![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Biochemistry and Molecular Biology, National Food Safety & Toxicology Center, and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan
Received October 6, 2005; accepted February 8, 2006
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
). These responses include a wasting syndrome, tumor promotion, teratogenesis, hepatotoxicity, immunotoxicity, and modulation of endocrine systems, which are mediated by the aryl hydrocarbon receptor (AhR), a member of the basic-helix-loop-helix-PAS (PER/ARNT/SIM) family (Poland and Knutson, 1982; Denison and Heath-Pagliuso, 1998). The proposed mechanism involves ligand binding to the cytoplasmic AhR and translocation to the nucleus where it forms a heterodimer with the aryl hydrocarbon receptor nuclear translocator (ARNT), another member of the basic-helix-loop-helix-PAS family. This heterodimer then binds specific DNA elements, termed dioxin response elements, in the regulatory regions of target genes leading to changes in gene expression (Hankinson, 1995). Evidence suggests that the adverse effects elicited by TCDD are due to the continuous and inappropriate AhR-mediated regulation of these target genes (Denison et al., 2002). Although the mechanisms of AhR/ARNT-mediated changes in gene expression are well established, TCDD modulation of gene expression associated with the toxic and biochemical effects remains poorly understood.
Like the AhR, the estrogen receptor (ER), a member of the nuclear receptor superfamily, is a ligand-activated transcription factor, which mediates many of the effects of estrogens (Nilsson et al., 2001). Upon ligand binding, ERs dissociate from heat shock and chaperone proteins, homodimerize, and interact with regulatory elements near estrogen responsive genes (Klinge, 2001). ERs are traditionally believed to mediate transcriptional responses through binding to estrogen response elements (EREs) but also via interactions with Fos/Jun at activator protein 1 sites, Jun/ATF-2 at variant cAMP response elements, and Sp1 at its response elements (Hall et al., 2001; Nilsson et al., 2001). The ER can also elicit cellular responses through ligand-independent, DNA binding-independent, and cell-surface (nongenomic) signaling mechanisms (Hall et al., 2001).
TCDD elicits a number of AhR-dependent antiestrogenic responses in the female reproductive tract, including the inhibition of estrogen-induced increases in uterine wet weight, DNA synthesis, and gene expression responses (for review, see Safe and Wormke, 2003). However, accumulating evidence suggests that TCDD also possesses estrogen-like activity. TCDD increases the DNA-binding activity of the ER independent of estrogen in the rat uterus (Chaffin et al., 1996) and treatment of MCF-7 cells with TCDD results in estrogen-like G0/G1 to S-phase transition and mitogenic effects (Abdelrahim et al., 2003). Furthermore, the ligand-activated AhR/ARNT complex directly associates with the unliganded ER to form a functional complex that binds EREs and activates transcription (Ohtake et al., 2003). Independent studies also confirmed ER-AhR interactions that may account for the cross-talk between these signaling pathways (Brunnberg et al., 2003; Beischlag and Perdew, 2005). In addition, 3-methylcholanthrene (3-MC) activation of the AhR in the absence of estrogen induced estrogenic responses in the mouse uterus (Ohtake et al., 2003). Moreover, TCDD mediates the induction of estrogen-dependent tumors in rats (Brown et al., 1998; Davis et al., 2000) and reportedly increases the incidence of endometriosis in laboratory animals and in women with high body burdens of TCDD (Rier et al., 1993; Koninckx et al., 1994; Cummings and Metcalf, 1996; Mayani et al., 1997).
To further characterize the apparent estrogenicity of TCDD, a comprehensive uterine time course analysis of gene expression was conducted in ovariectomized C57BL/6 mice. Temporal uterine responses to TCDD were compared with that of ethynyl estradiol (EE), an orally active estrogen, to identify similarities and differences in gene expression profiles. Moreover, mice were cotreated with the pure estrogen receptor (ER) antagonist ICI 182 780 to investigate the role of the ER in mediating the estrogen-like gene expression responses to TCDD.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Animal Treatments. For the dioxin study, animals (n = 5/treatment group/time point) were treated once by oral gavage with 30 µg/kg b.w. TCDD (provided by S. Safe, Texas A&M University, College Station, TX) or sesame oil (Sigma Chemical, St Louis, MO) as described previously (Boverhof et al., 2005). Animals in the estrogen study (n = 5/treatment group/time point) were treated once every 24 h by oral gavage on three consecutive days with 100 µg/kg b.w. 17
-Ethynylestradiol (EE) or sesame oil vehicle (Sigma Chemical) as described previously (Kwekel et al., 2005). Mice were sacrificed by cervical dislocation 2, 4, 8, 12, 18, 24, or 72 h after dosing. For the cotreatment studies, animals (n = 6/treatment group) were treated orally with either TCDD (30 µg/kg) or EE (100 µg/kg) with or without an i.p. injection of 10 mg/kg b.w. ICI 182 780 (Tocris Cookson Inc., Ellisville, MO) in 50 µl of 1x PBS. Whole uterine weights were recorded before (wet) and after (blotted) blotting with absorbent tissue. A section of the left uterine horn was removed for histology and fixed in 10% neutral buffered formalin (NBF; Sigma, St. Louis, MO). The remaining tissue was subsequently snap-frozen in liquid nitrogen and stored at -80°C. The doses were empirically derived to elicit robust TCDD-induced changes in gene expression or a maximal EE-induced uterotropic response (Boverhof et al., 2005; Kwekel et al., 2005). All doses were calculated based on average weights of the animals before dosing. All procedures were performed with the approval of the Michigan State University All-University Committee on Animal Use and Care.
Histological Processing and Assessment. Fixed uteri were embedded in paraffin according to standard histological techniques. Cross-sections (5 µm) were mounted on glass slides and stained with hematoxylin and eosin. All embedding, mounting, and staining was performed at the Histology/Immunohistochemistry Laboratory, Michigan State University (http://humanpathology.msu.edu/histology/index.html). Histological slides were evaluated according to standardized National Toxicology Program (NTP) pathology codes. Morphometric analyses were performed for each sample using image analysis software (Scion Image; Scion Corp., Frederick, MD) and standard morphometric techniques. The length of basal lamina underlying the luminal epithelium and corresponding area of the luminal epithelial cells was quantified for multiple representative sectors of each section to calculate luminal epithelial cell height.
RNA Isolation. Total RNA was isolated from whole uteri using TRIzol Reagent (Invitrogen, Carlsbad, CA) as per the manufacturer's protocol. Uteri were removed from -80°C storage and immediately homogenized in 1 ml TRIzol reagent using a Mixer Mill 300 tissue homogenizer (Retsch, Germany). Total RNA was resuspended in The RNA Storage Solution (Ambion, Austin, TX). RNA concentrations were calculated by spectrophotometric methods (A260) and purity assessed by the A260:A280 ratio and by visual inspection of 1 µg on a denaturing gel.
Array Experimental Design and Protocols. Spotted mouse cDNA microarrays were prepared in-house and consist of 13,361 features, representing 7948 unique genes (Unigene Build #144). Detailed protocols for microarray construction, labeling of the cDNA probe, sample hybridization, and slide washing can be found at http://dbzach.fst.msu.edu/interfaces/microarray.html. In brief, PCRamplified DNA was robotically arrayed onto epoxy-coated glass slides (Schott-Nexterion, Duryea, PA) using an Omnigrid arrayer (GeneMachines, San Carlos, CA) equipped with 48 (12 x 4) Chipmaker 2 pins (Telechem) at the Genomics Technology Support Facility at Michigan State University (http://www.genomics.msu.edu). Temporal changes in gene expression in mouse uteri were assessed using an independent reference design in which samples from treated animals are cohybridized with time-matched vehicle controls. Comparisons were performed on three of the five biological replicates (three independent mice) with two independent labelings of each sample (technical replicate incorporating a dye swap) for each treatment group. For the ICI microarray experiment, gene expression changes were analyzed using a loop design with comparisons performed on three randomly chosen samples from the six biological replicates (three independent mice) which included two independent labelings of each sample for each treatment group (Yang and Speed, 2002). A 3DNA Array 900 Expression Array Detection Kit (Genisphere, Hatsfield, PA) using 1 µg of total RNA was used for probe labeling in all microarray experiments, according to manufacturer's specifications. Samples were hybridized for 18 to 24 h at 42°C in a water bath. Slides were then washed, dried by centrifugation, and scanned at 635 (Cy5) and 532 nm (Cy3) on an Affymetrix 428 Array Scanner (Santa Clara, CA). Images were analyzed for feature and background intensities using GenePix Pro 5.0 (Molecular Devices, Union City, CA).
Array Data Normalization and Statistical Analysis. Data were normalized using a semiparametric approach (Eckel et al., 2005). Model-based t values were calculated from normalized data, comparing treated from vehicle responses per time-point. Empirical Bayes analysis was used to calculate posterior probabilities of activity [P1(t) value] on a per-gene and time-point basis using the model-based t value (Eckel et al., 2004). Gene lists were filtered for activity based on the P1(t) value, which indicates a greater likelihood of activity as the value approaches 1.0. A conservative P1(t) cutoff of 0.9999 combined with a differential expression of ±1.5-fold relative to time-matched vehicle controls was used to filter the expression data and to define active gene lists. All arrays were subjected to quality control assessment to ensure assay performance and data consistency. All data are stored within dbZach (http://dbzach.fst.msu.edu), a MIAME (Minimum Information About a Microarray Experiment) supportive relational database that ensures proper data management and facilitates data analysis. Complete data sets with annotation and P1(t) values are available in Supplementary Tables 1 and 2. Gene expression patterns that passed the established threshold criteria were visualized using hierarchical clustering (Gene-Spring 6.0; Silicon Genetics, Redwood City, CA). Comparative analysis was conducted using a multivariate correlation-based visualization application developed in-house. The program calculates correlations between the gene expression and significance values for the same genes from the EE and TCDD experiments.
Quantitative Real-Time PCR Analysis. For each sample, 1.0 µg of total RNA was reverse-transcribed by SuperScript II using an anchored oligo-dT primer as described by the manufacturer (Invitrogen). The resultant cDNA (1.0 µl) was used as the template in a 30-µl PCR reaction containing 0.1 µM each of forward and reverse gene-specific primers, designed using Primer3 (Rozen and Skaletsky, 2000), 3 mM MgCl2, 1.0 mM dNTPs, 0.025 IU of AmpliTaq Gold, and 1x SYBR Green PCR buffer (Applied Biosystems, Foster City, CA). Gene names, accession numbers, forward and reverse primer sequences and amplicon sizes are listed in Supplementary Table 3. PCR amplification was conducted in MicroAmp Optical 96-well reaction plates (Applied Biosystems) on a Prism 7000 Sequence Detection System (Applied Biosystems) using the following conditions: initial denaturation and enzyme activation for 10 min at 95°C, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. A dissociation protocol was performed to assess the specificity of the primers and the uniformity of the PCR-generated products. Each plate contained duplicate standards of purified PCR products of known template concentration covering 6 orders of magnitude to interpolate relative template concentrations of the samples from the standard curves of log copy number versus threshold cycle (Ct). No template controls (NTC) were also included on each plate. Samples with a Ct value within 2 S.D. of the mean Ct values for the NTCs were considered below the limits of detection. The copy number of each unknown sample for each gene was standardized to Rpl7 to control for differences in RNA loading, quality, and cDNA synthesis (Couse et al., 1995). Statistical significance of differentially expressed genes was determined using two-way analysis of variance followed by t test (SAS 9.1; SAS Institute, Cary, NC). For graphing purposes, the relative expression levels were scaled such that the expression level of the time-matched control group was equal to one.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Many of the genes identified as differentially expressed in response to EE and TCDD were unique to each compound; however, a number of transcripts were also commonly regulated (Table 1). Comparison of the active gene lists from each study revealed that 228 of the 281 genes regulated by TCDD were also regulated by EE (Fig. 1A). To ascertain the similarity of these 228 overlapping gene expression responses a Pearson's correlation analysis was performed on the temporal gene expression (-fold change) and significance [P1(t)] profiles. These paired data were plotted on a coordinate axis with the x-axis as the gene expression correlation and the y-axis as the significance correlation (Fig. 1B). A majority of the genes fall into the upper right quadrant, representing genes induced by TCDD and EE that exhibited highly correlated temporal gene expression and significance patterns. In total, 181 of the 228 genes regulated by both TCDD and EE exhibited a gene expression correlation greater than 0.3, suggesting that the temporal expression patterns for genes induced by TCDD were similar to the expression patterns induced by EE. Visualization after gene-based hierarchical clustering reveals the similarity of the EE and TCDD gene expression profiles while also illustrating the lower magnitude of change in response to TCDD (Fig. 1C). Additional clustering by treatment and time point illustrated that the 8-, 12-, 18-, and 24-h EE and 12-, 18-, and 24-h TCDD time points cluster together with the response to TCDD at 12 h displaying the greatest similarity to the EE groups (data not shown).
|
|
A number of uterine histological and morphological endpoints that comprise the enhanced uterotropic assay provide complementary phenotypic information for assessing the estrogenicity of a chemical (Odum et al., 1997; Diel et al., 2002; Moggs et al., 2004a). Previous studies have demonstrated that estrogens induce dramatic increases in uterine wet weight, luminal epithelial cell height, stromal thickness, and BrdU labeling (Carthew et al., 1999; Moggs et al., 2004b; Kwekel et al., 2005). In contrast, TCDD did not induce alterations in any of these histological or morphological endpoints (data not shown). These results indicate that although TCDD induces gene expression responses similar to that of EE, these alone are not sufficient to elicit an estrogen-like physiological response in the uterus. This may be attributed to the fact that only a subset of the total number of genes activated by EE were also regulated by TCDD, and these genes alone are not sufficient to mediate an estrogenic physiological response. Furthermore, the magnitude of the TCDD-mediated changes in gene expression was well below that seen for EE and may not surpass the threshold required to elicit a response.
Quantitative Real-Time PCR Verification of Results. To independently examine the estrogen-like gene expression responses of TCDD, six genes were chosen for verification by QRTPCR. Arginine-rich, mutated in early stage tumors (Armet), asparagine synthetase (Asns), activating transcription factor 4 (Atf4), expressed in nonmetastatic cells 1 (Nme1), proliferating cell nuclear antigen (Pcna), and solute carrier family 25 member 5 (Slc25a5) were specifically selected because they displayed similar responses to EE and TCDD and have been previously identified as estrogen inducible in the rodent uterus in independent studies (Watanabe et al., 2002; Fertuck et al., 2003; Moggs et al., 2004b; Kwekel et al., 2005). QRTPCR analyses confirmed the microarray results indicating these genes were induced by both EE and TCDD (Fig. 2). It is interesting that the induction profiles for both the QRTPCR and microarray data reveal that the TCDD-mediated responses temporally lagged relative to EE suggesting that these treatments exhibit different pharmacokinetic or pharmacodynamic characteristics. Otherwise, this may suggest that TCDD is mediating these responses through an indirect or secondary mechanism.
|
). To investigate the role of the ER in TCDD-mediated induction of known estrogen responsive genes, mice were treated with the pure estrogen receptor antagonist ICI 182 780 before vehicle, EE, or TCDD administration. Animals were sacrificed 12 h after treatment as this was the most active time point and exhibited the most similar EE- and TCDD-induced uterine gene expression profiles. As expected, EE-induced water imbibition at 12 h was completely inhibited by ICI 182 780 (Fig. 3A). Consistent with the earlier results, TCDD did not elicit a water imbibition response. Microarrays analyses were performed on these samples to examine the effect of ICI treatment on the gene expression responses to EE and TCDD. Of the 228 genes identified as commonly active between EE and TCDD in the temporal studies (Fig. 1A), 130 were common to the 12-h time point. Examination of these 130 genes revealed that 97 were responsive to EE and inhibited by ICI, with 91 of these genes displaying a greater than 75% inhibition. In response to TCDD treatment, 81 of these genes were regulated similarly to EE and were inhibited by ICI (Supplementary Table 4). Hierarchical clustering of the normalized intensity values from the microarrays revealed that the EE and TCDD treatment groups clustered together, whereas the EE/ICI and TCDD/ICI groups clustered with the vehicle control (Fig. 3B), further illustrating the similarity of EE- and TCDD-elicited gene expression responses and their inhibition by ICI 182 780. To verify the microarray data, QRTPCR was used to examine the same six transcripts induced by both EE and TCDD in Fig. 2. Cotreatment with ICI 182 780 completely inhibited EE and TCDD gene expression responses (Fig. 3C). The effect on each transcript was statistically significant with the exception of the TCDD-mediated induction of Slc25a5, which did not reach statistical significance (p = 0.10), as the optimal time point for TCDD induction is 18 h. However, the expected pattern of gene induction by TCDD and the inhibition of this response by ICI 182 780 were still evident. These results indicate that the EE and TCDD induction of these transcripts is dependent on the ER.
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). Although many of the estrogenic endocrine disruptors examined exhibited global gene expression patterns similar to that of estrogen, we observed little to no correlation to the responses induced by TCDD. The inability to detect the estrogenic response to TCDD in this study may have been limited by the use of a focused microarray platform that examined only a small subset of estrogen-responsive genes. Furthermore, the MCF-7 cell line may differ in cellular responses, complement of coactivators/corepressors, receptor content, or ratio of ER to AhR compared with the in vivo murine uterus. A second study examined the estrogenicity of TCDD by comparing uterine gene expression responses after estrogen or TCDD treatment at a single time point (6 h) in ovariectomized C57BL6/J mice (Watanabe et al., 2004). However, the mice used in this study were ovariectomized after first estrus, creating a uterine environment that was less responsive to estrogen (Quarmby and Korach, 1984), which may account for the smaller number of TCDD-inducible genes identified. Nevertheless, the results are consistent with our research and indicate that, although the number of genes regulated by TCDD is minimal compared with estrogen, a subset of the estrogen-responsive genes are also induced by TCDD.
ICI 182 780 inhibition of the estrogen-like gene expression responses of TCDD suggests that these response are ER-dependent. TCDD has been proposed to elicit estrogenic responses via direct ER binding (Watanabe et al., 2004) based on the reported estrogenic activity of PCB-77 (Nesaretnam et al., 1996), a coplanar PCB congener which binds the AhR. However, independent studies have not verified PCB-77 binding to the ER (Ramamoorthy et al., 1999), and TCDD does not bind the ER (Klinge et al., 1999). A more plausible mechanism involves the activation of unliganded ER by ligand-activated AhR or a coactivator relationship between these signaling pathways. Recent studies have demonstrated that TCDD induces the AhR to interact directly with ER- in the absence of estrogen (Klinge et al., 2000; Wormke et al., 2000). Moreover, TCDD increases the DNA-binding activity of the ER independent of estrogen in the rat uterus (Chaffin et al., 1996), and treatment of MCF-7 cells with TCDD results in G0/G1 to S-phase transition and estrogen like mitogenic effects (Abdelrahim et al., 2003). Studies have also shown that ER and AhR interact (Brunnberg et al., 2003; Beischlag and Perdew, 2005), and there is a discrepancy as to the coactivator or corepressor function of ER on AhR/ARNT-mediated induction of Cyp1a1 (Beischlag and Perdew, 2005; Matthews et al., 2005). Reports also indicate that the ligand-activated AhR/ARNT associates with the unliganded ER to form a functional complex that binds EREs (Ohtake et al., 2003). In vivo studies with 3-MC corroborate the concept that AhR activation in the absence of estrogen induces various estrogenic responses in the mouse uterus, including the induction of the estrogen-responsive genes Fos and Vegf, increases in uterine wet weight, and increases in BrdU-positive cells (Ohtake et al., 2003). However, in contrast to these results, we did not detect increases in uterine wet weight or increases in BrdU-positive cells. These endpoints may be specific to 3-MC or its metabolites, which have been reported to activate the ER independent of AhR (Abdelrahim et al., 2005).
Whether the ligand-bound AhR is directly or indirectly activating the ER has yet to be determined. Support for direct activation can be drawn from studies indicating the interaction capabilities of these receptors (Klinge et al., 2000; Wormke et al., 2000; Brunnberg et al., 2003; Beischlag and Perdew, 2005); however, indirect mechanisms, including induction of modulatory factors, activation of growth factor receptor signaling, or alterations in phosphorylation states, cannot be excluded and may explain the lagging transcriptional response of TCDD compared with EE. Moreover, TCDD activates only a subset of the estrogen-responsive genes. Further investigation and comparison of the response elements associated with these genes may provide new insights into the mechanisms associated with their regulation. This subset may represent genes that possess promoters constitutively occupied by the unliganded ER, allowing the activated AhR or induced factors to readily serve as cofactors. On the other hand, additional estrogen-responsive genes may actually be regulated by TCDD through the ER but may not have met the molecular threshold for transcriptional induction or the statistical criteria for inclusion.
To date, most studies have focused on the antiestrogenic activities of TCDD in the presence of estrogen, and therefore the weak estrogenic activities of TCDD have been underreported. The modest gene expression effects (e.g., 25-40% of that induced by EE), and the lack of a uterotropic response probably contributed to the preclusion of TCDD's estrogenic activity in previous studies. However, the use of immature ovariectomized mice in this study provided a more sensitive model for the detection of these responses in a physiological background devoid of estrogens. These results also illustrate the ability of microarrays to detect altered gene expression responses that, despite the absence of altered physiology, may still contribute to compromised functions or response thresholds.
The dual nature of TCDD as an antiestrogen in the presence of estrogen and estrogenic in its absence indicates that responses to TCDD may vary depending on life stage. Despite the inability to induce uterine weight alterations, TCDD may alter physiological thresholds for estrogenic responses that could affect other functions. For example, the antiestrogenic properties may be a contributing factor in compromised reproduction, breast cancer incidence, and earlier onset of menopause (Bertazzi et al., 2001; Jongbloet et al., 2002; Safe and Wormke, 2003; Eskenazi et al., 2005). In contrast, the subtle estrogen-like properties in the absence of estrogen may alter thresholds for estrogen-mediated responses, which could contribute to the earlier onset of puberty associated with TCDD exposure (Warner et al., 2004; Warner and Eskenazi, 2005; Wolff et al., 2005). This dual nature warrants further investigation and should be considered when interpreting the results of animal and epidemiological studies of TCDD.
In summary, TCDD induces an estrogen-like gene expression profile in the uteri of ovariectomized C57BL/6 mice in the absence of histopathological or morphological manifestations. Moreover, the pure estrogen antagonist ICI 182 780 inhibited the TCDD-mediated induction of these responses suggesting these effects are mediated via the ER, consistent with other studies demonstrating an AhR-ER interactions. Further research is required to more fully delineate the molecular interactions that occur between the ER and AhR and their potential physiological implications.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
ABBREVIATIONS: TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; AhR, aryl hydrocarbon receptor; ARNT, aryl hydrocarbon receptor nuclear translocator; ER, estrogen receptor; ERE, estrogen response elements; 3-MC, 3-methylcholanthrene; EE, 17-ethynylestradiol; ICI 182 780, faslodex; PCR, polymerase chain reaction; QRTPCR, quantitative real-time PCR.
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material. 
Address correspondence to: Timothy R. Zacharewski, Michigan State University, Department of Biochemistry and Molecular Biology, 501 Biochemistry Building, Wilson Road, East Lansing, MI 48824-1319. E-mail: tzachare{at}msu.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Abdelrahim M, Smith R 3rd, and Safe S (2003) Aryl hydrocarbon receptor gene silencing with small inhibitory RNA differentially modulates Ah-responsiveness in MCF-7 and HepG2 cancer cells. Mol Pharmacol 63: 1373-1381.
Beischlag TV and Perdew GH (2005) ER -AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription. J Biol Chem 280: 21607-21611.
Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, and Pesatori AC (2001) Health effects of dioxin exposure: a 20-year mortality study. Am J Epidemiol 153: 1031-1044.
Boverhof DR, Burgoon LD, Tashiro C, Chittim B, Harkema JR, Jump DB, and Zacharewski TR (2005) Temporal and dose-dependent hepatic gene expression patterns in mice provide new insights into TCDD-mediated hepatotoxicity. Toxicol Sci 85: 1048-1063.
Brown NM, Manzolillo PA, Zhang JX, Wang J, and Lamartiniere CA (1998) Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19: 1623-1629.
Brunnberg S, Pettersson K, Rydin E, Matthews J, Hanberg A, and Pongratz I (2003) The basic helix-loop-helix-PAS protein ARNT functions as a potent coactivator of estrogen receptor-dependent transcription. Proc Natl Acad Sci USA 100: 6517-6522.
Carthew P, Edwards R, Nolan B, Tucker M, and Smith L (1999) Compartmentalized uterotrophic effects of tamoxifen, toremifene and estradiol in the ovariectomized Wistar (Han) rat. Toxicol Sci 48: 197-205.
Chaffin CL, Peterson RE, and Hutz RJ (1996) In utero and lactational exposure of female Holtzman rats to 2,3,7,8-tetrachlorodibenzo-p-dioxin: modulation of the estrogen signal. Biol Reprod 55: 62-67.[Abstract]
Couse J, Curtis S, Washburn T, Lindzey J, Golding T, Lubahn D, Smithies O, and Korach K (1995) Analysis of transcription and estrogen insensitivity in the female mouse after targeted disruption of the estrogen receptor gene. Mol Endocrinol 9: 1441-1454.[Abstract]
Cummings AM and Metcalf JL (1996) Effect of surgically induced endometriosis on pregnancy and effect of pregnancy and lactation on endometriosis in mice. Proc Soc Exp Biol Med 212: 332-337.[Abstract]
Davis BJ, McCurdy EA, Miller BD, Lucier GW, and Tritscher AM (2000) Ovarian tumors in rats induced by chronic 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment. Cancer Res 60: 5414-5419.
Denison MS and Heath-Pagliuso S (1998) The Ah receptor: a regulator of the biochemical and toxicological actions of structurally diverse chemicals. Bull Environ Contam Toxicol 61: 557-568.[CrossRef][Medline]
Denison MS, Pandini A, Nagy SR, Baldwin EP, and Bonati L ((2002)) Ligand binding and activation of the Ah receptor. Chem Biol Interact 141: 3-24.[CrossRef][Medline]
Diel P, Schmidt S, and Vollmer G (2002) In vivo test systems for the quantitative and qualitative analysis of the biological activity of phytoestrogens. J Chromatogr B 777: 191-202.
Eckel JE, Gennings C, Chinchilli VM, Burgoon LD, and Zacharewski TR (2004) Empirical Bayes gene screening tool for time-course or dose-response microarray data. J Biopharm Stat 14: 647-670.[CrossRef][Medline]
Eckel JE, Gennings C, Therneau TM, Burgoon LD, Boverhof DR, and Zacharewski TR (2005) Normalization of two-channel microarray experiments: a semiparametric approach. Bioinformatics 21: 1078-1083.
Eskenazi B, Warner M, Marks AR, Samuels S, Gerthoux PM, Vercellini P, Olive DL, Needham L, Patterson D Jr, and Mocarelli P (2005) Serum dioxin concentrations and age at menopause. Environ Health Perspect 113: 858-862.[Medline]
Fertuck KC, Eckel JE, Gennings C, and Zacharewski TR (2003) Identification of temporal patterns of gene expression in the uteri of immature, ovariectomized mice following exposure to ethynylestradiol. Physiol Genomics 15: 127-141.
Hall JM, Couse JF, and Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276: 36869-36872.
Hankinson O (1995) The aryl hydrocarbon receptor complex. Annu Rev Pharmacol Toxicol 35: 307-340.[CrossRef][Medline]
Jongbloet PH, Roeleveld N, and Groenewoud HM ((2002)) Where the boys aren't: dioxin and the sex ratio. Environ Health Perspect 110: 1-3.[Medline]
Klinge CM (2001) Estrogen receptor interaction with estrogen response elements. Nucleic Acids Res 29: 2905-2919.
Klinge CM, Bowers JL, Kulakosky PC, Kamboj KK, and Swanson HI (1999) The aryl hydrocarbon receptor (AHR)/AHR nuclear translocator (ARNT) heterodimer interacts with naturally occurring estrogen response elements. Mol Cell Endocrinol 157: 105-119.[CrossRef][Medline]
Klinge CM, Kaur K, and Swanson HI (2000) The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1. Arch Biochem Biophys 373: 163-174.[CrossRef][Medline]
Koninckx PR, Braet P, Kennedy SH, and Barlow DH (1994) Dioxin pollution and endometriosis in Belgium. Hum Reprod 9: 1001-1002.
Kwekel JC, Burgoon LD, Burt JW, Harkema JR, and Zacharewski TR (2005) A cross-species analysis of the rodent uterotrophic program: elucidation of conserved responses and targets of estrogen signaling. Physiol Genomics 23: 327-342.
Matthews J, Wihlen B, Thomsen J, and Gustafsson JA (2005) Aryl hydrocarbon receptor-mediated transcription: ligand-dependent recruitment of estrogen receptor {alpha} to 2,3,7,8-tetrachlorodibenzo-p-dioxin-responsive promoters. Mol Cell Biol 25: 5317-5328.
Mayani A, Barel S, Soback S, and Almagor M (1997) Dioxin concentrations in women with endometriosis. Hum Reprod 12: 373-375.
Moggs JG, Goodman JI, Trosko JE, and Roberts RA (2004a) Epigenetics and cancer: implications for drug discovery and safety assessment. Toxicol Appl Pharmacol 196: 422-430.[CrossRef][Medline]
Moggs JG, Tinwell H, Spurway T, Chang HS, Pate I, Lim FL, Moore DJ, Soames A, Stuckey R, Currie R, et al. (2004b) Phenotypic anchoring of gene expression changes during estrogen-induced uterine growth. Environ Health Perspect 112: 1589-1606.[Medline]
Nesaretnam K, Corcoran D, Dils RR, and Darbre P (1996) 3,4,3',4'-Tetrachlorobiphenyl acts as an estrogen in vitro and in vivo. Mol Endocrinol 10: 923-936.[Abstract]
Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, and Gustafsson J-A (2001) Mechanisms of estrogen action. Physiol Rev 81: 1535-1565.
Odum J, Lefevre PA, Tittensor S, Paton D, Routledge EJ, Beresford NA, Sumpter JP, and Ashby J (1997) The rodent uterotrophic assay: critical protocol features, studies with nonyl phenols and comparison with a yeast estrogenicity assay. Regul Toxicol Pharmacol 25: 176-188.[CrossRef][Medline]
Ohtake F, Takeyama K, Matsumoto T, Kitagawa H, Yamamoto Y, Nohara K, Tohyama C, Krust A, Mimura J, Chambon P, et al. (2003) Modulation of oestrogen receptor signalling by association with the activated dioxin receptor. Nature (Lond) 423: 545-550.[CrossRef][Medline]
Poland A and Knutson JC (1982) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and related halogenated aromatic hydrocarbons: examination of the mechanism of toxicity. Annu Rev Pharmacol Toxicol 22: 517-554.[CrossRef][Medline]
Quarmby VE and Korach KS (1984) The influence of 17 beta-estradiol on patterns of cell division in the uterus. Endocrinology 114: 694-702.[Abstract]
Ramamoorthy K, Gupta MS, Sun G, McDougal A, and Safe SH (1999) 3,3'4,4'-Tetrachlorobiphenyl exhibits antiestrogenic and antitumorigenic activity in the rodent uterus and mammary cells and in human breast cancer cells. Carcinogenesis 20: 115-123.
Rier SE, Martin DC, Bowman RE, Dmowski WP, and Becker JL (1993) Endometriosis in rhesus monkeys (Macaca mulatta) following chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Fundam Appl Toxicol 21: 433-441.[CrossRef][Medline]
Rozen S and Skaletsky HJ (2000) Primer3 on the WWW for general users and for biologist programmers, in Bioinformatics Methods and Protocols: Methods in Molecular Biology (Misener S and Krawetz S eds) pp 365-386, Humana Press, Totowa, NJ.
Safe S and Wormke M (2003) Inhibitory aryl hydrocarbon receptor-estrogen receptor alpha cross-talk and mechanisms of action. Chem Res Toxicol 16: 807-816.[Medline]
Terasaka S, Aita Y, Inoue A, Hayashi S, Nishigaki M, Aoyagi K, Sasaki H, Wada-Kiyama Y, Sakuma Y, Akaba S, et al. (2004) Using a customized DNA microarray for expression profiling of the estrogen-responsive genes to evaluate estrogen activity among natural estrogens and industrial chemicals. Environ Health Perspect 112: 773-781.[Medline]
Warner M and Eskenazi B (2005) Correspondence: TCDD and puberty: Warner and Eskenazi respond. Environ Health Perspect 113: A18.[Medline]
Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, and Eskenazi B (2004) Serum dioxin concentrations and age at menarche. Environ Health Perspect 112: 1289-1292.[Medline]
Watanabe H, Suzuki A, Goto M, Ohsako S, Tohyama C, Handa H, and Iguchi T (2004) Comparative uterine gene expression analysis after dioxin and estradiol administration. J Mol Endocrinol 33: 763-771.
Watanabe H, Suzuki A, Mizutani T, Khono S, Lubahn DB, Handa H, and Iguchi T (2002) Genome-wide analysis of changes in early gene expression induced by oestrogen. Genes Cells 7: 497-507.[Abstract]
Wolff MS, Britton JA, and Russo JC (2005) TCDD and puberty in girls (Letter). Environ Health Perspect 113: A17;[Medline]author reply A18.
Wormke M, Stoner M, Saville B, and Safe S (2000) Crosstalk between estrogen receptor alpha and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Lett 478: 109-112.[CrossRef][Medline]
Yang YH and Speed T (2002) Design issues for cDNA microarray experiments. Nat Rev Genet 3: 579-588.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  N. Kiyosawa, J. C. Kwekel, L. D. Burgoon, K. J. Williams, C. Tashiro, B. Chittim, and T. R. Zacharewski o,p'-DDT Elicits PXR/CAR-, Not ER-, Mediated Responses in the Immature Ovariectomized Rat Liver Toxicol. Sci., February 1, 2008; 101(2): 350 - 363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Boverhof, L. D. Burgoon, K. J. Williams, and T. R. Zacharewski Inhibition of Estrogen-Mediated Uterine Gene Expression Responses by Dioxin Mol. Pharmacol., January 1, 2008; 73(1): 82 - 93. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. B. Okey An Aryl Hydrocarbon Receptor Odyssey to the Shores of Toxicology: The Deichmann Lecture, International Congress of Toxicology-XI Toxicol. Sci., July 1, 2007; 98(1): 5 - 38. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Eskenazi, M. Warner, S. Samuels, J. Young, P. M. Gerthoux, L. Needham, D. Patterson, D. Olive, N. Gavoni, P. Vercellini, et al. Serum Dioxin Concentrations and Risk of Uterine Leiomyoma in the Seveso Women's Health Study Am. J. Epidemiol., July 1, 2007; 166(1): 79 - 87. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
