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Ovary |
Department of Epidemiology and Preventive Medicine,3 Program in Toxicology, University of Maryland, Baltimore, Maryland 21201
School of Pharmacy,4 University of Wisconsin, Madison, Wisconsin 53705
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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apoptosis, follicle, follicular development, ovary, toxicology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The creation of AhR-deficient (AhRKO) mice has provided a unique tool for investigating the role of the AhR in both nonreproductive and reproductive tissues. Studies using AhRKO mice indicate that the AhR plays an important role in the female reproductive system [4–6]. The AhRKO mice produce smaller litters than wild-type (WT) mice, and they have difficulties maintaining conceptuses and rearing pups to weaning [4]. In addition, whereas AhRKO and WT mice have similar numbers of primordial and primary follicles during adult life, AhRKO mice have fewer preantral and antral follicles than WT mice during this same time period [6].
The mechanism by which AhR deficiency reduces the number of preantral and antral follicles is not understood. It is possible that AhRKO mice have fewer preantral and antral follicles than WT mice because of a decreased number of follicles that grow to preantral and antral stages. Alternatively, it is possible that AhRKO mice have fewer preantral and antral follicles than WT mice because the incidence of atresia is increased in the preantral and antral follicles of AhRKO ovaries compared to WT ovaries.
Both of these possibilities are supported by studies conducted using nonovarian tissues [7, 8] and by studies conducted using primordial and primary ovarian follicles [9]. For example, Zaher et al. [7] have shown that livers from AhRKO mice have higher levels of two factors known to inhibit proliferation, transforming growth factor (TGF) ß1 and TGFß3, than livers from WT mice. Similarly, Elizondo et al. [8] have shown that embryonic fibroblast cultures from AhRKO mice produce higher levels of TGFß than WT cultures. Matikainen et al. [9] have shown that the promoter for the pro-apoptotic factor bax contains two core AhR response elements in the mouse ovary and that bax levels are increased in primordial and primary follicles in response to the AhR-agonist 9,10-dimethylbenz[a]anthracene (DMBA).
These findings suggest that the AhR may be involved in regulating atresia of primordial and primary follicles, but whether such an interaction exists in regulating atresia of larger follicles is unknown. Thus, the first objective of the present study was to test the hypothesis that the AhR regulates the number of preantral and antral follicles, either by increasing the number of follicles that grow to the preantal and antral stages or by decreasing the incidence of atresia in preantral and antral follicles. Because alterations in follicular growth or atresia can affect the ability to ovulate [10], a second objective was to compare ovulation in WT and AhRKO mice.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The AhRKO mice (homozygotes and heterozygotes) and their WT littermates were generated as described by Schmidt et al. [11] and generously provided by Dr. Christopher A. Bradfield (McArdle Laboratory for Cancer Research, Madison, WI). The mice were housed in clear plastic cages and maintained on a 12L:12D (lights on 0600h) cycle in a temperature-controlled room (24 ± 1°C) with 35% ± 4% relative humidity. The mice were provided feed (Harlan, Madison, WI) and tap water for consumption ad libitum. The University of Maryland Institutional Animal Use and Care Committee approved all protocols involving mice.
Screening/Genotyping of Mice
The screening/genotyping protocol used here was an adaptation of that described previously by Benedict et al. [6]. Ear-punch tissues from pups were lysed in 9 µl of buffer containing proteinase K (4 mg/ml) [12]. Digestion was carried out at room temperature for 30 min, followed by incubation at 100°C for 3 min. The lysate was then subjected to polymerase chain reaction (PCR) using primers as described previously [6]. The PCR conditions were as follows: 40 cycles of 94°C for 45 sec, 55°C for 1 min, and 72°C for 3 min. The PCR products were then sized by agarose gel electrophoresis. The WT (AhR+/+) mice were identified by the presence of a 670-base pair (bp) product. Homozygous AhRKO (AhR-/-) mice were identified by the presence of a 580-bp product. Heterozygous (AhR+/-) mice were identified by the presence of both the 580-bp and 670-bp products. Only homozygous AhRKO and WT mice were used in each experiment.
Measurement of Follicular Growth
Three separate assays were used to determine whether follicular growth differed by genotype: 1) morphological assessment of the number of follicles that reached the preantral and antral stages over time, 2) morphological assessment of follicular size over time, and 3) measurement of ovarian and follicular growth in response to eCG. To morphologically assess the number of follicles that reached the preantral and antral stages over time, ovaries were harvested from AhRKO and WT mice on Postnatal Days (PNDs) 8, 32, 45, and 53 and fixed in Kahle fixative. These days were chosen because our previous study showed that AhRKO mice have decreased numbers of preantral and antral follicles compared to WT mice by PND 53, but not before this time point [6]. The ovaries were placed in histology specimen bags, dehydrated through an ethanol series, embedded in Paraplast (VWR Scientific, Baltimore, MD), serially sectioned (thickness, 8 µm), mounted onto glass slides, and stained with Weigert hematoxylin-picric acid methyl blue. Every 10th section was marked for analysis, and the total number of preantral and antral follicles in each of the marked sections was counted as described previously [6, 13, 14]. Follicles were counted as preantral follicles if they contained an intact oocyte, more than one layer of granulosa cells, and lacked antral spaces. Follicles were counted as antral follicles if they contained an intact oocyte, more than one layer of granulosa cells, and antral spaces. To avoid double-counting of follicles, only follicles containing an oocyte with a visible nucleus were counted. To avoid bias, all ovaries were analyzed without knowledge of genotype or age. In addition, three investigators independently counted follicles in all sections and compared their results; inconsistencies were resolved before including the data in the analysis. The total number of preantral and antral follicles was determined by multiplying the number of preantral or antral follicles in the marked sections by 80 to account for every 10th section being used in the analysis and for cutting the sections at a thickness of 8 µm [6, 13, 14]. Because the results did not differ when the numbers of preantral and antral follicles were analyzed separately or when the numbers of preantral and antral follicles were combined (i.e., total number of preantral follicles plus antral follicles), the data were combined for presentation purposes.
To morphologically assess the size of follicles in AhRKO and WT mice, the diameters of all preantral and antral follicles in the marked sections were measured in two perpendicular axes (vertical and horizontal) using a calibrated micrometer on a light microscope at 25x magnification as described previously [15, 16]. The mean of the two diameters was calculated to obtain a mean diameter per follicle, and then the mean of all follicle diameters was calculated to estimate the total mean diameter of all preantral and antral follicles in each ovary. All measurements were done without knowledge of genotype or age, and only follicles containing an oocyte with a visible nucleus were measured to avoid double measurements and to help insure that a consistent area of each follicle was measured. Because a difference existed between when the data for preantral and antral follicles were analyzed separately and when the data were combined, the data are presented as the mean diameter of preantral follicles by genotype and the mean diameter of antral follicles by genotype.
To assess ovarian and follicular growth in response to eCG, WT and AhRKO mice (PNDs 21–28) were injected s.c. with 10 IU of eCG (Sigma Chemical Co., St. Louis, MO). The mice were killed exactly 36 h later, and the ovaries were removed and cleared of fat, oviduct, and bursa. The ovaries were then weighed and placed in a watchglass containing minimum essential medium (MEM; Invitrogen, Carlsbad, CA). Next, each ovary was dissected under a microscope with watchmaker forceps to remove the largest antral follicles. Follicle diameter was then measured in two perpendicular axes with an inverted microscope. The mean of the two diameters was calculated to obtain a mean diameter per follicle.
Measurement of Follicular Atresia
Atresia was compared in AhRKO and WT mice using three different assays: 1) morphometric assessment of the number and percentage of atretic follicles over time, 2) terminal deoxynucleotidyl transferase dUTP nick-end-labeling (TUNEL) assays, and 3) 3'-end labeling of fragmented DNA. For morphometric assessment of the number of atretic follicles, ovaries were harvested from AhRKO and WT mice on PNDs 32, 45, and 53. These time points were selected because we previously observed differences in follicle numbers by genotype between PNDs 32 and 53, but not before this time period [6]. The ovaries were fixed in Kahle fixative and processed for histological evaluation as described above. Healthy and atretic follicles were classified using strict morphological criteria and without knowledge of genotype or age. Follicles were classified as healthy if they contained an intact oocyte, organized granulosa cell layers, and few (<10%) pyknotic bodies. Atretic follicles were classified as those containing a degenerating oocyte, disorganized granulosa cell layers, and/or more than 10% of the granulosa cells appearing pyknotic. The percentage of atretic follicles was estimated by taking the total number of atretic preantral and antral follicles, dividing by the total number of preantral and antral follicles (both healthy and atretic), and then multiplying by 100.
To conduct TUNEL assays, ovaries were collected from WT and AhRKO mice on PNDs 32, 45, and 53. These time points were selected because we previously observed a difference in follicle numbers by genotype between PNDs 32 and 53, but not before this time period [6]. The ovaries were fixed in Kahle solution and serially sectioned (thickness, 8 µm). At least eight random sections per ovary (three to five ovaries per genotype, one ovary per animal) were then subjected to TUNEL assays using a kit obtained from Intergen (Purchase, NY) and by following the manufacturer's instructions. Because this kit stains apoptotic cells brown, the number of follicles containing a significant number of brown cells (
10%) was counted in each section to estimate the number of atretic follicles per section. This analysis was done without knowledge of genotype or age. In addition, two investigators independently performed these counts, and any discrepancies were resolved before data analysis.
To conduct 3'-end labeling of fragmented DNA, WT and AhRKO mice (PNDs 21–28) were injected s.c. with 10 IU of eCG (Sigma Chemical Co., St. Louis, MO) to induce growth of a cohort of follicles to the antral stage. These mice were killed 36–48 h later, and the ovaries were removed and cleared of fat, oviduct, and bursa. The ovaries were then placed in a watchglass containing MEM with 0.1% BSA, 100 U/ml of penicillin, and 100 µg/ml of streptomycin sulfate on ice. Each ovary was then dissected under a microscope with watchmaker forceps to remove large antral follicles. Antral follicles (n = 8–10) from each genotype were immediately snap-frozen as a time-zero control. In addition, some antral follicles (n = 8–10) from each genotype were placed separately in scintillation vials filled with 3 ml of supplemented MEM. The vials were then sealed and placed in a 37°C incubator for 24 h to induce apoptosis. After 24 h, the follicles were removed from the vials and snap-frozen. Next, DNA was extracted from the follicles and subjected to 3'-end labeling to measure apoptosis as described previously by Tilly and Hsueh [17].
Measurement of Ovulation
The ability of AhRKO and WT mice to ovulate was determined by morphological assessment of the number of corpora lutea in the ovary over time [15, 16]. Briefly, ovaries were collected from WT and AhRKO mice on PNDs 32, 45, and 53. The ovaries were fixed in Kahle solution and processed for histological evaluation as described above. Sections were used to count the number of corpora lutea without knowledge of genotype or age. To avoid double-counting, each corpus luteum was followed through consecutive sections to insure that it was only counted once.
Statistical Analysis
Means ± standard errors of the mean (SEM) were calculated for the number of preantral and antral follicles, the size of follicles, ovarian weight and follicular size in response to eCG, the percentage of atretic antral follicles, the fold-change in 3'-end labeling, and number of corpora lutea. When no differences were observed in the results obtained by comparing the number of preantral and antral follicles separately by genotype versus comparing the combined number of preantral and antral follicles by genotype, the data were combined and presented as the total number of preantral and antral follicles by genotype. Differences in the means between either genotype group or time points were evaluated using the Student t-test when comparing two groups and analysis of variance (ANOVA) followed by a Scheffe post-hoc test when comparing multiple groups. Significance was assigned at P 
0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In WT ovaries, a 2-fold increase was observed in the total number of follicles that reached the preantral and antral stages between PND 8 and PND 32 (Fig. 1) (P 0.0001), a 1.5-fold increase was observed in the total number of follicles that reached the preantral and antral stages between PND 32 and PND 45 (P 0.019), and no difference was observed in the total number of follicles that reached the preantral and antral stages between PND 45 and PND 53. In AhRKO ovaries, however, a 2.6-fold increase was observed in the total number of follicles that reached the preantral and antral stages between PND 8 and PND 32 (Fig. 1) (P 0.001), no change was observed in the total number of follicles that reached the preantral and antral stages between PND 32 and PND 45, and a 40% decrease was observed in the total number of follicles that reached the preantral and antral stages between PND 45 and PND 53 (P 0.02).
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These changes in the numbers of follicles that reached the preantral and antral stages over time resulted in WT and AhRKO ovaries having similar numbers of preantral and antral follicles on PND 8 and on PND 32. However, they also resulted in WT ovaries approaching a greater number of preantral and antral follicles compared to AhRKO ovaries on PND 45 (P 0.14) and in WT ovaries having 2-fold more preantral and antral follicles than AhRKO ovaries on PND 53 (P 0.003).
Despite the differences in numbers of follicles that reached the preantral and antral stages in WT and AhRKO ovaries, no significant differences were observed in the mean diameter of preantral follicles in WT and AhRKO mice on PND 32 through PND 53 (Fig. 2). Additionally, no significant differences were observed in the mean diameters of the antral follicles in WT and AhRKO ovaries on PND 32 and on PND 45. By PND 53, however, AhRKO ovaries contained antral follicles that were approximately 20% larger in diameter than those in WT ovaries (Fig. 2) (P 0.0005).
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When WT and AhRKO mice were treated with eCG, ovarian weight gain was reduced in AhRKO mice compared to WT mice (Fig. 3). Before treatment with eCG, ovarian weight was similar in WT and AhRKO mice. Exactly 36 h after eCG injection, however, WT ovaries weighed 0.68 ± 0.12 mg, whereas AhRKO ovaries only weighed 0.28 ± 0.06 mg (Fig. 3A) (P 0.05). After isolation from the eCG-treated ovaries, the largest follicles from WT mice were 211 ± 10 µm in diameter, whereas those from AhRKO ovaries were only 182 ± 6 µm in diameter (Fig. 3B) (P 0.02).
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Effect of the AhR on Atresia
To determine whether the decreased number of follicles in AhRKO ovaries on PND 53 resulted from an increased incidence of atresia in AhRKO ovaries versus WT ovaries, AhRKO and WT ovaries were subjected to three different assays for measurement of atresia. All three assays indicated that no significant differences existed between the incidence of atresia in WT and AhRKO mice at any time point (Figs. 4 and 5). Morphological evaluation of the number of atretic follicles indicated that WT and AhRKO ovaries contained similar numbers of atretic follicles on PNDs 32, 45, and 53 (Fig. 4A). It also indicated that approximately 20% of all follicles were atretic in both WT and AhRKO ovaries on PND 32 and PND 45 (Fig. 4B) and that approximately 10% of the follicles were atretic in both WT and AhRKO ovaries on PND 53 (Fig. 4B). Similarly, TUNEL staining revealed that two to three follicles per section contained apoptotic DNA in both WT and AhRKO ovaries at all time points. In addition, 3'-end labeling of fragmented DNA indicated that both WT and AhRKO follicles had a 15-fold increase in apoptotic DNA after 24 h in culture (Fig. 5).
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Although the number of atretic follicles and incidence of apoptosis were similar in WT and AhRKO ovaries at each selected time point, the number of healthy preantral and antral follicles differed in WT and AhRKO ovaries by PND 53. By PND 53, WT ovaries contained approximately 1.9-fold more healthy follicles compared to AhRKO ovaries (Fig. 4A) (P 0.006).
Effect of the AhR on Ovulation
The WT and AhRKO ovaries contained similar numbers of corpora lutea on PND 32 (Fig. 6). By PND 45, however, WT ovaries approached having more corpora lutea than AhRKO ovaries (P 0.08), and by PND 53, WT ovaries contained significantly more corpora lutea than AhRKO ovaries (Fig. 6) (P 0.02).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The lack of an effect of the AhR on atresia was unexpected, because a previous study by Matikainen et al. [9] showed that the AhR interacts with factors responsible for the regulation of ovarian atresia. More specifically, a single dose of the potent AhR-agonist DMBA caused an accumulation of bax mRNA in the ovary and Bax protein in the oocytes of primordial and primary follicles [9]. These findings suggest an interaction between the AhR and Bax during atresia of primordial and primary follicles, but whether such an interaction occurs during atresia of preantral and antral follicles is unclear. Our results do not directly negate such an interaction. However, they do suggest that it is expendable in preantral and antral follicles, because we did not observe that the AhR regulates atresia of preantral and antral follicles in the mouse.
Although the decreased number of preantral and antral follicles in AhRKO mice may not result from an increased incidence of atresia in AhRKO ovaries versus WT ovaries, three lines of evidence suggest that it may result from alterations in follicular growth. First, morphological assessment of preantral and antral follicle numbers revealed a significant increase in the total number of follicles that reached the preantral and antral stages between PND 32 and PND 53 in WT, but not in AhRKO, ovaries. Second, morphological assessment indicated that the increase in the total number of preantral and antral follicles in WT ovaries was seemingly caused by an increase in the number of healthy follicles (i.e., those follicles that are likely to be growing in the ovary) and not by an increase in the number of atretic follicles (i.e., those follicles that are dying in the ovary). Third, experiments in which WT and AhRKO mice were dosed with eCG at 21–28 days of age showed that ovarian weight and follicular size were significantly increased in WT mice compared to AhRKO mice. Because eCG is known to increase the numbers and sizes of follicles growing to the antral stage [18–20], these data indicate that fewer follicles grew in response to eCG in AhRKO ovaries compared to WT ovaries and that the AhRKO follicles grew to a smaller size than the WT follicles.
Despite the decreased number of follicles that reached the preantral and antral stages over time and the reduced responsiveness to eCG in AhRKO mice compared to WT mice, AhRKO ovaries contained preantral follicles that were similar in size to those in WT ovaries. Additionally, AhRKO ovaries contained antral follicles that were similar in size to those in WT ovaries on PND 32 and PND 45. In contrast, AhRKO ovaries contained antral follicles that were larger than those in WT ovaries on PND 53. Although the reasons for this are unknown, it is possible that the decline in actual numbers of follicles on PND 53 leads to alterations in hormone and/or growth factor levels. In turn, these altered hormone and/or growth factor levels may influence the actual size of the remaining follicles by increasing granulosa/thecal cell proliferation and/or the amount of follicular fluid accumulation. The hypothesis that the AhR might regulate the amount of follicular fluid is supported by the study of Abbott and Buckalew [21], which indicated that the aryl hydrocarbon nuclear translocator (ARNT) is required for vascularization and regulation of vascular endothelial growth factor (VEGF). Because appropriate vascularization and VEGF levels are important for regulating the size of the antrum [22–24] and ARNT heterodimerizes with AhR, a lack of the AhR could result in alterations in antral size.
The fact that morphological assessment of follicular size indicates that antral follicles from AhRKO mice are larger than those from WT mice on PND 53 while the eCG experiments indicate that antral follicles from AhRKO mice are smaller than those from WT mice may seem contradictory. However, these two experiments measure different endpoints. Morphological assessment of follicular size provides information about the actual size of follicles in vivo, and the eCG experiments provide an indication of the ability of the ovary and follicles to respond to hormonal treatment. Collectively, these data may indicate that AhRKO follicles possess altered responsiveness to hormone-signaling pathways that regulate growth and are normally mediated by the AhR in WT mice.
The slowed growth of follicles to the preantral and antral stages in the AhRKO ovaries compared to the WT ovaries has several potential explanations. First, it is possible that deletion of the AhR alters the levels or functions of receptors that bind hormones or growth factors that regulate follicular growth. Several studies indicate that cross-talk occurs between the AhR and epidermal growth factor (EGF) receptor [25–28]. Many of these studies involve exposure to the potent AhR ligand known as TCDD [25–28], and many indicate that exposure to TCDD often results in phenotypes similar to those observed in the AhRKO mice [29–32]. Although the reasons for this are unclear, they may include an ability of TCDD to down-regulate the expression of the AhR [33, 34] or to interfere with the interaction between the AhR and its signaling pathways [32]. Lin et al. [25] have shown that TCDD causes an 80–90% decrease in the maximum binding capacity of EGF receptors in the livers of female mice. Because EGF is thought to stimulate follicular growth [35], it is possible that AhR deletion alters the ability of EGF to bind to its receptor and that this results in slowed follicular growth and/or reduced responsiveness to eCG. Similarly, studies have shown that cross-talk occurs between the AhR and estrogen receptors (ER) [28, 36–39]. TCDD has been shown to decrease ER-mediated responses, such as estrogen-induced uterine wet weight gain and cell proliferation, progesterone-receptor binding, peroxidase activity, and EGF-receptor binding [28, 39, 40]. Thus, it is possible that the AhR deletion decreases either ER levels or ER-binding capacity in the ovary and that this decreases the numbers of follicles that reach the preantral and antral follicle stages and/or respond to eCG. In addition, it is possible that cross-talk occurs between the AhR and receptors for FSH or LH. In the present study, the AhRKO ovaries were less responsive to eCG, a compound that has both FSH-like and LH-like activity [17, 18]. Therefore, it is possible that the ability of eCG to bind FSH or LH receptors is reduced in AhRKO mice. Our findings are consistent with those of Roby et al. [41], which suggest that TCDD decreases eCG responsiveness and hCG binding in the ovary. Our findings also are consistent with those of several studies showing that TCDD reduces the steroidogenic responsiveness of the rat testis to hCG and luteinizing hormone [42–44].
Alternatively, the AhR deletion may decrease the number of follicles that reach the preantral and antral stages by affecting the expression of enzymes involved in the metabolism of 17ß-estradiol or other estrogens. In turn, this may alter the growth of ovarian follicles because adequate levels of estrogens in the ovary may be required for normal follicular growth [10, 35, 45]. This hypothesis is supported by several studies showing that the AhR mediates the transcription of cytochrome P450s involved in estrogen metabolism [46, 47].
In addition to affecting follicular growth, the AhR may affect ovulation in mice. Our data indicate that in the absence of the AhR, the number of corpora lutea decrease concomitant with the reduction in the number of preantral and antral follicles, suggesting that AhR deletion reduces the number of follicles that ovulate and become corpora lutea. These results are consistent with those of several studies indicating that TCDD directly blocks ovulation in rats [48–51]. Because TCDD has been shown to block ovulation in rats by decreasing gonadotropin-receptor binding, estradiol production, and cAMP levels [48, 49], it is possible that AhR deletion blocks ovulation via similar mechanisms.
In conclusion, these findings suggest that the AhR may alter the growth of ovarian follicles to the preantral and antral stages and that the AhR may help to regulate ovulation in the mouse. Future studies should investigate the mechanism by which AhR deletion disrupts follicular growth, hormone responsiveness, and ovulation. Such studies may provide insight regarding the physiological role of this receptor.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Jodi A. Flaws, University of Maryland School of Medicine, 660 West Redwood Street, Howard Hall 133, Baltimore, MD 21201. FAX: 410 706 1503; jflaws{at}epi.umaryland.edu
Received: 20 May 2002.
First decision: 24 June 2002.
Accepted: 13 November 2002.
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