Toxicological Sciences 56, 141-149 (2000)
Copyright © 2000 by the Society of Toxicology
Gestational Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Developmental Defects in the Rat Vagina
,§,¶,1
* Program in Toxicology,
Program in Human Health and the Environment, and
¶ Department of Anatomy, University of Maryland School of Medicine, Baltimore, Maryland 21202; and
School of Pharmacy and
§ Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53706
Received July 21, 1999; accepted January 24, 2000
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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At puberty, female rats exposed in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibit a persistent thread of mesenchymal tissue surrounded by keratinized epithelium that partially occludes the vaginal opening. Our objective was to determine the earliest time during fetal development that morphological signs of this vaginal canal malformation could be detected and to obtain greater insight into mechanisms involved in this effect. Pregnant rats were administered a single dose of vehicle (control) or TCDD (1.0 µg/kg, po) on gestation day (GD) 15 and were sacrificed on GD 18, 19, 20, and 21 for histological evaluation of female. Gestational exposure to TCDD affected vaginal morphogenesis as early as GD 19, 4 days after exposure of pregnant dams. In exposed fetuses, the thickness of mesenchymal tissue between the caudal Mullerian ducts was increased, which resulted in a failure of the Mullerian ducts to fuse, a process normally completed prior to parturition. In addition, TCDD exposure appeared to inhibit the regression of Wolffian ducts. Thus, TCDD interferes with vaginal development by impairing regression of the Wolffian ducts, by increasing the size of interductal mesenchyme, and by preventing fusion of the Mullerian ducts. Taken together, these effects appear to cause the persistent vaginal thread defect observed in rats following in utero and lactational TCDD exposure.
Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin); rat; vagina development; urogenital sinus; Mullerian duct; Wolffian duct; birth defect; gestational exposure.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during critical periods of organogenesis has profound effects on development and can result in specific abnormalities of structure and function in several organ systems (Birnbaum, 1995
; Murray et al., 1979). There is clear evidence indicating that in utero and lactational exposure to this toxicant alters the development and functional capacity of the male reproductive system (Peterson et al., 1993; Roman and Peterson, 1998). In male rats and hamsters, in utero and lactational exposure to TCDD resulted in decreased epididymal and ejaculatory sperm counts, decreased seminal vesicle and ventral prostate weights, and demasculinized and feminized sexual behavior (Bjerke and Peterson, 1994; Faqi et al., 1998; Gray et al., 1995; Mably, 1992a,b,c).
In female rats, prenatal exposure to TCDD on gestation day (GD) 11, 15, or 18 had no effect on ovarian morphology or on the primordial follicle pool (Flaws et al., 1997), although pre- and postnatal exposure is reported to reduce the number of antral follicles (Heimler et al., 1998). Exposure to TCDD on GD 8 resulted in decreased fertility, increased incidence of constant estrous, and cystic endometrial hyperplasia in offspring (Gray and Ostby, 1995). Female rats exposed to TCDD on GD 15 showed delayed puberty, reduced ovarian weight, and malformations in the external genitalia (Gray and Ostby, 1995; Flaws et al., 1997). In LE Hooded rats exposed to TCDD on GD 15, 65% displayed clefting of the clitoris, and 80% exhibited a permanent thread of tissue across the vaginal orifice (Gray and Ostby, 1995). Histological analyses have shown that the vaginal thread consists of mesenchyme surrounded by keratinized epithelial cells (Flaws et al., 1997). The same malformations have been observed in Holtzman rats exposed to TCDD on GD 11, 15, or 18 (cleft clitoris 55–96% incidence and vaginal thread 36–44%), but were seen most frequently in animals exposed on GD 11 and 15 (Flaws et al., 1997). Vaginal threads have been observed in a dose-dependent fashion in rats exposed in utero to a single maternal dose of TCDD ranging from 0.20 to 0.80 µg/kg (Gray et al., 1997). These defects have been observed as early as postnatal day (PND) 2 and are permanent, persisting through PND 195–204 (Flaws et al., 1997). This indicates that the vaginal thread is a developmental defect associated with morphogenesis of the vagina and introitus.
The goals of this study were to determine the etiology of the developmental defect that results in the vaginal thread and to determine when the TCDD-induced birth defect first becomes apparent. We performed a histological comparison of the reproductive tracts of female fetuses exposed in utero to vehicle (control) or TCDD (1 µg/kg, po) on GD 15. We report that TCDD alters several aspects of vaginal development in the fetal rat, which may be related to the persistent appearance of a postnatal vaginal thread.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Animals.
Timed-pregnant Holtzman rats were obtained from Harlan Sprague-Dawley Inc. (Madison, WI) on GD12 (GD1, sperm positive). Dams were housed individually in the University of Wisconsin School of Pharmacy animal facility in clear plastic cages (41 x 20 x 20 cm) containing aspen chips for bedding and maintained on 12-h light/12-h dark cycles at a controlled room temperature of 22 ± 1°C. The animals were provided tap water and feed (Rat Chow 5012, Purina Mills, St. Louis, MO) ad libitum. All procedures involving the rats were approved by the University of Wisconsin Institutional Animal Use and Care Committee and conducted in accordance with The Guiding Principles in the Use of Animals in Toxicology.
On GD15, rats received a single oral dose (2 ml/kg) of 1 µg/kg TCDD (98% purity, Cambridge Isotope Laboratories, Woburn, MA) or an equivalent volume of vehicle (Wesson, corn oil/acetone, 19:l, v:v). Four or five control and treated dams were selected per gestation day to provide fetuses for each of four gestation days (GD 18, 19, 20, and 21). Dams were euthanized on GD 17, 18, 19, 20, or 21 of pregnancy and fetuses were collected. These days were selected for this study after preliminary work had shown that the first visible difference between control and treated fetuses was seen on GD 19. Pregnant dams were housed, dosed, and terminated at the University of Wisconsin. Tissues were collected and fixed at the University of Wisconsin. Fixed tissues were then shipped by overnight mail to the University of Maryland for histological processing and morphological evaluation.
Histology.
Fetuses were euthanized and the posterior half of each fetus was placed in Bouin's fixative for 24 h and then transferred to 70% ethanol for at least 24 h prior to dissection. Sex was confirmed by gonadal inspection. The litter was the experimental group. Two or three female fetuses were randomly selected from each litter from three or four litters per treatment per gestation day, resulting in a total number of fetuses between six and eight. Fetuses that were dead at the time of collection were excluded from the study; this was a small number of animals (seven altogether). The posterior half of each fetus (minus gastrointestinal tract, liver, tail, and extremities) was embedded in paraplastTM (VWR Scientific, Baltimore, MD) by routine procedures. Complete serial sections (8 µm) were mounted on "subbed" glass slides and stained with Weigert's iron hematoxylin followed by picric acid-methyl blue counterstain.
Microscopic analysis.
All prepared tissue sections were first examined under a dissecting microscope (12x) to locate pertinent sections that were then further examined under higher power (400x). The following features were evaluated: individual Mullerian ducts, fused Mullerian ducts plus or minus septum, thickness and length of mesenchyme between ducts, fusion of Mullerian ducts with the urogenital sinus, presence or absence of Wolffian duct remnants, length of remnants and relationship of the Wolffian ducts to the Mullerian ducts, and/or urogenital sinus. Representative regions were photographed with a Zeiss photomicroscope.
A preliminary scan was performed to identify the areas of interest. Progressing in a rostral to caudal direction, beginning near the caudal end of the kidneys, the last histological section with unfused Mullerian ducts (prospective uterine horns) was identified. The first histological section displaying fused Mullerian ducts was then noted, as was the gradual formation of a single lumen. Finally, approaching the caudal end, the first section with two unfused, individual ducts was marked. Two measurements of the mesenchyme between the unfused regions of the Mullerian ducts were taken. The length of this region was determined by counting all sections exhibiting interductal mesenchyme. The number of sections measured per fetus varied, due in part to age and treatment as well as to interfetal variability. The width or thickness of the interductal mesenchyme was determined by measuring the area between the ducts in every section with unfused Mullerian ducts and calculating the mean width for each individual. The litter means were then used for statistical comparison of gestation day and treatment.
Serial sections were scanned to identify the section in which the rostral end of the regressing Wolffian duct could be seen. Beginning with this section, all serial sections containing ductal remnants were counted until the Wolffian ducts fused with the Mullerian ducts (GD 19, 20, and 21) or with the urogenital sinus (GD 18). Wolffian duct length was calculated as the number of serial sections containing WD remnants x section thickness (8 µm). These values were used to determine the means/litter, and the means/age and treatment.
Statistical analysis.
Statistical analysis of data was performed using ANOVA (Origin, Microcal Software). All data were analyzed by 2-way analysis of variance (ANOVA) to test variances within litters and treatments as well as between treatments. Data are presented as litter means/age and treatment ± SEM. Significance was set at p < 0.05.
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RESULTS |
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Mullerian and Wolffian Duct Development in Control Animals
The normal progression of prenatal development of the female urogenital system from GD 16 to 21 is illustrated schematically in Figure 1
. At the outset, the Mullerian and Wolffian ducts cross but remain distinct, and the Mullerian ducts are separated by a mesenchymal structure (Fig. 1A). During development, the Wolffian ducts regress and the Mullerian ducts fuse, followed by regression of the tissue, forming an interductal septum and formation of a single lumen (the Mullerian-derived vagina) (Fig. 1B). The vagina and introitus are derivatives of the Mullerian ducts and the urogenital sinus. During normal development, the Mullerian ducts develop parallel to Wolffian ducts, with the Mullerian ducts running lateral to the Wolffian ducts. As the Mullerian ducts approach the caudal end of the embryo, they cross over the Wolffian ducts (Fig. 1A), run medial to the Wolffian ducts for a short distance, then fuse with the urogenital sinus (Fig. 1B). The rostral unfused Mullerian ducts develop into the uterine horns (Fig. 1B). The lower portions of the Mullerian ducts fuse to form the upper three-fifths of the vagina, while the lower two-fifths of the vagina develops from the urogenital sinus as described by Boutin and Cunha (1996). Formation of the vagina from the Mullerian ducts requires morphogenesis of a single vaginal lumen from the two Mullerian ducts. This is accomplished by fusion of the Mullerian ducts and regression of interductal septum of mesenchyme and epithelial cells (Fig. 1B).
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On GD 17, histological sections from vehicle-exposed, control fetuses clearly showed evidence of Mullerian duct fusion in the caudal region, as previously described by Del Vecchio (1982). However, fusion of the Mullerian ducts was not yet complete, and two separate Mullerian ducts were distinguishable. At the rostral end, where the Mullerian ducts crossed over the Wolffian ducts meeting midline, the Mullerian ducts were closely apposed and appeared as two distinct ducts lined with epithelial cells and separated by mesenchyme. Progressing caudally, the tissue between the Mullerian ducts gradually decreased, first the mesenchyme and then the midline epithelial cells, which resulted in the formation of a single lumen. More caudally, a septum of epithelial cells split the lumen into two halves, indicating incomplete fusion of the two Mullerian ducts. Still more caudally, mesenchymal tissue was observed midline between the ducts; so that in the most caudal region, the Mullerian ducts were similar in appearance to the ducts at the most rostral end (appearing as two fully distinct ducts separated by mesenchyme).
On GD 17, regression of the Wolffian ducts was well advanced in the control group (shown schematically in Fig. 1B
). The caudal end of the Mullerian ducts had fused with the Wolffian ducts, as previously described (Bok and Drews, 1983). On GD 17, the Wolffian ducts, but not the Mullerian ducts, appeared to have fused with the urogenital sinus. However, by GD 18, the Mullerian ducts had made contact with the urogenital sinus.
Through GD 20, fusion of the caudal Mullerian ducts was still incomplete, as evidenced by the presence of an interductal septum composed of epithelial cells alone or both epithelial and mesenchymal cells. However, the amount of mesenchyme decreased from GD 18 to 20. On GD 20, two of seven control fetuses exhibited fusion along the entire length of the Mullerian-derived vaginal anlagen. By GD 21, the Mullerian ducts in five of seven (71%) vehicle-exposed, control fetuses had completely fused, and the full length of the Mullerian-derived vagina consisted of a single lumen lined with epithelium surrounded by mesenchyme (Fig. 1B). The Wolffian ducts had completely regressed by GD 21.
Mullerian Duct Development in TCDD-Exposed Animals
In utero exposure to TCDD resulted in clear variations in prenatal development of the female reproductive tract, as shown schematically in Figure 1C. On GD 17 there was no visible difference between control and treated fetuses. However, by GD 19 there appeared to be more mesenchymal tissue between the unfused caudal portion of the Mullerian ducts in the TCDD-exposed fetuses compared to control (Figs. 2A and 2B). This difference persisted through GD 21. Shown schematically in Figure 1C, this persistent thread of mesenchyme directly or indirectly prevented fusion of the Mullerian ducts in TCDD-exposed fetuses.
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Between GD 19 and 21, the width of mesenchyme in control fetuses decreased each day (Fig. 3
). By GD 21 the septum had completely regressed in five out of seven controls. This was in contrast to the TCDD-exposed fetuses in which there was no significant change in the measured width of interductal mesenchyme between GD 19 and 21 (Fig. 3). The decrease observed in controls may have been due in part to overall growth in size of the fetus during this period; the lack of a decrease in TCDD-exposed fetuses is particularly striking given the induction of growth retardation associated with prenatal exposures to this toxicant.
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On GD 19, the length of unfused Mullerian ducts (number of serial sections) was the same in both groups (Fig. 4
) as was the width (as noted above in Fig. 3). On GD 20 and 21, the mean length of unfused Mullerian ducts in TCDD-treated fetuses was significantly greater than in controls due to the fact that over this period the length of unfused Mullerian ducts in control fetuses decreased, whereas there was no significant change in the TCDD-treated fetuses (Fig. 4). In TCDD-exposed fetuses, thicker mesenchyme between the Mullerian ducts appeared to be associated with an increased length of unfused Mullerian ducts.
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Wolffian Duct Development in TCDD-Exposed Animals
On GD 17, the first time point examined, Wolffian duct regression appeared to have progressed to the same extent in both control and treated fetuses. However, on GD 18 the Wolffian duct remnants in TCDD-treated fetuses appeared larger in diameter than control (Figs. 5A and 5B
). This difference between TCDD-exposed and control fetuses persisted through GD 21. Although TCDD exposure did not appear to alter fusion (Fig. 6), the enlarged Wolffian ducts in TCDD-treated fetuses resulted in dysmorphogenesis of the vagina, because Wolffian ducts contribute to the development of the vagina (Bok and Drews, 1983).
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The effect of TCDD on the size of the Wolffian ducts and the shape of the developing vagina was such that it was possible to differentiate between TCDD-treated or control fetuses by histological observation alone. On GD 19, the Mullerian-derived vagina in control fetuses was more blunt or round in shape and when fused with the urogenital sinus had more of an hourglass shape (Fig. 6A
). By comparison, the vagina in TCDD-exposed fetuses was more elongated, and portions derived from the Wolffian ducts were larger than controls and extended like ears above the urogenital sinus-derived portion of the vagina (Fig. 6B). By GD 20, only short remnants of the Wolffian ducts remained in control fetuses. However, Wolffian duct remnants were still substantial in TCDD-exposed fetuses. By GD 21, the Wolffian ducts in the control fetuses had completely regressed, whereas ductal remnants persisted in the TCDD-treated fetuses. In this study, we did not examine animals after birth, so we could not determine the persistence of these remnants in the postnatal period.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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This study has shown that prenatal exposure to TCDD leads to altered development of the rat vagina as early as GD 19, 4 days after treatment of the dams. TCDD interfered with two critical morphogenetic events in the formation of the female reproductive tract: regression of the Wolffian ducts and fusion of the Mullerian ducts. Delay in Wolffian duct regression in fetuses exposed to TCDD resulted in persistent ductal remnants and dysmorphogenesis of the vagina. The persistence of these Wolffian duct remnants is not known. Altered regression of the mesenchyme between the Mullerian ducts resulted in persistence of interductal mesenchyme in TCDD-exposed fetuses. These results indicate that the vaginal thread in rats exposed to TCDD in utero and via lactation, as first reported by Gray and Ostby (1995), is derived from persistent interductal mesenchyme. Our results suggest that it may be due to an irreversible perturbation of normal prenatal developmental events that directly or indirectly prevents complete fusion of the Mullerian ducts. As the animal grows in size, the threadlike structure may become relatively smaller and remain near the vaginal opening, where it is visible to external examination. These results are consistent with those of Flaws et al. (1997), who observed the thread in newborn rats, indicating that this is a prenatal event, and Gray et al. (1997), who found in a cross-fostering study that the in utero but not lactational TCDD exposure induces vaginal thread formation.
Although these results explain the etiology of the TCDD-induced vaginal thread, the mechanisms by which TCDD induces these events at the molecular level are unknown. TCDD has been shown to inhibit or augment cellular response to several hormones or growth factors, including estrogens, androgens, EGF, and TGF (Astroff et al., 1990; DeVito et al., 1992). These critical regulators of development function within a tightly defined program and exert control over many developmental processes, including the timing of morphogenetic signals and events such as cell proliferation (hyperplasia or hypoplasia, metaplasia, neoplasia), cell movement, receptor expression, apoptosis, and terminal differentiation. TCDD-induced modulation or interference with the activity of hormones or growth factors could impact on the timing of morphogenetic events in the developing reproductive tract.
The effects of TCDD on vaginal development are not unique to this chemical, but they may be species specific. Wolf et al. (1999) reported no vaginal threads in hamsters exposed in utero, although these animals had other urogenital malformations. Female mice exposed prenatally to the synthetic estrogen diethylstilbestrol exhibited abnormalities of the reproductive tract, including cervical enlargement, prominent Wolffian duct remnants, and, in the most severely affected cases, the Mullerian ducts failed to fuse (Newbold and McLachlan, 1982). In the present study, the occurrence of unfused Mullerian ducts in one GD 21 control fetus suggests that the vaginal thread can arise in the absence of TCDD. Similar incidents have been reported by others. Gray and Ostby (1995) reported that 2.5% of control rats exhibited permanent vaginal threads. We have also observed a low incidence of threads in untreated female Holtzman rats (Sommers, unpublished results). Female offspring derived from matings of NMR1 Dwarf rats x Holtzman rats were found to have vaginal threads (Dan Johnson, University of Kansas, Kansas City, KS, personal communication). Together, these findings show that although the vaginal defect does occur in a small percent of controls, in utero exposure to TCDD significantly increases its occurrence.
It is possible that the increased thickness of the mesenchymal tissue between the Mullerian ducts is due to TCDD-induced cell proliferation. The proliferative effect of TCDD has been reported in other developing systems (Abbott et al., 1989; Fox et al., 1993; Hudson et al., 1986). In mice, TCDD exposure induced hyperplasia of ureteric epithelial cells and resulted in hydronephrosis (Abbott et al., 1987). Alternatively, TCDD exposure may block developmentally appropriate cell death, such as in the developing palate, where TCDD inhibited regression of the medial edge epithelium and resulted in cleft palate (Abbott et al., 1989). Current research in our group is examining the effects of TCDD on both apoptosis and proliferation within the female reproductive system.
The role of TCDD-mediated endocrine disruption in these events is not known. TCDD may interfere with the specific temporal and spatial pattern of hormones and growth factors and their respective receptors that regulate development of the reproductive tract (Bentvelsen et al., 1994; Bentvelsen et al., 1995; Cooke et al., 1991a,b; Cunha et al., 1992; Prins and Birch, 1995; Prins and Birch, 1997). Studies have shown that proliferation of the ureteric epithelial cells (Abbott and Birnbaum, 1990a) and persistence of medial edge palatal epithelium (Abbott and Birnbaum, 1990b) in TCDD-exposed fetuses was associated with increased expression of EGF receptors. Estrogen has been found to be a potent regulator of EGF receptors. Increases in estrogen receptor mRNA were reported in uterus and ovary of female rats exposed to TCDD on GD 15 (Chaffin et al., 1996). In the rat, estradiol produced a 3-fold increase in uterine EGF receptor levels (Mukku and Stancel, 1985). In the mouse, EGF receptors were important mediators of estrogen-induced growth and differentiation in both uterus and vagina (Nelson et al., 1991). However, the interactions between TCDD and EGF may be tissue specific. Astroff et al. (1990) reported an inhibition of estrogen-induced increases of uterine EGF receptors in immature female Sprague-Dawley rats exposed to TCDD.
Persistent Wolffian duct remnants in TCDD-exposed female fetuses could be due to TCDD-induced changes in the sensitivity of the female fetus to androgens or to alterations in androgen receptor expression. The in utero exposure of rats to 5
-dihydrotestosterone caused stabilization of the Wolffian ducts in female fetuses and a shift towards a male pattern of androgen receptor expression in the developing reproductive tract (Bentvelsen et al., 1995). Stabilization and differentiation of the Wolffian ducts in the male fetus is dependent on the presence of testosterone (Cunha et al., 1987; Jost, 1953) and an increase in androgen receptors (Bentvelsen et al., 1994; Bentvelsen et al., 1995; Traish and Wotiz, 1987), compared to the female fetus, in which there is a decrease in androgen receptor expression (Bentvelsen et al., 1994).
In utero and lactational exposure to TCDD also affects the development of the reproductive system in male rats (Faqi et al., 1998). Recently, Roman and co-workers demonstrated that in utero TCDD exposure impairs the initial outgrowth of prostatic epithelium from the urogenital sinus in male rat fetuses and induces changes in the shape of the urogenital sinus (Roman et al., 1998). The defect we observed in female fetuses (persistent interductal mesenchyme and incomplete fusion of the Mullerian ducts) was observed near the point of fusion between the Mullerian/Wolffian ducts and the urogenital sinus. This is approximately the same region where the prostatic buds emerge from the urogenital sinus and invade the periurethral mesenchyme in male rat fetuses. This process, in males, begins on GD 18.5 and is complete by GD 20.5 (Timms et al., 1994). Thus, the TCDD-induced defect in female fetuses occurs at a similar location and time as prostatic budding in males. TCDD also impairs mesenchymal differentiation in male rats (Roman et al., 1998). The mesenchyme surrounding the prostatic buds differentiates into smooth muscle shortly after birth (Prins and Birch, 1995). On PND 1, in control rats, the mesenchyme nearest the urogenital sinus begins to condense around the prostatic buds and differentiates into smooth muscle (Roman et al., 1998). The newly differentiated smooth muscle stains strongly for androgen receptor compared to undifferentiated mesenchymal cells, which exhibit a lower incidence and a lower intensity of androgen receptor staining. In TCDD-exposed rats, by PND 1 few mesenchymal cells had differentiated into smooth muscle in the prostate, and androgen receptor staining was reduced (Roman et al., 1998). On PNDs 14, 21, and 32, in utero and lactational TCDD exposure increased the thickness of periductal smooth muscle in the prostate (Roman et al., 1998). At these times the smooth muscle cells were increased in number, hypertrophied, and interspersed with fibroblastic cells (Roman et al., 1998), demonstrating that in utero and lactational TCDD exposure alters periurethral mesenchyme development in male rats as well as in female rats, as demonstrated in this study.
In conclusion, although dioxin is a recognized human carcinogen, these studies demonstrate that prenatal exposure to TCDD, in some species, can have subtle yet profound noncarcinogenic effects on the development of the female reproductive system. The fact that TCDD can alter prenatal development of the rat vagina raises concerns that TCDD may elicit other changes in these tissues, changes that may not become apparent until later in development or during reproductive life.
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ACKNOWLEDGMENTS |
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This research was funded in part by a VA Merit Award (E.K.S., A.N.H.), the Bressler Foundation (A.N.H.), and Heinz Family Foundation (E.K.S., M.K.D.), and by NIH grants ES07263 (A.N.H.) and ES01332 (R.E.P.). M.K.D. was supported as a postdoctoral fellow on an NIEHS Toxicology Training Grant.
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NOTES |
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1 To whom correspondence should be addressed at University of Maryland School of Medicine, Program in Human Health and the Environment, 10 S. Pine Street, Baltimore, MD 21201–1509. Fax: (410) 706-0727.
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