ToxSci Advance Access originally published online on June 12, 2007
Toxicological Sciences 2007 99(1):118-125; doi:10.1093/toxsci/kfm148
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Metabolic Barrier against Bisphenol A in Rat Uterine Endometrium
* Department of Veterinary Biochemistry, School of Veterinary Medicine
Department of Environmental Biochemistry
Department of Biology, Faculty of Environmental System, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan 069-8501
1 To whom correspondence should be addressed at Laboratory of Veterinary Biochemistry, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido 069-8501, Japan. Fax: +81-11-387-5890. E-mail: h-yokota{at}rakuno.ac.jp.
Received March 9, 2007; accepted June 1, 2007
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ABSTRACT |
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Exposure to environmental chemicals with estrogenic activity during the early stage of pregnancy can seriously affect embryonic development and the maintenance of pregnancy. To estimate the metabolism and pharmacodynamics of a xenoestrogen, bisphenol A, in a reproductive organ, the metabolite of bisphenol A was analyzed after incubating a rat uterine sac in buffer solutions containing the chemical. When the inner or the outer side of the uterine sac was exposed to bisphenol A, the concentration of the parent chemical was decreased in buffer solution and then, only one metabolite, bisphenol A-glucuronide, was observed only in the outer, that is, the maternal, side. A small amount of the parent chemical could pass through the uterine sac without being modified. Uridine diphosphate (UDP)-glucuronosyltransferase (UGT) was shown by immunohistochemical staining analysis to be distributed in epithelial cells of the endometrium, oviduct, and uterine glands. Based on measurements of enzyme activity and on Western blot analysis, UGT activity toward bisphenol A and UGT protein were identified in the microsomal fractions prepared from rat uterus. UGT isoforms, such as UGT1A1, 1A2, 1A5, 1A6, and 1A7, were expressed, and MRP-1 (multidrug resistance-associated protein) and MRP-3, which are well-known to be transporters of various drug-glucuronides, were detected in the rat uterus by reverse transcription-PCR. These results elucidate the rat uterine barrier system by showing that most bisphenol A perfused into the uterus was glucuronidated in the epithelium, resulting in transport of glucuronides to the maternal side.
Key Words: bisphenol A; uterus; UDP-glucuronosyltransferase; drug-barrier; endometrial cells.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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A number of industrial chemicals have been reported to act as endocrine disrupters in mammals and other animals. One prominent endocrine disrupter, bisphenol A, has been shown to have estrogenic activity that adversely affects the reproductive system (Chen et al., 2002
; Kim et al., 2001). A single high dose of bisphenol A (37.5–150 mg/kg) was reported to induce cell differentiation and c-fos proto-oncogene expression (Steinmetz et al., 1998), early puberty in female offspring, significantly hastening vaginal opening and onset of estrous (Howdeshell et al., 1999). The effects of lower doses (human exposure levels) of bisphenol A, on F1 animals have been described (vom Saal and Hughes, 2005). The age at vaginal opening of F1 mice exposed in utero to bisphenol A (20 µg/kg), was earlier, while very low doses (2 µg/kg) had no such effect (Honma et al., 2002). These findings suggest that uterine function in drug metabolism is an important determinant of whether there are adverse effects from exposure to bisphenol A on the next generation.
After fertilization, the embryo moves through the oviduct and is implanted into the endometrium where cell division occurs. An increased risk of developing endometrial cancer has been shown by exposure to tamoxifen, which is metabolized to a genotoxic intermediate through oxidation and O-sulfation by CYP3A4 and sulfotransferase in endometrial cells (Kim et al., 2003, 2004). An association between endometriosis and the null mutation of glutathione S-transferase (GST) M1, which is involved in the metabolism of a wide range of environmental toxins and carcinogens, has been noted in some populations (Baranova et al., 1996, 1997, 1999). An increased risk of recurrent pregnancy loss (RPL) has been suggested to be related to polymorphism of GST M1 and T1 (Sata et al., 2003). Drug-metabolizing enzymes that are expressed in the endometrium obviously have a critical role in adverse embryotoxic and teratogenic effects. Conjugation with glucuronic acid is a major pathway in the biotransformation, elimination, and detoxification of a wide variety of lipophilic endogenous compounds, drugs, toxins, carcinogens, teratogens, and other xenobiotics (Dutton, 1980). Glucuronidation reactions are catalyzed by a family of closely related UDP-glucuronosyltransferase (UGT) isoforms (Burchell and Coughtrie, 1989). The distribution and intracellular localization of UGT may be important in the body's chemical defenses against potential toxins. The metabolic dynamics and the elimination of various xenobiotics have been shown to be directed by glucuronidation and transportation of the resultant glucuronides to the liver and kidneys. However, the expression and roles of UGT in endometrial tissue have not been investigated in detail.
In this study, we examined the roles of UGTs and multidrug resistance-associated proteins (MRPs) in the metabolism and transport of bisphenol A in the uterus and found that most of the bisphenol A perfused in the rat uterus was excreted as a glucuronide into the maternal side.
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MATERIALS AND METHODS |
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Animals and chemicals.
Mature (9- to 12-week-old) female Wistar rats were purchased from Sankyo Lab Co. (Sapporo, Japan). Cholic acid was purchased from Nissui Yakuhin Co. (Tokyo, Japan), further purified, and then converted to its sodium salt (Imai, 1979
). UDP-glucuronic acid was obtained from Nakarai Yakuhin Co. (Kyoto, Japan). Bisphenol A, pancreatine, and insulin were obtained from Sigma (St Louis, MO). Nu-Serum and Matrigel (EHS-tumor matrix) were purchased from BD Biosciences (Bedford, MA). Tissue culture media and supplements were obtained from Gibco Laboratories (Invitrogen, Carlsbad, CA).
Preparation of microsomes.
Animals were individually housed under standard conditions and maintained ad libitum on a standard diet. Rats were handled according to the Laboratory Animal Control Guidelines of Rakuno Gakuen University based on the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health of the United States of America. Rats in diestrus were sacrificed by exsanguination via the abdominal aorta under anesthesia with 60% urethane (0.3 ml/100 g body weight). Livers and uteri were removed, minced, and homogenized with four volumes of 0.15M KCl solution containing 1mM ethylenediaminetetraacetic acid. The homogenate was centrifuged for 20 min at 9000 x g, and the supernatant fraction was centrifuged at 105,000 x g for 60 min to obtain microsomes. Protein concentration was determined using the method of Lowry (Loewry et al., 1951) with bovine serum albumin as the standard.
Enzyme assay.
UGT activities in liver and uterine microsomes with respect to 1-naphthol and bisphenol A, which were activated by 0.01% sodium cholate, were assayed in 200 µl of 50mM Tris–HCl buffer (pH 7.4) solution containing 0.5mM MgCl2 and 0.25mM substrate (1-naphthol or bisphenol A) at 37°C. Enzyme reaction products were analyzed using the high-performance liquid chromatography (HPLC) system as previously described (Yokota et al., 1999).
Antibodies.
Rat phenol UGT corresponding to the UGT1A6 isoform was purified, and polyclonal antibodies against the isoform were prepared according to previously described methods (Yokota and Yuasa, 1989b; Yokota et al., 1989a). The antibodies bind to rat UGT1A family members, which have a common carboxyl-terminus region. UGT2B1-specific antibodies were obtained from Dr. Ikushiro. Antibodies against UGT2B1 were prepared as antipeptides corresponding to the carboxyl-terminal region (517–529, CRKTANMGKKKKE) of UGT2B1, and specificity of the antibody was confirmed using the method described by Ikushiro (Ikushiro et al., 1997).
Immunoblotting analysis.
Microsomal protein fractions were prepared from rat livers and uteri, and the proteins (10 µg) were subjected to sodium dodecyl sulfate (SDS)–polyacrylamide slab-gel electrophoresis. The polypeptide bands thus separated were transferred to a nitrocellulose membrane, and immunoreactive bands were detected using the two polyclonal antibodies recognizing the UGT1A family members or UGT2B1 isoform based on a slight modification (Yokota and Yuasa, 1989b) of the method of Howe and Hershey (1981).
Immunohistochemistry analysis.
Each uterus was fixed in 4% paraformaldehyde/phosphate-buffered saline (PBS), pH 7.0. After dehydration in serial concentrations of ethanol and xylene, it was embedded in paraffin and sectioned into 10-µm-thick slices. Sections were mounted on a cover slip and dried overnight at 45°C. Following deparaffinization and hydration, the sections were immersed in PBS-BT buffer (0.1 g bovine serum albumin, 50 µl of Tween 20, 0.1 g NaN3 in 100 ml PBS). Cell suspensions of lung macrophages were smeared on a cover slip coated with 3-aminopropyltriethoxy-silane (Sigma Chemical Co.) and fixed for 1 h in 4% paraformaldehyde/PBS. After treatment with cold methanol for 10 min, semidried specimens were immersed in PBS-BT buffer for 30 min at room temperature (RT). Immunostaining of smeared cells and sections was as follows. After incubation in normal goat serum (Sigma Chemical Co.) for 30 min, anti-UGT antibodies/PBS-BT (1:100 dilution) were applied on the cover slip for 2 h at RT. After being washed three times with PBS/BT, the specimens were treated with fluorescein isothiocyanate–conjugated goat anti-rabbit immunoglobulin (Cappel Products, Costa Mesa, CA) PBS-BT (1:500 dilution) containing propidium iodide (PI, Sigma) for 1 h at RT. The cover slip was mounted on a slide with 70% glycerin containing 5% n-propyl gallate. For control studies for specific immunofluorescence, specimens were incubated with PBS. Stained cells and sections were examined under a confocal laser scanning microscope (Fluoview, Olympus, Japan).
Reverse transcription-PCR.
Total RNA was isolated from peritoneal macrophages using an RNeasy mini kit (QIAGEN, Heidelberg, Germany). Before reverse transcription-PCR (RT-PCR), DNase digestion was done in all RNA preparations. Complementary DNA (cDNA) was synthesized from total RNA with Superscript II (Invitrogen, Carlsbad, CA) reverse transcriptase. The coding regions of the respective cDNA species were amplified by PCR with oligonucleotide primers that were designed by reference to the sequences of rat UGT1A family members (Grams et al., 2000). A UGT1A1 sense primer, 5'-TGGTGTGCCGGAGCTCATGTTCG-3'; UGT1A2 sense primer, 5'-GGAAGAATATCAGCGGGAAATACTGGGC-3'; UGT1A3 sense primer, 5'-ATTTTCTCTGAAGTTAGTTCTACAG-3'; UGT1A5 sense primer, 5'-GTGGTCTTTGAAACAGGCAACTATGTG-3'; UGT1A6 sense primer, 5'-CCTCAGTGAACGCGGACACGAC-3'; UGT1A7 sense primer, 5'-CAGTTGGCAGCTGGGAAAACCA-3'; and UGT1A8 sense primer, 5'-GGCACATGG-GAAAGTCGTTGA- 3' were designed from their isoform-specific regions. An antisense primer, 5'-CTGGAATCTCTGAGACCATGGATC-3', was designed from the UGT1A family common region. A UGT2B family sense primer, 5'-GGAAGAATTTGTTCAGAGC-3', and an antisense primer, 5'-AACAGCTGCTCCTTTGGC-3', were designed from the common region of the family. An MRP-1 sense primer, 5'-TCGAATGTCCTCTAAGATGGAGAC-3'; MRP-1 antisense primer, 5'-GGAACTCTACACGGCCTGAATG-3'; MRP-2 sense primer, 5'-AGGAACTGGAAGACCTTCATGAAGC-3'; MRP-2 antisense primer, 5'-CAGTGTACGGCGAAGACTATTTTC-3'; MRP-3 sense primer, 5'-GCTATCCGACCTGGAGTCTAATATC-3'; and MRP-3 antisense primer, 5'-AGGACGGTTGCTCTCCAACAC-3' were synthesized for amplification of MRP cDNA. All cDNA bands amplified by PCR were sequenced by a Model 310 sequencer (Applied Biosystems, Foster City, CA).
Drug metabolism and pharmacodynamics in rat uterine sac.
Uterine drug metabolism was investigated by exposing the uterine sac obtained from diestrus female rats to xenobiotics in a semi-in vitro system. As shown in Figure 1, the rat uterine sac was incubated with Krebs-Henseleit buffer containing the chemical. The buffer in the right tube was perfused through the serosal side of the uterus, and the buffer in the left tube was perfused through the mucosal side of the uterus. 1-Naphthol (final concentration: 25µM) or bisphenol A (final concentration: 25µM) was added into one of the tubes, and then the metabolites in the buffer in both tubes were analyzed by HPLC.
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HPLC analysis.
The sample buffers in the above-described reaction tubes were filtered by a disposal disk filter (HPLC-DISK 3; Kanto Co., Tokyo, Japan) and then analyzed using an HPLC system consisting of a Tosoh TSK-gel 80TM reversed-phase column (7.8 mm x 30 cm). Filtered samples were injected and eluted with an acetonitrile/H2O/acetic acid (36:65:0.1/vol:vol:vol) solution as described previously (Yokota et al., 1999
). The eluted peaks were confirmed as being each glucuronide metabolite using an authentic standard. |
RESULTS |
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On an HPLC chromatograph of the 1-napthol-metabolites present after 100-min incubation in the buffer from the serosal side tube, one main peak corresponding to 1-naphthol-glucuronide was observed, which disappeared after ß-glucuronidase treatment (Figs. 2A and 2B). When bisphenol A was added to the serosal side, bisphenol A-glucuronide was observed as the main metabolite in the buffer of the serosal tube (Figs. 2C and 2D). No other minor metabolites were observed in the medium on HPLC chromatography. These data indicated that in the rat uterus both chemicals were mainly metabolized to glucuronides. Figures 3 and 4 show the amounts of the various metabolites. When 1-naphthol was added to the serosal side tube (Fig. 3), the 1-naphthol level decreased in the tube and the 1-naphthol-glucuronide level increased, mainly on the serosal side of the uterus. A small amount of 1-naphthol was detected in the mucosal side tube. When bisphenol A was added to the serosal side tube, the bisphenol A level decreased and the bisphenol A-glucuronide level increased in that tube, mainly on the serosal side of the uterus; a small amount of free bisphenol A was detected on the mucosal side (Fig. 3). Since the metabolites were produced linearly during the perfusion assay for 100 min, indicating that viability of the uterus was not lost, the slow decrease in both chemicals over time shown in Figures 3D and 4C was estimated to be due to saturation in the uterine sac with the parent chemical. The recovery by this system ranged from 55% to 70% for 1-naphthol and 75% to 76% for bisphenol A. These data, which are shown in Figure 3, indicate that 1-naphthol and bisphenol A added to the outer serosal side of the uterine sac are glucuronidated in epithelial cells and that glucuronide is excreted into the serosal side (maternal side). As shown in Figure 4, when 1-naphthol was added on the mucosal side, the 1-naphthol level decreased on the mucosal side, and the 1-naphthol-glucuronide level increased, mainly on the serosal side. When bisphenol A was added to the mucosal side, bisphenol A levels decreased on the mucosal side while bisphenol A-glucuronide increased, mainly on the serosal side of the uterus; only a small amount of free bisphenol A was detected on the serosal side.
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The distribution of UGT in the rat uterus with respect to 1-naphthol and bisphenol A was investigated. Results of immunohistochemical analysis using antibodies against UGT isoforms, such as UGT1A family members, are shown in Figure 5. Expression of UGTs (light green staining) was observed in epithelial cells of the endometrium, oviducts, and uterine glands (Fig. 5). A high level of activity of UGT, which is a major phase II drug-metabolism enzyme acting on 1-naphthol, was observed in the uterine microsomes. UGT activity with respect to bisphenol A was also detected in the uterine microsomes (data not shown). Results of Western blot analysis using specific antibodies against UGT1A family members (Fig. 6A) and using antibodies against the UGT2B1 isoform of rat uterine microsomes are shown in Figure 6. Antibodies against UGT1A subfamily isoforms bound to several minor bands corresponding to liver UGTs were observed (panel A), and unknown main bands that had a higher molecular mass were present in the rat uterus (Fig. 6A). However, panel B shows that no bands correspond to UGT2B1, which is a major hepatic isoform that results in glucuronidation of bisphenol A, in the rat uterus (Fig. 6B).
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To determine the UGT isoforms expressed in the rat uterus, the messenger RNA expression of UGT isoforms was analyzed by RT-PCR (Fig. 7). UGT1A subfamily members, UGT1A1, 1A2, 1A5, 1A6, and 1A7, were amplified, but UGT2B subfamily members were not detected in the rat uterus, which was in agreement with the Western blot data shown in Figure 6. Expressions of MRP, which transports the glucuronides of drugs out of cells (Borst and Elferink, 2002
), were assayed by RT-PCR (Fig. 8). MRP-1 (141 bp) and MRP-3 (99 bp) were expressed in rat uterus as previously described for human specimens (Langmann et al., 2003). These findings indicate that 1-naphthol and bisphenol A are glucuronidated in epithelial cells, and the resultant glucuronides are excreted into the serosal side (maternal side). Thus, it appears to be difficult for free chemicals to pass through the uterus; furthermore, after glucuronidation the products return to the maternal side.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONSUPPLEMENTARY DATAFUNDINGREFERENCES |
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In the early stage of pregnancy, exposure to toxic chemicals can have serious adverse effects on embryonic development. During fertilization and implantation, the inside of the uterus must be free of environmental pollutants as well other potentially harmful substances such as drugs. After fertilization, the embryo moves through the oviduct and is implanted in endometrial cells where development occurs. The embryo obtains nutrition from uterine milk secreted by uterine glands through epithelial cells. Baranova et al. (1996
, 1997, 1999) reported an association between the GST M1 null mutation and endometriosis in some populations, while Hadfield et al. (2001) showed that the combination of GST M1 and CYP1A1 MSP1 polymorphism was associated with a slightly increased risk of endometriosis in another patient population. CYP1A1 and GST enzymes act by metabolizing procarcinogens into reactive, carcinogenic intermediates, which are subsequently catalyzed by enzymes such as GST and UGT in the phase II detoxification process. Recently, it was reported that women with GST M1 null polymorphism might have an increased risk of RPL (Sata et al., 2003). These findings indicate that environmental pollutants, medicines, and toxic drugs have serious adverse effects on the endometrium and embryo, which have low levels of detoxification enzyme activities. As a final defense, it is thought that uterine GST and UGT isoforms expressed in the epithelium of the endometrium play critical roles in preventing these effects.
In this study, we showed that UGTs glucuronidating drugs were expressed in the epithelial cells of the rat uterus. Furthermore, only glucuronides were mainly excreted to the serosal maternal side by any of the transporters, as seen in Figure 6. MRPs are members of the adenosine triphosphate–binding cassette transporter superfamily. Recently, it was reported that MRP-1, MRP-2, and MRP-3 are expressed in the human uterus (Langmann et al., 2003; Nishimura and Naito, 2005) and that these MRPs participate in the transport of the glucuronides of various drugs and endogenous bioactive substrates (Borst and Elferink, 2002). We also observed the expression of two isoforms of MRP (MRP-1 and MRP-3) in Figure 7. The location of MRPs within cells determines the direction of excretion from uterine epithelial cells of resultant glucuronides of chemicals. MRP-1 and MRP-3 have been reported to be located at the basolateral membrane (Borst and Elferink, 2002), suggesting that these MRPs have a role in protecting the inside of the uterus against exposure to drugs.
Several significant isoforms of UGT have been shown to be expressed in the human uterus (Lepine et al., 2004). Duguay et al. (2004) were the first to report the significance of uterine UGT. Based on RT-PCR and Western blot analysis, they showed that UGT1A1 is distributed in human endometrial tissue and suggested that a lower UGT1A1 expression level reduces the risk of endometrial cancer by altering the degree of glucuronidation of 2-hydroxy estrogen, which is an inhibitor of cell proliferative metabolites. In the rat uterus, we have for the first time shown that UGT isoforms of 1A1, 1A2, 1A5, 1A6, and 1A7 are expressed in epithelial cells of the endometrium, uterine gland, and oviduct. UGT1A6 glucuronidates various planar phenols such as 1-naphthol (Burchell et al., 1995), and UGT1A7 has broad substrate specificity, glucuronidating both planar and nonplanar compounds, polycyclic aromatics, and compounds with bulky side chain ring substitutions (Webb et al., 2005); thus, the two isoforms must play important roles in the drug-barrier in the rat uterus. If the system present in endometrial cells protects against endogenous substrates that have significant bioactivities permeating across uterine tissues, then UGT1A1, which glucuronidates bilirubin, estradiol, and all-trans-retinoic acid (Tsuji, 2005), would have a significant role in the uterine barrier against endogenous bioactive molecules. Bernard et al., using RT-PCR and immunohistochemistry, showed that human UGT isoforms, such as UGT1A1, 1A3, 1A8, 1A9, and 2B7, are expressed in the endometrium (Lepine et al., 2004). Human UGT1A1 was reported to catalyze the glucuronidation of common drugs, such as SN-38 and ethenyl estradiol (De Leon, 2003). These UGT isoforms have been shown to glucuronidate various xenobiotics and endogenous substrates (Burchell et al., 1995; Radominska-Pandya et al., 1999). These findings suggest that uterine UGTs, both in humans and rats, and transporters play important roles in the uterine drug-barrier system, which protects the embryo and uterus from deleterious effects of free and toxic drugs. Further investigation of endometrial cell glucuronidation activity of uterine UGT isoforms (UGT1A1, 1A2, 1A5, 1A6, and 1A7) with respect to various new chemicals as substrates should provide important information for determining the side effects of medicines and environmental pollutants on the uterus and embryo.
Under normal conditions, the protection of the embryo from an adverse maternal environment during early pregnancy is considered to be the result of a permeability barrier created by the tight junctions of uterine epithelial cells. The tight junction-associated proteins ZO-1, claudin-1, and occludin are present in the apical region of uterine epithelial cells, and appear to play a role in the very dynamic tight-junctional network of uterine epithelial cells that is present during early pregnancy (Orchard and Murphy, 2002). The blood–brain barrier has cellular tight junctions and transport systems that serve to actively transport various xenobiotics, including drugs and their metabolites (Tsuji, 2005). Drug-barrier systems have been found to function based on the low permeability of the tight junctural cell layer and by the transportation of drugs from the cells. We have documented glucuronidation and one-way transportation in the epithelial cells of the intestine (Inoue et al., 1999, 2003), in the kidney (Narukawa et al., 2004; Yokota et al., 1997), and in the uterus (this study) using organ perfusion methods. Extrahepatic UDP-glucuronosyltransferase has a significant role in such cooperative systems, which, along with glucuronide transporter(s), are regarded as the "metabolic drug-barrier" of epithelial cells.
Kurebayashi et al. (2005) reported that significant radioactivity of 14C-bisphenol A was detected in rat uterus orally administered radio-labeled bisphenol A, indicating that bisphenol A reached the uterus through the blood. However, the administered bisphenol A was detected in fetuses only just before delivery after dosage to pregnant rats had been reduced, suggesting that the barrier system of the rat uterus was protective against bisphenol A transportation during early stage of pregnancy.
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SUPPLEMENTARY DATA |
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Supplementary data are available online at http://toxsci.oxfordjournals.org/.
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FUNDING |
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Grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan; Grant-in-aid for High Technological Research Center (Rakuno Gakuen University) from the Ministry of Education, Science and Culture of Japan.
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