ToxSci Advance Access originally published online on March 14, 2007
Toxicological Sciences 2007 97(2):504-511; doi:10.1093/toxsci/kfm051
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Tetrabromodiphenyl Ether (BDE 47) Evokes Estrogenicity and Calbindin-D9k Expression through an Estrogen Receptor–Mediated Pathway in the Uterus of Immature Rats
* Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea
Department of Obstetrics and Gynecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5
1 To whom correspondence should be addressed. Fax: +82-43-267-3150. E-mail: ebjeung{at}chungbuk.ac.kr.
Received January 4, 2007; accepted February 22, 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Polybrominated diphenyl ethers (PBDEs), a class of organic brominated flame retardants, have been increasing in the environment and in the tissues and milk of animals, including humans. To date, 209 PBDE congeners have been reported. Among these, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) is the dominant congener found in humans and animals. A number of studies have suggested that BDE 47 possesses the potential to disrupt the endocrine system, as well as reproductive functions. This suggests that BDE 47 may act as a developmental neurotoxin and endocrine disruptor. In this study, we employed immature rats as a developmental model to examine the potential involvement of BDE 47 in the induction of calbindin-D9k (CaBP-9k), which is a novel biomarker for screening estrogenic compounds. Beginning on postnatal day 16, BDE 47 was administered to immature rats in a dose- and time-dependent manner for 3 days. The biological effects of BDE 47 on the induction of CaBP-9k mRNA and protein were examined by semiquantitative RT-PCR and western blotting, respectively. In addition, the physiological role of the estrogen receptor (ER) in BDE 47–induced CaBP-9k expression was examined in vivo. Treatment with a high dose of BDE 47 (200 mg/kg body weight [BW]/day) resulted in a significant increase in CaBP-9k mRNA and protein 24 h after injection, whereas a modest increase was observed with low and medium doses (50 and 100 mg/kg BW/day). Additionally, treatment with the high dose of BDE 47 induced a clear uterotrophic response. Cotreatment with ICI 182,780, an ER antagonist, completely reversed the BDE 47–induced increases in uterine wet weight and CaBP-9k mRNA and protein. Taken together, these results demonstrate that BDE 47 exposure results in increases in CaBP-9k mRNA and protein in the uteri of immature rats. The biochemical pathway for BDE 47–induced activity may involve the ER-mediated signaling pathway. These results provide new insights into the estrogenic effects of BDE 47 at a critical developmental stage of the female reproductive system.
Key Words: BDE 47; uterus; endocrine disruptors; estrogenicity.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Numerous studies have focused on the health risks of low-level exposure to environmental contaminants, both natural and synthetic, that are believed to act as endocrine disruptors (EDs) in humans and animals. EDs can alter normal hormone regulation via several mechanisms, such as binding to hormone receptors, mimicking hormones, or blocking the action of hormones. It also has been reported that some substances may stimulate or inhibit enzymes that play essential roles in hormone synthesis. Some of these chemicals possess estrogen-like activities and can bind to estrogen receptors (ERs) and induce or modulate ER-mediated responses (Dang et al., 2007
; Gray et al., 1997).
Polybrominated diphenyl ethers (PBDEs) are a well-known class of organic brominated flame retardants (BFRs). They have been found in air, soil, sediments, humans, wildlife, and fish (Alaee et al., 2003; Darnerud, 2003; Darnerud et al., 2001; Siddiqi et al., 2003; Strandberg et al., 2001). PBDE concentrations are increasing in the environment as well as in the tissues and milk of animals, including humans (Alaee and Wenning, 2002; Stoker et al., 2005). To date, 209 PBDE congeners have been reported. These vary in the number and position of their bromine residues (Birnbaum and Cohen Hubal, 2006; Birnbaum and Staskal, 2004; Staskal et al., 2005, 2006a,b). However, the mechanisms by which humans and wildlife are exposed remains unclear. Some evidence from animal experiments suggests that PBDEs may disrupt thyroid hormone homeostasis (Darnerud et al., 2001; Hooper and McDonald, 2000; McDonald, 2002; Zhou et al., 2002). Other reports have indicated that PBDEs may possess estrogen-like activities and that the metabolism of these chemicals may modulate or induce biological responses similar to pseudoestrogens (Meerts et al., 2000, 2001; Siddiqi et al., 2003). In addition, PBDEs may cause adverse fetal effects via maternal exposure, and infants may be contaminated with PBDEs via maternal milk (Eriksson et al., 2001). However, there have been only limited in vivo studies of the estrogen-like activities of PBDEs.
2,2',4,4'-Tetrabromodiphenyl ether (BDE 47) is the dominant PBDE congener found in humans and animals. It has been found in almost all environmental specimens and living organisms (Staskal et al., 2006b). The biological and toxicological properties of BDE 47 may be determined by its bromine substitution pattern (Birnbaum and Staskal, 2004). A number of studies have suggested that BDE 47 has the potential to disrupt endocrine homeostasis (Darnerud et al., 2001; Hooper and McDonald, 2000; McDonald, 2002; Zhou et al., 2002), as well as reproductive functions (Staskal et al., 2006a). In addition, it has been demonstrated that BDE 47 may act as a developmental neurotoxin and an ED (Birnbaum and Staskal, 2004; Eriksson et al., 2001; Stoker et al., 2004). The toxicokinetic properties of BDE 47 have been investigated in order to elucidate the health risks of this chemical (Staskal et al., 2005, 2006a,b). However, information on the toxicological effects of BDE 47 on the male and female reproductive tracts is very limited.
Numerous in vitro and in vivo experimental systems have been developed to evaluate the health risks of ED exposure. In vitro methods include ER-binding assays, MCF cell proliferation assays, and the yeast-estrogen-screen cell assay (Miller et al., 2000; Seifert et al., 1988). In vivo methods include an uterotrophic bioassay in ovariectomized (OVX) adult and immature rodents, age at vaginal opening in prepubescent rats, vaginal cytology in adult OVX rats, and estrus cyclicity in intact rats (Balaguer et al., 1999; Gray et al., 1997). Induced biomarkers for detecting EDs include pS2, MUC1, the androgen receptor, the progesterone receptor (PR), the ER, clusterin, complement C3, lactoferrin, vitellogenin, and cathepsin B (Heppell et al., 1995; Ren et al., 1997). Recently, calbindin-D9k (CaBP-9k) has been shown to be a novel biomarker for screening EDs (An et al., 2002, 2003). CaBP-9k, a cytosolic protein, is a member of the family of vitamin D–dependent calcium-binding proteins with high affinity for calcium (Christakos et al., 1989; Kumar et al., 1989). It has been reported that the CaBP-9k gene is localized on the X chromosome. It consists of three exons and carries four Alu repeats (Jeung et al., 1992, 1994). It has been demonstrated that CaBP-9k is expressed primarily in the intestine, kidney, uterus, bone (Armbrecht et al., 1989; Delorme et al., 1983; Mathieu et al., 1989; Seifert et al., 1988), lung (Dupret et al., 1992), and pituitary gland (Nguyen et al., 2005). Functionally, CaBP-9k is involved in intestinal calcium absorption and is regulated at the transcriptional and posttranscriptional levels by 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D (Darwish and DeLuca, 1992; Roche et al., 1986; Wasserman and Fullmer, 1989). For its hormonal functions, the CaBP-9k gene is controlled primarily by sex steroid hormones. In rat uteri, the expression of the CaBP-9k gene is upregulated by estrogen and downregulated by progesterone during the estrous cycle and in early pregnancy (Krisinger et al., 1992, 1994; L'Horset et al., 1993, 1994). Additionally, our previous study demonstrated that uterine CaBP-9k is a useful biomarker to detect the estrogenicity of EDs in immature rats (Dang et al., 2007).
In this study, we employed immature rats as an in vivo model to demonstrate the estrogenicity of BDE 47 in the induction of CaBP-9k mRNA and protein during critical developmental stages of the reproductive system. Immature rats were treated with BDE 47 in a dose- and time-dependent manner, and the expression levels of CaBP-9k mRNA and protein were measured by semiquantitative RT-PCR and western blot analyses, respectively. In addition, ICI 182,780, an antiestrogen, was used to examine the potential involvement of ERs in the BDE 47–induced response in vivo.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals and treatments.
Immature female Sprague-Dawley (SD) rats (16 days old) were obtained from Biolink Co. Ltd (Cheongju, Korea). All animals were maintained in polycarbonate cages and used after acclimation to an environmentally controlled room (temperature 23 ± 2°C, relative humidity 50 ± 10%, frequent ventilation, 12-h light-dark cycle). They were fed soy-free pellet food (Samyang Ltd, Seoul, Korea) and tap water ad libitum throughout the experimental period, as described in our previous studies (Dang et al., 2006
, 2007). All experimental procedures and animal use were approved by the Ethics Committee of the Chungbuk National University.
In the dose-dependent experiment, immature rats (n = 3) were sc injected with BDE 47 (ChemService, West Chester, PA) dissolved in corn oil (Sigma–Aldrich Corp., St Louis, MO) at doses of 50, 100, and 200 mg/kg body weight (BW) and euthanized after 24 h. For the positive control (n = 3), SD immature rats were given 50 µg/kg BW of 17
-ethinyl estradiol (EE). As a negative control, three immature rats were injected sc with corn oil. In parallel with the dose-dependent experiment, a time-dependent experiment was performed, in which five groups of three animals were injected sc with a high dose of BDE 47 (200 mg/kg BW), with EE (50 µg/kg BW) as a positive control or with corn oil as a negative control. The groups were euthanized at 3, 6, 12, 24, and 48 h after injection.
In addition, one group of rats was treated with a high dose (200 mg/kg BW) of BDE 47, and the other group was sc injected with ICI 182,780, an ER antagonist, at a dose of 25 µg per rat 30 min before treatment with BDE 47 (200 mg/kg BW). The rats were euthanized 24 h after injection.
Semiquantitative RT-PCR.
Rats were euthanized by inhalation of carbon dioxide. The uteri were excised rapidly and washed in cold sterile 0.9% NaCl as previously described (Hong et al., 2005). Total RNA was extracted using Trizol reagent (Invitrogen, Carlsbad, CA) according to manufacturer's suggestions, and the concentration of total RNA was determined by the absorbance at 260/280 nm. An internal control gene, 1A, was employed to control for variation in mRNA concentrations in the PCRs (Dang et al., 2006). Briefly, total RNA was purified as described above, and 2 µg of total RNA from the immature rats were reverse transcribed into first-strand cDNA using Moloney-Murine Leukemia Virus reverse transcriptase (Ambion Inc., Austin, TX) and a 9-mer random primer. Aliquots of 1 µl were amplified using different numbers of cycles and annealing temperatures. The reactions were performed as follows: 95°C for 5 min, 95°C for 30 s, 55°C for 30 s, and 72°C 45 s, with an extension at 72°C for 10 min. Cycling kinetics were performed using 20, 25, and 30 cycles to ensure linearity of PCR product detection. The PCR product (8 µl) was loaded on a 2% agarose gel and stained with ethidium bromide. The intensity of the PCR band was scanned and analyzed with the Molecular Analysis Program version 4.5.1 (Quantity One, Bio-Rad, Hercules, CA).
Western blot analysis.
Protein was extracted with Proprep solution (Intron Co., Seoul, South Korea) according to the supplier's suggestions. Fifty micrograms of cytosolic protein was loaded on 15% SDS-PAGE gels and transferred to PVDF membranes (Amersham Pharmacia Biotech, Rockville, MD) using a tank transfer system (Bio-Rad) according to the manufacturer's instructions. Membranes were blocked from nonspecific reactions overnight in PBS-Tween containing 5% skim milk, prior to incubation with a rabbit polyclonal antibody (1:500) specific for rat CaBP-9k. Horseradish peroxidase–conjugated secondary antibody (1:3000) from Santa Cruz Biotechnology (Santa Cruz, CA) was visualized using a Western light chemiluminescent system (Amersham Pharmacia Biotech). CaBP-9k levels were quantified by the Chemi Doc XRS system using Quantity One Software (Bio-Rad) and standardized against the beta-actin levels of each sample.
Data analysis.
The data were represented as the means ± SDs and analyzed by one-way ANOVA followed by Tukey's multiple comparison test. A value of p < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Uterotrophic Response to BDE 47 Exposure
Dose and time responses following BDE 47 exposure were examined by an uterotrophic bioassay on the uteri of immature rats. The time course was considered to be a critical step in understanding the dose-response relationship of EDs. As shown in Figure 1A, a significant increase in uterine wet weight was observed at 24 h after injection with a high dose (200 mg/kg BW) of BDE, whereas a modest increase was observed with the low and medium doses (50 and 100 mg/kg BW). A significant increase was seen as early as 6 h after injection with a high dose of BDE 47 (p < 0.05). The uterotrophic response level peaked at 12 h and continued until 24 h after the injection (Fig. 1B). As expected, EE treatment (50 µg/kg BW) induced a tremendous increase as early as 3 h and peaked at 6 h after injection (p < 0.001). Treatment with ICI 182,780 (25 µg) completely reversed the BDE 47–induced increase in uterine wet weight in immature rats (Fig. 1C), indicating that the uterotrophic effect evoked by BDE 47 was completely attenuated in the presence of the ER antagonist ICI 182,780. These results suggest that the BDE 47–induced increase in uterotrophic responses is mediated through an ER-dependent pathway.
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Effects of BDE 47 on Expression of CaBP-9k mRNA
The effect of BDE 47 on the induction of CaBP-9k mRNA was evaluated in the uteri of immature rats by semiquantitative RT-PCR. As seen in Figure 2, a significant increase in CaBP-9k mRNA expression was observed in a dose-dependent manner following BDE 47 exposure (50, 100, and 200 mg/kg BW). In a time course experiment, CaBP-9k mRNA was significantly induced by a high dose (200 mg/kg BW) of BDE 47, as compared with the vehicle, at all time points (Fig. 3). CaBP-9k mRNA increased significantly as early as 3 h and peaked at 6 h after the injection (p < 0.05). As shown in Figure 3, a significant increase in the mRNA with high dose of BDE 47 was observed until 48 h after the injection. EE-induced CaBP-9k mRNA expression peaked at 12 h and continued until 48 h after injection (Fig. 2). As shown in Figure 4, cotreatment with ICI 182,780 completely reversed BDE 47–induced CaBP-9k mRNA induction in the uteri of immature rats. These results indicate that the significant biological effect of BDE 47 on the induction of CaBP-9k mRNA may involve an ER-mediated physiologic response in vivo.
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Effects of BDE 47 on the Expression of CaBP-9k Protein
The dose- and time-dependent effects of BDE 47 on the expression of CaBP-9k protein were assessed by western blot analysis. As shown in Figure 5, a high dose of BDE 47 (200 mg/kg BW) induced an increase in CaBP-9k after 24 h. In a time-dependent experiment, injection with a high dose of BDE 47 significantly increased uterine CaBP-9k protein in immature rats (Fig. 6). A significantly increased level of CaBP-9k was observed as early as 3 h and peaked at 24 h after treatment, as compared with the vehicle (p < 0.05). This upregulation continued until 48 h after treatment (Fig. 6). As a positive control, the administration of a single dose of EE (50 µg/kg BW) induced a significant increase in CaBP-9k protein as early as 3 h and peaked at 24 h (p < 0.001). As seen in Figure 7, the level of CaBP-9k protein increased significantly at 24 h in response to BDE 47, whereas cotreatment with ICI 182,780 significantly attenuated the BDE 47–induced expression of CaBP-9k in the uteri of immature rats.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Numerous studies have reported on the possibility that EDs in the environment may modulate the endocrine systems of animals and humans and cause potentially adverse health effects. EDs are naturally occurring or synthetic chemicals that can alter normal hormone regulation via several mechanisms, such as binding to hormone receptors, mimicking hormones, or blocking the action of hormones. Some EDs may stimulate or inhibit enzymes that play essential roles in hormone synthesis. Even very low levels of EDs can alter functioning of the endocrine system (Dang et al., 2007
).
PBDEs are a well-known class of BFRs that have been found in air, soil, sediments, humans, wildlife, and fish (Alaee et al., 2003; Darnerud, 2003; Darnerud et al., 2001; Siddiqi et al., 2003; Strandberg et al., 2001). To date, 209 PBDE congeners have been reported (Birnbaum and Cohen Hubal, 2006; Birnbaum and Staskal, 2004; Staskal et al., 2005, 2006a,b). These have been divided into 10 groups of homologs that vary in their number of bromines (Birnbaum and Cohen Hubal, 2006). The positions of the bromines may determine the biological and toxicological effects of PBDEs. It has been demonstrated that chemical structures with fewer bromines may be more toxic than the higher bromine congeners (Birnbaum and Staskal, 2004). However, the mechanisms by which humans and wildlife are exposed to PBDEs remain unclear. A recent study reported that high concentrations of PBDEs were found in rat maternal and neonatal tissues, suggesting that these chemicals may interfere with normal sexual development and sexually dimorphic behavior (Lilienthal et al., 2006). However, there have been only limited in vivo studies on the estrogenic activities of PBDEs. A dominant PBDE congener, BDE 47, appears to possess the potential to disrupt endocrine and reproductive functions (Birnbaum and Staskal, 2004; Eriksson et al., 2001; Stoker et al., 2004). The estrogenicity of PBDEs, including BDE 47, is considered to be about the same as that of biphenol A, an environmental estrogenic compound (Meerts et al., 2001). A few biomarkers, i.e., cytochrome P450 (CYPs), were employed to evaluate in vivo effects of BDE 47; a significant increase of CYP2B was observed at the high dose of BDE 47 (100 mg/kg BW) in female mice (Staskal et al., 2005). The present study was designed to examine the biological effects of BDE 47 on the induction of CaBP-9k, a novel biomarker for ED screening, using an immature rat model.
A significant increase in uterine wet weight is observed as early as 6 h and peaks at 12 h after injection with a high dose (200 mg/kg BW) of BDE 47. Significant increases in wet weight continue until 24 h after injection. In addition, the uterotrophic response evoked by BDE 47 is attenuated significantly in the presence of the ER antagonist ICI 182,780, indicating that BDE 47 may act via an ER-mediated physiologic response. It has been demonstrated that the uterotrophic bioassay can identify environmental chemicals with ER-mediated actions (Owens and Ashby, 2002). This method is also considered to be a reliable test in vivo for screening estrogenic agonists and antagonists. Previous studies have suggested that the toxicokinetics of BDE 47 differ between developing and adult mice (Staskal et al., 2006a). However, knowledge of the toxicological effects of BDE 47 on male and female reproductive tracts is very limited. Furthermore, the in vivo estrogenic activity of this chemical has yet to be examined, especially during critical windows of sensitivity to ED exposure.
CaBP-9k, a vitamin D–dependent calcium-binding protein, has been shown to be a novel biomarker for detecting the estrogenicity of EDs in estrogen-sensitive tissues. The expression of CaBP-9k mRNA and protein induced by ED exposure is considered to be a very sensitive and powerful tool for detecting estrogenic activities of environmental chemicals (Choi and Jeung, 2003). In a previous study, we demonstrated that a single injection with an estrogenic compound increased the uterotrophic response and the induction of CaBP-9k mRNA and protein in the uterus of immature rats during the critical developmental stage of the reproductive system (Dang et al., 2007). In addition, the existence of an ED susceptibility window in reproductive tissues has been reported previously by us and others (Dang et al., 2006; Naciff et al., 2003).
In the present study, we used immature rats as an in vivo model for evaluating the estrogenicity of BDE 47 in the induction of CaBP-9k. Both CaBP-9k mRNA and protein were enhanced significantly at 24 h following a high dose of BDE 47 (200 mg/kg BW). It is of interest that, although even low and medium doses of BDE 47 significantly increased the levels of CaBP-9k mRNA, only the high dose significantly increased the expression of CaBP-9k protein. The levels of CaBP-9k mRNA peaked at 6 h and continued until 48 h after treatment, whereas the highest expression of CaBP-9k protein was observed at 24 h. A difference in response to BDE 47 between CaBP-9k mRNA and protein may be explained by translational efficiency. As expected, after treatment with a single dose (50 µg/kg BW) of EE, the expression of CaBP-9k mRNA and protein was enhanced significantly at 3 h, with the highest responses at 12 and 24 h.
The induction of CaBP-9k mRNA and protein by a single injection of an ED appears to be mediated by an ER-dependent pathway in the uterus of immature rats (Dang et al., 2007). Two ER subtypes (ER and ERß) have been shown to regulate events involving estrogen. Although ER and ERß share some functional characteristics, distinct molecular mechanisms control their genes (Frasor et al., 2003). In immature rats, the induction of uterine CaBP-9k is influenced by EDs through the ER-mediated pathway, but not the ERß pathway (Lee et al., 2005). In addition, it has been reported that genistein significantly induces the CaBP-9k gene, indicating that ER may play a role in uterine CaBP-9k gene expression in immature rats (Lee et al., 2004). In our previous study, we demonstrated that the ED-induced expression of CaBP-9k mRNA and protein was reversed or abolished by coadministration of RU486 or ICI 182,780. This indicates that these synthetic chemicals may possess both progestogenic and estrogenic characteristics and could act via PRs and ERs in the induction of uterine CaBP-9k mRNA and protein in the immature mouse model (Jung et al., 2005). A comparative in vivo assessment of CaBP-9k transcriptional and translational levels is a critical step toward understanding the mechanism underlying the estrogenic activities of EDs (Dang et al., 2007). In the present study, the potential involvement of ERs in the induction of ER-mediated physiologic responses was examined via the biochemical pathway of BDE 47 action in vivo. Interestingly, the estrogenic effect of BDE 47 on the expression of CaBP-9k mRNA and protein in immature rat uteri was completely antagonized by 25 µg of pure ICI 182,780. This suggests that the BDE 47–induced uterotrophic effect and induction of CaBP-9k expression are mediated by the ER and an ER-dependent pathway. PBDEs may stimulate ER-mediated luciferase induction in vitro and act as agonists of both ER and ERß (Meerts et al., 2001). An alteration in programmed cell death also may be induced by BDE 47. An increase in apoptosis and a decrease in antiapoptotic gene expression following BDE 47 exposure in vitro have been reported (Hook et al., 2006). However, our knowledge of the biological and toxicological properties of BDE 47 is very limited, especially in estrogenic target tissues. The findings in the present study provide new insights into the estrogenicity of BDE 47, as well as PBDEs, in vivo.
In conclusion, we demonstrated that exposure to BDE 47 results in an increase in uterine weight and the induction of CaBP-9k mRNA and protein expression in the uteri of immature rats. The biochemical pathway of BDE 47's in vivo action may involve the ER and ER-mediated pathway. These findings provide new insights into the estrogenic effect of BDE 47 in estrogen-responsive tissues, especially during the critical developmental stage of female reproductive system.
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ACKNOWLEDGMENTS |
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This work was supported by the Research Project on the Production of Bio-organs (no. 200508010701) of the Ministry of Agriculture and Forestry and the Ministry of Education and Human Resources Development, the Ministry of Commerce, Industry and Energy, and the Ministry of Labor through the fostering project of the Lab of Excellency. In addition, the authors acknowledge a graduate fellowship provided by the Brain Korea 21 Project in 2006.
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  V. H. Dang, T. H. Nguyen, K.-C. Choi, and E.-B. Jeung A Calcium-Binding Protein, Calbindin-D9k, Is Regulated through an Estrogen-Receptor Mediated Mechanism following Xenoestrogen Exposure in the GH3 Cell Line Toxicol. Sci., August 1, 2007; 98(2): 408 - 415. [Abstract] [Full Text] [PDF]
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