-ß. PBDEs have also been demonstrated to induce both phase I and II metabolic enzymes. Induction of uridinediphosphate-glucuronosyltransferase (UDPGT), ethoxyresorufin-O-deethylase (EROD), and pentoxyresorufin-O-deethylase (PROD) activities have been found in both mice and rats exposed to various commercial mixtures and/or BDE-47 (Carlson, 1980a
,b
; Fowles et al., 1994
; Hallgren and Darnerud, 1998
; von Meyerinck et al., 1990
). Carlson (1980a) concluded that the induction potency of the commercial mixtures was negatively correlated to the degree of bromination. Furthermore, some PBDE mixtures were suggested to be either solely phenobarbital-type inducers, such as DE-71 and DE-79 (Carlson, 1980a
), or mixed-type inducers (i.e., phenobarbital and dioxin type) of xenobiotic metabolism, such as Bromkal 70 (von Meyerinck et al., 1990
). BDE-47 has been shown to be a mixed-type inducer (Hallgren and Darnerud, 1998
). Recently, some PBDE congeners (BDE-47, -77, and -138) were shown to exhibit Ah receptorantagonistic activity in vitro (Meerts et al., 1998
). Information on the induction of UDPGT is limited to one study using single doses of the three commercial mixtures; Carlson (1980a) found increased UDPGT activity with DE-71 and DE-79, but not DE-83R. Clearly, the data available for PBDE effects on thyroid homeostasis are limited.
The present studies were conducted to contrast and compare the dose-response relationships of short-term exposure to three commercial PBDE mixtures (DE-71, DE-79, and DE-83R) on T4, triiodothyronine (T3), and TSH concentrations, as well as hepatic enzymatic activities (EROD, PROD, and UDPGT). These mixtures are representative of the three types of commercial mixtures used worldwide (Sjodin, 2000). These data are needed to increase our understanding of mechanism(s) by which PBDEs interfere with thyroid hormone homeostasis.
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MATERIALS AND METHODS |
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Chemicals and treatment.
DE-71 (lot 7550OK20A), DE-79 (lot 8525DG01A), and DE-83R (lot 7480DL10C) were generously supplied by the Great Lakes Chemical Corporation (West Lafayette, IN) (Table 1). The compositions of the different lots were reported to contain 58.1% penta-BDE and 24.6% tetra-BDE for DE-71; 30.7% octa-BDE and 45.1% hepta-BDE for DE-79 (Carlson, 1980a
); and more than 98% deca-BDE for DE-83R (Table 1
). Analysis of the DE-71 mixture compared to another commercial penta-BDE (Bromkal 70-5DE) suggests that the composition may be closer to 35% tetra and 45% penta (see Sjodin, 2000). The dosing solution (or suspension for DE-83R at concentrations of 3 mg/kg/day or above) was prepared by mixing the compounds with corn oil, sonicating for 30 min at 40°C, and diluting in series with corn oil to the desired concentrations (Table 1
). These doses were selected on the basis of results of pilot studies that measured body weights, liver weights, and thyroid hormone concentrations in small numbers of subjects (data not shown). Dosing solutions were administered in 1.0 ml/kg corn oil. All chemicals used in enzyme assays were purchased from Sigma Chemical Co. (St. Louis, MO) and were of the highest grade commercially available.
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Thyroid hormone assay.
Serum total T4 and T3 were measured in duplicate by standard radioimmunoassay (RIA) kits (Diagnostic Products Corporation, Los Angeles, CA). Serum TSH concentrations were analyzed in duplicates with a double antibody RIA method (Zoeller and Rudeen, 1992). Rat TSH RIA kits (including rat TSH antiserum NIDDK-antirat TSH-RIA-6; rat TSH reference preparation NIDDK-rTSH-RP3) were obtained through NIDDK's National Hormone & Pituitary Program. I-125labeled TSH was purchased from Covance Laboratories (Vienna, VA). Intraassay and interassay coefficients of variance for all assays were below 10%.
Hepatic enzyme activities assay.
Liver microsomal fractions were prepared as described previously (DeVito et al., 1993). Microsomal protein concentrations were determined using a protein assay kit (Bio-Rad, Richmond, CA) with bovine serum albumin as the standard. Hepatic microsomal EROD (a marker for CYP1A1 activity) activity was assayed using the method of DeVito et al. (1993). A similar method (DeVito et al., 1993
) was used to measure hepatic microsomal PROD (a marker of CYP2B activity) activity, using pentoxyresorufin as a substrate. All substrate concentrations were 1.5 nM. Both EROD and PROD values were calculated as picomoles (pmol) resorufin per milligram protein per minute, and graphically represented as percentage of control activity.
Hepatic microsomal T4-UDPGT activity was assayed based on the method of Visser et al. (1993). 125Ilabeled T4 was purchased from NEN Life Science Products Inc. (Boston, MA). Aliquots of liver microsomes were diluted to 2 mg protein/ml with 100 mM Tris-HCl (pH = 7.8) containing 5 mM MgCl2. Then 100 µl diluted microsomes was incubated without detergent at 37°C, with purified 1 µM 125I-labeled T4 (around 50,000 dpm) as substrate, 100 µM 6-n-propyl-2-thiouracil (for preventing de-iodination), and 5 mM UDPGA (as cofactor, or no UDPGA for blanks) over a 30-min period. The reaction was stopped by the addition of 200 µl ice-cold methanol, followed by centrifugation at 4°C at 3000 rpm for 5 min. Two hundred microliters of supernatant was transferred to a microtube and mixed with 750 µl 0.1N HCl. The T4-glucuronyl product (T4-G) was then separated by chromatography on Supelco Filtration Column filled with 2 ml lipophilic Sephadex LH-20 in gel suspension. The column was eluated with 2 ml of 0.1N HCl and 8 ml deionized water, and the collected fractions were counted for radioactivity for 1 min on the gamma counter. The calculated UDPGT activity was expressed as picomoles T4-G per milligram protein per minute.
Data analysis.
All data were analyzed as the percentage of the respective control means. Absolute control values are presented in Table 2. One-way ANOVAs followed by Duncan's Multiple Range Tests were used to compare differences among treatment groups, with acceptable significance levels set at p < 0.05. All data are presented as mean ± SEM (n = 8, except for 0.3 mg/kg/day for DE-71 where n = 4). No-observed-effect-levels (NOELs) were defined as the lowest dose without significant effect.
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RESULTS |
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NOELs and model estimates for BMDs and BMDLs are shown in Table 3. NOELs and BMDs are fairly similar for most end points. The comparison of BMDs and NOELs for T4 and UDPGT values were the exception. BMD estimates of T4 and UDPGT were better estimates of potency compared to NOELs, based on visual inspection of the data.
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DISCUSSION |
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DE-71 and DE-79 had similar effects on thyroid hormones. Both compounds decreased circulating total serum T4 concentrations in a dose-dependent manner, reaching 7580% decreases at the highest doses of DE-71 (300 mg/kg/day) and DE-79 (100 mg/kg/day). Total serum T3 was affected to a much smaller degree, with only 2530% decreases. There were no effects of either mixture on TSH concentrations. This pattern of effects is consistent with other reports of exposure to PBDE mixtures and individual congeners. Darnerud and Sinjari (1996) demonstrated decreased total plasma T4 in both rats and mice exposed for 14 days to 18 or 36 mg/kg/day of Bromkal 70. These same authors also exposed mice to 18 mg/kg/day BDE-47 and found a 31% decrease in total plasma T4. Hallgren and Darnerud (1998) found decreases in both total and free plasma T4 with no increase in TSH following a 14-day exposure of female rats to 18 mg/kg/day BDE-47. Mice exposed for 14 days to up to 72 mg/kg/day DE-71 had decreased free and total serum T4 (Fowles et al., 1994). These data clearly demonstrate that PBDEs impact circulating concentrations of T4.
Two conclusions can be drawn from the hepatic enzyme assays. The first conclusion is that both DE-71 and DE-79 are mixed-type inducers of hepatic enzymatic activity. Second, these two mixtures may decrease circulating concentrations of T4, at least partially, by increasing hepatic glucuronidation. Evidence in support of the conclusion of mixed induction includes increases in both EROD (induced by activation of the Ah receptor) and PROD activities [induced via interactions of multiple genes associated with the phenobarbital responsive unit (Ganem et al., 1999)] (see Fig. 3
). These findings are consistent with a number of previous investigations. Early work by Carlson (1980a,b) showed that both 14- and 90-day exposure to penta- and octa-BDE mixtures increased hepatic benzo-[a]-pyrene and p-nitroanisole metabolism. Consistent with our findings, Carlson (1980a) also failed to find any hepatic enzyme induction with 14-day exposures to a deca-BDE mixture. von Meyerinck et al. (1990) found increased EROD and benzphetamine N-demethylation activity in hepatic tissue from mice treated for 14 days with Bromkal 70. Increased EROD and PROD activity were found in mice exposed to DE-71 for 14 days, but only increased PROD was found following acute exposure (Fowles et al., 1994
). The small amount of induction of EROD in these mice (about 3.3-fold), compared to the 20-fold induction in rats found in the current study, could be due to species differences and/or the differences in the commercial mixtures used. More recently, Hallgren and Darnerud (1998) reported increased EROD (3-fold) and PROD (14-fold) activities in rats after 14 days of exposure to BDE-47.
One of the mechanisms responsible for thyroid hormone depletion is induction of the phase II UDPGT enzymes in liver and subsequent biliary elimination of thyroxine as T4-glucuronide (for review see: Mackenzie et al., 1997). Hallgren and Darnerud (1998) demonstrated a small increase in T4-gluronidation following exposure to BDE-47. DE-71 and DE-79 exposure resulted in increased napthol glucuronidation in rats exposed for 14 days (Carlson, 1980a). T4 glucuronidation is associated with several isozymes of UDPGTs (Visser et al., 1993
), one of which (UDPGT 1A6 isozyme) is controlled by the arylhydrocarbon (Ah) receptor signal transduction pathway (Brouwer et al., 1998
). Hepatic UDPGT induction has been suggested as the dominant mechanism for thyroid hormone depletion by dioxinlike polyhalogenated aromatic hydrocarbons (PHAHs) (Kohn et al., 1996
; Schuur et al., 1997
). However, the mechanisms by which PBDEs (a class of PHAHs) interfere with thyroid hormone homeostasis are not well studied and are often inconclusive. In our study, a dose-related reduction in plasma T4 concentrations was consistent with a dose-related induction in hepatic UDPGT activity, suggesting that T4 glucuronidation was one factor contributing to the reduction in serum T4. DE-79 showed potency comparable to DE-71 in plasma T4 depletion, but induced UDPGT only approximately half as much as DE-71. This suggests mechanisms other than T4 glucuronidation may also contribute to the plasma T4 depletion. The thyroid gland itself may be affected by bromine, if liberated from the PBDE, which would inhibit iodine uptake into the thyroid (Velicky et al., 1998
). However, this is not necessarily a tenable argument, as iodine uptake inhibitors such as perchlorate cause decreases in both T3 and T4 (Wolf, 1998
), and in the present study, DE-71 and DE-79 affected T4 predominantly. Interference with the pituitarythyroid axis is not a likely mechanism of PBDEs, as the present results did not show significant changes in TSH concentrations in spite of the considerable reduction in serum T4 and modest decreases in serum T3. TSH increases have been reported following 4-day exposures to other xenobiotics (O'Connor et al., 1999
), so the lack of TSH increase may not be due to the short duration of exposure. Alternatively, hydroxylated PBDEs have been shown in vitro to displace T4 from binding to the plasma transport protein, transthyretin (Meerts et al., 2000
). This could result, hypothetically, in increased hepatic catabolism of thyroid hormones (Meerts et al., 2000
). However, whether the hydroxylated PBDEs tested by Meerts et al. (2000) are metabolites of the PBDE mixtures examined in the present study is unknown.
The lack of effect of DE-83R, which consists of more than 98% of the highly brominated deca-BDE, is consistent with negative findings from other short-term dosing studies in rats. A 14-day exposure to deca-BDE in rats failed to find any evidence of induction of CYP proteins or UDPGT activity (Carlson, 1980a). This may be due to low solubility of this compound in aqueous solutions as well as the corn oil vehicle, and very limited absorption of these very highly brominated congeners. In rats orally administered specific congeners, more than 86% of the dose for 2,2',4,4'-tetra-BDE (Orn and Lasson-Wehler, 1998) and 57% of the dose for 2,2',4,4',5-penta-BDE (Hakk et al., 1999
) were retained after 72 h. A 12-day feeding study with deca-BDE found absorption of less than 1% of the administered dose (el Dareer et al., 1987
). Chronic exposures to deca-BDE, however, have revealed thyroid and liver tumors (NTP, 1986
). These results suggest that prolonged exposure to the deca-BDE can result in the accumulation of this chemical or its metabolites in rodents. Induction of hepatic enzymes and disruption of thyroid hormones may, therefore, be likely following longer exposures.
A comparison of NOELs and BMDs suggest that the latter may provide better potency estimates for comparisons of dose-effect functions. For example, the NOELs for T4 reduction are 10 and 3 mg/kg/day for DE-71 and DE-79, respectively. The BMDs for the same groups were 12.7 and 9.2 mg/kg/day. This difference between NOELS and BMDs is primarily due to increased variability in the DE-71dosed animals compared to the DE-79 animals, causing the ANOVA-based approach to require greater differences between treated and control means to reach statistical significance. In the BMD approach, this variation does not lead to an increased estimate and therefore provides a better approximation of potency. Another disparity between NOEL and BMD estimates can been seen in the UDPGT data. The NOEL estimates indicate that DE-79 is more potent than DE-71; however, BMD estimates indicate the opposite. This difference is due primarily to dose spacing. The BMD model can extrapolate between doses and thus provides a more accurate estimate of the potency (Allen et al., 1994; Foster and Auton, 1995
).
In summary, our data show that 4-day in vivo DE-71 or DE-79 exposures induced hypothyroxinemia and UDPGT activity in weanling female rats. DE-71 and DE-79 demonstrated comparable potency and efficacy in terms of decreasing levels of serum thyroid hormones (T4 and T3), but different capability in inducing hepatic enzyme activities. Both DE-71 and DE-79 were mixed inducers of hepatic biotransformation enzymes, but DE-71 showed more dioxin-like effects while DE-79 showed more phenobarbital-like effects. The T4-depleting effects of DE-71 and DE-79 are likely to involve multiple mechanisms of interference in addition to thyroid hormone metabolism. DE-83R (mostly deca-BDE) was ineffective in altering levels of serum thyroid hormones or hepatic EROD, PROD, or UDPGT activity, most likely due to the limited absorption of this highly brominated mixture.
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ACKNOWLEDGMENTS |
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NOTES |
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1 To whom correspondence should be addressed at Neurotoxicology Division, MD-74B, National Health and Environmental Effects Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711. Fax: (919) 541-4849. E-mail: crofton.kevin{at}epa.gov.
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