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REPRODUCTION-DEVELOPMENT |
Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital/Harvard Medical School (T.M.M., T.M., Y.M., G.I.P., J.L.T.), Boston, Massachusetts 02114; Departments of Pathology and Medicine, Dana-Farber Cancer Institute/Harvard Medical School (S.J.K.), Boston, Massachusetts 02115; and Department of Environmental Health, Boston University Schools of Medicine and Public Health (D.H.S.), Boston, Massachusetts 02118
Address all correspondence and requests for reprints to: Dr. Jonathan L. Tilly, Massachusetts General Hospital, VBK137C-GYN, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: jtilly{at}partners.org
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Abstract |
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-napthoflavone (ANF). Immunohistochemical analysis revealed an accumulation of Bax protein in germ cells of fetal ovaries exposed to PAHs before the onset of apoptosis, whereas cotreatment with ANF inhibited the induction of Bax expression. The functional importance of increased Bax expression to the cytotoxic response was confirmed by findings that fetal ovarian germ cell loss caused by in utero exposure of wild-type female fetuses to PAHs was not observed in Bax-deficient female fetuses exposed in parallel. We conclude that a central role exists for the AHR in transducing the actions of PAHs in fetal ovarian germ cells, and that the proapoptotic Bcl-2 family member, Bax, is a required mediator of PAH-induced oocyte loss in female fetuses exposed to PAHs in utero. |
Introduction |
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/ß (3) having been identified as in vivo survival factors for developing oocytes. The second stimulus for germ cell deletion is meiotic recombination defects, a conclusion drawn principally from studies of mice deficient in the serine-threonine protein kinase encoded by the ataxia telangiectasia-mutated (Atm) gene (4). In addition, a case has been made for cell death associated with the breakdown of germline cysts, a process best studied in Drosophila melanogaster (5), but also recently identified in mice (6), as a reason for perinatal germ cell loss. We previously reported that the aromatic hydrocarbon receptor (AHR), a member of the Per-Arnt-Sim gene family of evolutionarily conserved transcription factors (7, 8), is abundantly expressed in oocytes, and that AHR loss of function in mice results in attenuated fetal oocyte death (9). As a consequence, Ahr mutant females are endowed with a significantly larger reserve of primordial oocytes at birth (9, 10), findings that collectively underscore the existence of a prominent physiological role for the AHR in regulating PCD during female gametogenesis. However, characterization of the intracellular mechanisms by which the AHR modulates apoptosis in fetal oocytes has been hindered by the fact that the identity of the natural ligand(s) for this receptor has not yet been unequivocally established.
One approach to circumvent this problem is to use chemicals, such as polycyclic aromatic hydrocarbons (PAHs), that are known to pharmacologically activate the AHR in many cell types (7, 8). Indeed, it is has been known for over 2 decades that injection of female mice with PAHs causes a rapid depletion of primordial and primary oocytes (11), and that the ovotoxic effects of PAHs in vivo can be prevented by the selective AHR antagonist, -napthoflavone (ANF) (12). Moreover, female mice exposed in utero to PAHs (13) or to cigarette smoke (14) are endowed with a fraction of the primordial oocytes present in control female mice exposed to vehicle during fetal development. Given that PAHs are present at significant levels in tobacco smoke (13, 15), these data suggest that the reduced fecundity observed in adult human females exposed to cigarette smoke during gestation (16) is due at least in part to the cytotoxic effects of cigarette smoke-derived PAHs on fetal oocytes.
If PAHs use the AHR to kill female germ cells, it is likely that genes important for the execution of oocyte apoptosis would be transcriptional targets for the PAH-activated receptor. In recent studies we identified consensus AHR response elements in the promoter of the gene encoding Bax (17), a proapoptotic member of the Bcl-2 family of cell death regulators (18, 19). We further showed in mice that PAH-mediated activation of the AHR in germinal vesicle stage oocytes triggers transcriptional activation of the bax promoter in an AHR-dependent fashion, and that in vivo exposure of prepubertal female mice to PAHs leads to Bax protein accumulation in primordial oocytes, followed by apoptosis. Importantly, this increased expression of Bax was shown to be dependent upon the presence of functional AHR, and primordial oocyte destruction in postnatal mouse ovaries caused by PAH exposure was shown to require both AHR and Bax (17).
Although these investigations provide insight into how PAHs kill oocytes within primordial follicles of the postnatal ovary, the relevance of these findings to understanding AHR function, in the absence or presence of chemical ligand exposure, to fetal ovarian germ cells remains to be established. For example, targeted disruption of the bax gene in mice attenuates primordial and primary oocyte death (atresia) in postnatal life, leading to a dramatic extension of functional ovarian life span into advanced chronological age (20). On the other hand, Bax deficiency does not alter the number of primordial oocytes endowed at birth (20) or rescue Atm-null fetal oocytes from PCD (3). Interestingly, however, female gametogenic failure resulting from reduced expression of the antiapoptotic Bcl-2 family member, Bcl-xL, can be prevented by bax gene knockout (21). Thus, whether Bax is involved in mediating female germ cell death appears to be determined by both the developmental status of the oocyte and the stimulus for apoptosis. Finally, given the discordant neonatal ovarian phenotypes of Ahr and bax mutant female mice, the relationship between AHR and Bax in controlling fetal ovarian germ cell fate is unclear. We therefore designed experiments to determine whether PAHs act via the AHR to trigger apoptosis in fetal oocytes, and whether PAH-induced fetal oocyte death is correlated with and dependent upon increased expression of Bax.
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Materials and Methods |
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Fetal ovarian cultures
As detailed previously (23), female fetuses were removed on embryonic d 13.5 (e13.5) from timed-pregnant, wild-type female mice. Genital ridges containing the developing fetal ovaries were then isolated and either fixed immediately (time zero) or cultured for 24–72 h with 100 ng/ml SCF, 100 ng/ml leukemia inhibitory factor (LIF), and 50 ng/ml IGF-I to prevent spontaneous germ cell apoptosis (23). In some cultures, vehicle (acetone) or 9,10-dimethylbenz[a]anthracene-3,4-dihydrodiol (DMBA-DHD), a PAH known to bind with and activate the AHR (24), was included in the absence or presence of the AHR-selective antagonist, ANF (25). Freshly isolated ovaries or ovaries obtained at the termination of culture were then fixed and processed for Bax immunostaining (see Analysis of Bax expression below) or for assessment of the number of nonapoptotic germ cells per section, as previously described (23).
Analysis of Bax expression
After a 4-h fixation in 4% paraformaldehyde buffered with 0.1 M sodium phosphate, fetal ovaries were paraffin-embedded, sectioned, and analyzed by immunohistochemistry with high temperature antigen unmasking, essentially as previously described (26). For these studies, a 1:50 dilution of an affinity-purified rabbit polyclonal antibody raised against murine Bax (P-19, Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was used, and ovaries from the different experimental groups were always processed in parallel. In addition, the specificity of the immunostaining conditions with murine ovarian tissue has been previously documented (17).
In vivo studies of PAH responses in bax mutant mice
Heterozygous (+/-) bax mutant male and female mice were mated to generate timed pregnancies with both wild-type and Bax-deficient fetuses present in utero. On e14.5, pregnant females were given a single ip injection of vehicle (corn oil) or DMBA (1 mg/kg BW), and the pregnancies were allowed to progress to term. Ovaries were then collected from female offspring on d 4 postpartum, fixed, paraffin-embedded, and serially sectioned for analysis of the number of nonatretic oocyte-containing primordial, primary, and small preantral follicles per ovary, as previously described (20, 27). Follicles at these immature stages of development were deemed atretic if the oocyte was degenerating (convoluted and condensed or fragmented) or absent (20, 27). At the time of ovarian collection, a tail sample was taken from each neonate for DNA isolation and PCR-based genotype determination (20).
Data presentation and analysis
Graphs depict the mean ± SEM of results from three independent experiments. For quantitative analyses, one-way ANOVA with Scheffé’s F test or t test was used to compare mean values, and P < 0.05 was chosen to indicate a statistically significant difference. Photomicrographs representative of results obtained in three independent experiments are provided for qualitative analysis of Bax immunohistochemistry or ovarian histology.
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Results |
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). However, treatment of cytokine-supported ovaries with increasing amounts of DMBA-DHD caused a pronounced reduction in viable germ cell numbers (Fig. 1), an effect determined to be a result of increased apoptosis using both morphological (Fig. 2) and biochemical (in situ DNA cleavage analysis; data not shown) approaches. Furthermore, and in keeping with the known ability of DMBA-DHD to bind with and activate the AHR (24), cotreatment of PAH-exposed fetal ovaries with the AHR antagonist ANF (25) completely reversed the proapoptotic effects of DMBA-DHD in germ cells (Fig. 1).
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, A and B). However, inclusion of DMBA-DHD in cytokine-supported cultures caused a marked increase in Bax immunoreactivity in many germ cells (Fig. 2C). Furthermore, the majority of Bax-positive germ cells had not yet initiated cellular or nuclear condensation indicative of apoptosis, suggesting that Bax accumulation preceded the onset of cell death (Fig. 2C). Finally, and in agreement with the observed ability of ANF to inhibit PAH-induced fetal germ cell loss (Fig. 1), inclusion of ANF completely eliminated the increase in Bax accumulation in germ cells resulting from DMBA-DHD treatment (Fig. 2D).
Bax is required for PAH-induced fetal oocyte death
Although these observations support the idea that the PAH-activated AHR signals death in developing fetal oocytes via increased expression of Bax, proof of the functional importance of Bax to the cytotoxic response was still needed. Therefore, we designed a final set of studies to determine whether Bax deficiency could, in fact, protect the fetal ovarian germline from apoptosis caused by in utero PAH exposure. These studies revealed that, consistent with previously published findings (20), the absence of Bax did not alter the size of the neonatal endowment of primordial oocytes in the absence of DMBA exposure (Fig. 3). Moreover, and again in agreement with previously published data (13, 14), in utero exposure of wild-type fetuses to PAHs resulted in the birth of females with a markedly reduced reserve of oocyte-containing primordial follicles, as shown by both qualitative (Fig. 4, A and B) and quantitative (Fig. 3) analyses. In striking contrast, bax mutant fetuses exposed to PAHs in parallel were born with a normal endowment of primordial follicles (Fig. 3). In addition, the ovarian architecture of bax mutant neonates exposed to PAHs during pregnancy (Fig. 4C) was histologically indistinguishable from that of females exposed to vehicle during gestation (Fig. 4A).
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Discussion |
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Such results were important, because we could then work under the assumption that the AHR, once bound and activated by PAHs (or its natural ligand?), functions as a transcriptional modulator of genes important for fetal oocyte apoptosis to be initiated. In this regard, previous studies of murine fetal ovarian development had established a link between increased Bax expression and oocyte apoptosis (29). The principal conclusion drawn from this correlative set of observations was then supported by findings that gametogenic failure in mutant mice expressing reduced levels of Bcl-xL in the germline could be rescued by simultaneous inactivation of the bax gene (21). However, Bax deficiency by itself does not affect the incidence of fetal ovarian germ cell death (20) and does not rescue fetal oocytes from apoptosis induced by meiotic defects (3).
Given that the evidence supporting a role for Bax in controlling fetal ovarian germ cell fate is apparently paradigm specific, we next explored whether the PAH-activated AHR increases Bax expression in fetal ovarian germ cells as a step toward promoting their demise. Using immunohistochemistry, we detected extremely low levels of Bax protein in e13.5 fetal ovaries before culture or after a 24-h culture with cytokines, consistent with the fact that fetal germ cell apoptosis is absent or very low under both of these conditions (23). However, treatment of fetal ovaries with PAHs caused a marked increase in Bax protein accumulation in many germ cells, a response that was abolished by cotreatment with the AHR antagonist ANF. In light of these data and the finding that Bax was detected in germ cells before evidence of apoptosis, we concluded that an increase in Bax expression driven by the PAH-activated AHR is one possible mechanism responsible for the initiation of fetal oocyte death under these experimental conditions.
Nonetheless, we believed that it was critical to extend these correlative data by establishing whether Bax was functionally needed for fetal ovarian germ cells to die in response to in utero PAH exposure. To accomplish this objective, heterozygous (bax+/-) females were mated with heterozygous males to ensure that direct comparisons could be made between the ovarian responses of wild-type and Bax-deficient female fetuses to PAH exposure in the same intrauterine environment. Furthermore, before undertaking the experiments, extensive preliminary trials were conducted to establish a dose of DMBA that effectively killed developing oocytes without causing fetal death in utero (data not shown). Interestingly, we found that a dose as low as 1 mg/kg given to the mother was sufficient to destroy over three quarters of the oocyte pool available for primordial follicle formation in the developing female fetuses. This unexpected finding may be significant in that the dose of PAH needed to trigger extensive levels of oocyte apoptosis in the fetal ovaries is far less than the amount of PAH required (i.e. 50 mg/kg) to cause comparable levels of oocyte depletion in postnatal ovaries (30). As such, one could envisage that even a brief window of exposure of the fetal ovaries to PAHs, such as that which probably occurs when women smoke while pregnant, would be sufficient to cause irreparable long-term harm to the developing germ line (16).
Whatever the case, the results from this final series of experiments revealed that in utero exposure of wild-type female fetuses to PAHs resulted in a severely compromised endowment of primordial follicles in the ovaries at birth. In contrast, Bax-deficient female fetuses exposed to PAHs in parallel were born with a normal number of primordial follicles in their ovarian reserves, suggesting that the fetal ovarian damage resulting from transplacental exposure to PAHs is completely dependent upon the presence of functional Bax protein. Of additional note, there were no differences observed in the numbers of early growing (primary and small preantral) follicles in ovaries of wild-type and bax mutant neonates exposed to vehicle or PAHs during gestation. These findings indicate that a single injection of PAHs into pregnant female mice shortly after midgestation reduces the numbers of oocytes available in the developing fetal ovaries for primordial follicle formation. However, the rate at which primordial follicles activate growth to the primary stage remains unchanged, at least early in neonatal life, even if the ovaries contain only a fraction of the primordial follicle reserve normally endowed in females at birth.
In summary, these results provide mechanistic insight into the cytotoxic effects of PAHs in fetal ovarian germ cells both in vitro and in vivo. In addition to confirming that PAHs induce apoptosis in developing female germ cells, these data indicate that the bax gene is a likely target for the PAH-activated AHR in fetal oocytes. Importantly, we confirmed the functional requirement for Bax in mediating the apoptotic response of fetal ovarian germ cells to PAHs, thus fully substantiating the positive correlation between increased Bax expression and fetal germ cell death. Unfortunately, with the identity of the natural ligand(s) for the AHR still uncertain, the relevance of these data to further understanding the biological function of the AHR in the developing female germ line remains to be established. Nonetheless, given the complexity of the molecular framework that probably governs prenatal oocyte apoptosis (1, 28), our current efforts are focused on evaluating the possibility that other PCD-related genes are also targets for the PAH-activated AHR in female germ cells.
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Footnotes |
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1 T.M.M., T.M., and Y.M. contributed equally to this study. 
2 Investigator with the Howard Hughes Medical Institute.
3 Investigator with the Steven and Michele Kirsch Foundation.
Abbreviations: AHR, Aromatic hydrocarbon receptor (Ahr, designation of the gene); ANF, -napthoflavone; Atm, ataxia telangiectasia- mutated gene (ATM, designation of the protein); DMBA, 9,10-dimethylbenz[a]anthracene; DMBA-DHD, 9,10-dimethylbenz[a]anthracene-3,4-dihydrodiol; e13.5, embryonic d 13.5; LIF, leukemia inhibitory factor; PAH, polycyclic aromatic hydrocarbon; PCD, programmed cell death; SCF, stem cell factor.
Received September 4, 2001.
Accepted for publication September 28, 2001.
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-napthoflavone. Teratogen Carcinogen Mutagen 5: 463–472
-Naphthoflavone antagonism of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced murine lymphocyte ethoxyresorufin-O-deethylase activity and immunosuppression. Mol Pharmacol 32:169–172[Abstract]
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