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Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction

Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Grosse Steinstrasse 52, D-06097, Halle (Saale), Germany and ¹ Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg (MB) R3E0W3 Canada

Correspondence should be addressed to P Pocar; Email: paola.pocar{at}medizin.uni-halle.de

	Abstract

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
The dioxin/aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor responsive to both natural and man-made environmental compounds. AhR and its nuclear partner ARNT are expressed in the female reproductive tract in a variety of species and several indications suggest that the AhR might play a pivotal role in the physiology of reproduction. Furthermore, it appears to be the mediator of most, if not all, the adverse effects on reproduction of a group of highly potent environmental pollutants collectively called aryl hydrocarbons (AHs), including the highly toxic compound 2,3,7,8-tetrachlor-odibenzo-p-dioxin (TCDD). Although a large body of recent literature has implicated AhR in multiple signal transduction pathways, the mechanisms of action resulting in a wide spectrum of effects on female reproduction are largely unknown. Here we summarize the major types of molecular cross-talks that have been identified for the AhR and linked cell signaling pathways and that are relevant for the understanding of the role of this transcription factor in female reproduction.

	Introduction

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
The aryl hydrocarbon receptor (AhR) is a member of the basic helix–loop–helix (bHLH)-Per-ARNT-Sim (PAS) family of transcriptional regulators that control a variety of developmental and physiological events, including neurogenesis, tracheal and salivary duct formation, toxin metabolism, circadian rhythms, response to hypoxia, and hormone receptor function. The unique feature of all bHLH-PAS proteins is the PAS domain, named after the first three proteins identified with this motif, the Drosophila Per, human ARNT and Drosophila Sim (Nambu et al. 1991). The PAS domain consists of 260–310 amino acids (Crews et al. 1988) and incorporates two well-conserved hydrophobic repeats, termed PAS-A and PAS-B, separated by a poorly conserved spacer. Overall, the PAS domain is not well conserved and, given its size and diversity in sequence, can mediate a number of diverse biochemical functions. Facilitating partner selection during formation of bHLH-PAS heterodimers (Huang et al. 1993), binding small molecules (Dolwick et al. 1993), and conferring target gene specificity of bHLH-PAS heterodimers are important functions of PAS-domains (Zelzer et al. 1997).

The AhR and its nuclear partner ARNT are two founding members of the bHLH-PAS family and their dimerization to form an active transcription factor complex has become a paradigm in studying mechanisms of bHLH-PAS protein function. Unliganded AhR is located in the cytoplasm associated with heat shock protein 90 (hsp90) (Denis et al. 1988, Perdew 1988) and a 38 kDa, immunophilin-related protein (XAP2) (Carver & Bradfield 1997, Ma & Whitlock 1997, Meyer et al. 1998). Ligand binding to the AhR is presumed to produce conformational changes in the AhR protein which result in the exposure of an AhR nuclear localization signal and the translocation of the whole complex into the nucleus (Pollenz et al. 1994). Within the nucleus, the AhR–ligand complex dissociates from associated proteins and dimerizes with ARNT (Reyes et al. 1992), to reconstitute an active transcription factor which binds defined DNA sequences with high affinity. Binding of the ligand-activated AhR–ARNT transcriptionally active complex to its specific DNA recognition site, the xenobiotic-responsive element (XRE), within the promoter region of AhR-regulated genes results in their increased transcription (Denison et al. 1988). Much of our understanding of AhR function derives from analyses of the mechanisms by which its prototypical ligand 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) induces the transcription of CYP1A1. This gene encodes the microsomal enzyme cytochrome P4501A1 which oxygenates various xenobiotics as part of their stepwise detoxification (Conney 1982). Although the transcriptional activation of P450 family members by AhR ligands is well known, additional routes of AhR-mediated actions have been proposed. For instance, TCDD causes a rise in Ca²⁺uptake within 5 min in Hepa-1 cells which can not be explained on the basis of transcriptional changes (Puga et al. 1992). Furthermore, Enan and Matsumura (1995) demonstrated that TCDD induces changes in protein phosphorylation through the activation of protein tyrosine kinases within 10 min. This rapid effect is AhR dependent and occurs under cell-free conditions in the absence of a nucleus. On the basis of these observations a TCDD-induced protein phosphorylation pathway may be considered as a separate route of AhR signaling from the well-established nuclear translocation-dependent pathway. A scheme of the two different signaling pathways of the AhR upon ligand binding is shown in Fig. 1.

View larger version (28K): [in this window] [in a new window]   Figure 1 Binding of the ligand to the AhR results in the release of associated proteins and translocation to the nucleus followed by dimerization with ARNT. The AhR–ARNT complex binds the XRE promoting target gene transcription. Ligands can also exert their effects in the cytoplasm through AhR-associated protein kinases to alter the function of a variety of proteins through a cascade of protein phosphorylation.

View larger version (22K): [in this window] [in a new window]   Figure 2 Molecular structure of some AhR ligands.

This review summarizes AhR-mediated cellular responses in the female reproductive tract, particularly focusing on the molecular cross-talk identified between AhR and other cell signaling pathways.

	AhR cross-talk with steroid hormone receptors

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
Most AhR/steroid receptor interactions have been studied in human breast cancer and endometrial carcinoma cell lines. The liganded AhR targets specific genomic core inhibitory dioxin/xenobiotic responsive elements (iDRE/iXRE). Functional iXREs are present within the promoter regions of the estrogen-inducible pS2, cathepsin D and c-fos genes (Safe et al. 2000). In HEC-1A human endometrial carcinoma cells, AhR–ARNT complexes competitively inhibit the binding of ER-alpha to imperfect Estrogen response element (ERE) sites adjacent to or overlapping with XRE sites (Klinge et al. 1999). TCDD-activated AhR inhibits estradiol (E2)-induced cathepsin D expression in MCF-7 breast cancer adenocarcinoma cells by binding to an iXRE within the promoter of the cathepsin D gene, thus preventing the formation of a transcriptionally active ER-SP1 complex (Duan et al. 1999, Wang et al. 2001). A similar AhR-mediated inhibitory AhR/ER cross-talk was demonstrated for the c-fos protooncogene promoter in MCF-7 (Safe et al. 2000). Liganded AhR–ARNT and ligand-activated ER-alpha do not directly interact but both ligand-activated transcription factor complexes can physically interact with and compete for SP1 protein (Kobayashi et al. 1996, Wang et al. 1998a). The liganded AhR was also shown to inhibit binding of ER-alpha to an ERE in the pS2 promoter by interaction with Activator protein-1 (AP-1) proteins (Gillesby et al. 1997). AP-1 consists of a heterodimer of c-jun and c-fos and promotes the binding of liganded ER-alpha to AP-1 DNA binding sites. Interaction of liganded AhR with AP-1 proteins promotes binding to a XRE/AP-1-like motif and, at the same time, prevents binding of ER-alpha to a neighboring ERE. Thus, AhR can function as a ligand-activated transcriptional repressor by binding to iXRE overlapping or neighboring ERE/AP-1 sites or ERE/SP1 sites respectively, quenching transcriptionally active ER/SP1 or ER/AP-1 complexes (Fig. 3A).

View larger version (28K): [in this window] [in a new window]   Figure 3 (A) Mechanisms of genomic inhibition of steroid-mediated transcription by ligand-activated AhR. Transcriptional inhibition depends on iXREs within promoter regions of estrogen-regulated genes which prevent ER transcriptional activity by: (a) being located close by to neighboring EREs; (b) disrupting the formation of ER–SP-1 or ER–AP-1 DNA complexes; and (c) competing for limited cofactors (e.g. NF-1). These mechanisms apply to interactions of the AhR with all sex steroid hormone receptors interactions and are shown here for the estrogen receptor (ER). (B) Activation of AhR by exogenous ligands can rapidly reduce the levels of ER protein by proteasomal degradation. The exact mechanism by which liganded AhR initiates that degradation is presently unknown. (C) AhR-mediated mechanisms leading to the activation of sex steroid hormone signaling in the absence of estrogen. (a) Upon binding of the ligand, a conformational change causes the release of active c-Src from the cytoplasmic AhR–protein complex. c-Src activates several protein kinases leading to phosphorylation and activation of ER. (b) A direct association of AhR–ARNT complexes with nuclear ER and the cofactor p300/CBP in the absence of E2. (c) Activation of steroid hormone receptor by direct protein interaction with the AhR–ARNT complex in the absence of hormone has so far only been observed for the ER.

In human MCF-7 breast cancer cells, agonist-activated AhR–ARNT complexes have been shown to associate directly with ER-alpha and ER-beta in the absence of estrogen resulting in transcriptional activation of ERE-dependent genes (Ohtake et al. 2003). This ERE-dependent estrogenic effect of liganded AhR requires direct interaction of the nuclear AhR–ARNT complex with unliganded ER and the cofactor p300/CBP (Fig. 3C). By contrast, in the presence of estrogen, liganded AhR exhibits anti-estrogenic effects by suppressing estrogen-bound ER-mediated DNA binding. These results strongly indicate that the AhR-mediated regulation of estrogenic effects depends on the concentration of estrogens. This may partially explain the weak estrogenic effects of PCB 126 in the uterus of ovariectomized, as opposed to normal, rats (Lind et al. 1999).

Apart from its transcriptional activity and independent of its nuclear localization, ligand-bound AhR appears to act via a second pathway which is located in the cytoplasm. Unliganded AhR in the cytoplasm is associated with HSP90, XAP2, p23 and the tyrosine kinase c-Src (pp60^src). Upon ligand binding, active c-Src appears to be released from this aggregate resulting in the stimulation of other protein kinases (Perdew 1988, Hutchison et al. 1992, Matsumura 1994, Vogel & Matsumura 2003). Active c-Src may phosphorylate and activate steroid receptors such as ER resulting in estrogenic effects in the absence of estrogens. Thus, by triggering protein kinases ligand-activated AhR may elicit multiple and unpredicted cellular responses (see reviews of Matsumura 1994, and Carlson and Perdew 2002).

Apart from the studies mentioned above, to date there have been only a few reports on the cross-talk between AhR and ER in reproductive-related cells. In porcine follicular cells, recent studies indicate a TCDD-induced decrease in estrogen synthesis and that the exposure to the action of AhR or ER blockers (alpha naphthoflavone and 4-OH-tamoxifen respectively) is able to completely reverse the inhibitory effect (Gregoraszczuk 2002). A further report indicates a potentiation of TCDD activity through contemporary exposure to estradiol in mouse ovarian cells, and that this effect can be reversed through exposure to specific ER blockers (Son et al. 2002). Despite the fact that the precise molecular mechanisms involved in these phenomena have not been yet further investigated, these studies strongly suggest that a positive cross-talk between the two signaling pathways exists in ovarian cells.

Investigations on the interaction of AhR with other steroid hormone receptors have revealed a bi-directional cross-talk. Recently, an anti-androgenic effect of ligand-activated AhR was described in LNCaP prostate cancer cells. Interaction of the AhR ligand complex with AP-1 proteins resulted in diminished induction of prostate-specific-antigen (PSA) by testosterone. However, this was not caused by a decrease in intracellular levels of the androgen receptor (AR) or concentrations of intracellular dihydrotestosterone (DHT) (Kizu et al. 2003). Although this interaction was shown in LNCaP human prostate cancer cells, the presence of AR within the ovary (Pelletier et al. 2000) and endometrium (Slayden et al. 2001, Apparao et al. 2002, Brenner et al. 2002) would suggest the presence of a potential AhR/AR cross-talk to also be effective within female reproductive organs.

On the other hand, steroid hormone receptors can also inhibit AhR signal transduction and this inhibitory nuclear receptor cross-talk is caused by competition of AhR and ER for the rate-limiting co-regulators ERAP140 and SMRT (Nguyen et al. 1999). In the human endometrial carcinoma cell line ECC-1, competition was described for nuclear factor-1 (NF-1), a transcription factor capable of binding both ER-alpha and AhR. Competitive binding of NF-1 by estrogen-activated ER resulted in diminished TCDD-mediated CYP1A1 transcriptional activation (Ricci et al. 1999). A unidirectional inhibitory progesterone receptor (PR)/AhR cross-talk involves both PR isoforms, PR-A and PR-B, and repression of AhR–ARNT transcriptional activity requires the active progesterone responsive element (PRE)-binding form of PR-B, but not PR-A (Kuil et al. 1998).

In conclusion, AhR activation can result in the inhibition or promotion of steroid hormone signaling in reproductive tissues and this may, in part, explain the contradictory results of estrogenic or anti-estrogenic effects mediated by AhR ligands. Environmental AhR ligands have been implicated in promoting endometriosis and endometrial cancer in various species (Cummings et al. 1996, Johnson et al. 1997, Mann 1997, Mayani et al. 1997, Rier 2002). Yet, epidemiological data from the accidental exposure to TCDD in Seveso, Italy (1976), have revealed a decrease in the incidence of endometrial carcinoma in TCDD-exposed women (Bertazzi et al. 1997). Similarly, TCDD appears to have a breast cancer protective function (Greenlee et al. 2001). The molecular mechanisms by which TCDD exerts these anti-tumorigenic effects are unknown.

	Cell cycle and apoptosis

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
It is now clear that the AhR plays a pivotal role in cell cycle regulation (Ma & Whitlock 1996, Vaziri & Faller 1997, Puga et al. 2002) and apoptosis (Zaher et al. 1998, Reiners & Clift 1999). The inhibition of estrogen-mediated induction of cell cycle activators such as cyclin D1 and the activation by liganded AhR of CDK2, CDK4 and CDK7 (Wang et al. 1998b) suggest a supportive role for AhR in E2-dependent tumor growth in the female reproductive tract (Bertazzi et al. 1997). However, the AhR also has a direct influence on the cell cycle by induction of the cyclin/cdk inhibitor p27 (Kip1) as demonstrated in rat 5L hepatoma cells (Ge & Elferink 1998). Upon nuclear translocation, liganded AhR engages in a protein–protein interaction with retinoblastoma protein (pRb) via two binding motifs: a high-affinity LXCXE motif located within the N-terminal 364 amino acids and a low-affinity binding site located within the glutamine-rich transactivation domain of the AhR. Ligand-activated AhR binds preferentially to hypophosphorylated Rb (pRb) which represents the active form of Rb leading to G1 arrest in rat L5 hepatoma cells (Ge & Elferink 1998). AhR synergizes with pRb in potentiating the repression of E2F-dependent transcription inducing cell cycle arrest (Puga et al. 2000). As hypophosphorylated Rb is limited to G0 and G1 phases of the cell cycle, so is pRb-dependent AhR action (Elferink et al. 2001). In MCF-7 cells, the direct interaction of liganded AhR with hypophosphorylated Rb was shown to be independent of ARNT and therefore does not require XRE-mediated transcriptional activity. This non-genomic function of AhR deserves further investigation, since alterations in cell cycle progression in exposed tissues by potential endogenous (Carlson & Perdew 2002) and environmental AhR ligands may contribute significantly to the physiological roles of this bHLH transcription factor.

At or near the G₁/S boundary lays the point of divergence between continuation of the cell cycle and apoptosis. Apoptosis plays a critical role in reproduction, during development and in the maintenance of tissue and organ homeostasis (Scott et al. 1996, Jacobson et al. 1997) and many toxicants exert their cytotoxic effects by virtue of apoptosis. Several studies implicate the fine-tuned balance between the levels of AhR battery enzymes and the AhR as an important factor in aiding the cell to choose between apoptosis and continued cell proliferation. Immunohistochemical analysis of embryonic tissues showed that AhR expression is developmentally regulated and occurs in regions undergoing tissue remodeling processes (Abbott et al. 1995). Up-regulation of AhR and ARNT expression was observed during early outgrowth and elevation of palatal shelves. In addition, altered relative expression of these two bHLH transcription factor genes was observed after exposure to TCDD and this correlated with a higher incidence of cleft palate in developing mice (Abbott et al. 1999). Furthermore, stimulation of resting T cells with mitogens resulted in a marked increase of AhR expression paralleled by an increase in apoptosis (Crawford et al. 1997). Comparisons of the sensitivities of AhR +/+ and AhR –/– mice to the exposure of TCDD revealed thymic atrophy as a result of T-cell apoptosis in wild-type mice, but not in TCDD-resistant AhR –/– mice (Fernandez-Salguero et al. 1996, Kamath et al. 1997). Also, reduced liver size in AhR null mice was associated with incidence of apoptosis (Zaher et al. 1998). Several other studies have demonstrated the ability of a variety of AhR ligands – such as DMBA, BaP and TCDD – to induce apoptosis in various cell types of non-reproductive tissues, including pre-B cells (Jyonouchi et al. 1999), Hepa1c1c7 murine hepatoma cells (Lei et al. 1998) and mouse epidermis (Miller et al. 1996). However, the molecular mechanisms by which these chemical compounds induce programmed cell death remain unclear.

In the ovary, apoptosis is the principal mechanism by which oocyte depletion is mediated under both normal and pathologic conditions (Perez & Tilly 1997, Morita & Tilly 1999, Pru & Tilly 2001). It has been known for over two decades now that exposure of female mice to AhR ligands causes a rapid depletion of primordial and primary oocytes (Mattison et al. 1989) and these ovotoxic effects can be prevented by selective AhR antagonists (Shiromizu & Mattison 1985). Thus, it is tempting to suggest that in the ovary genes involved in the regulation of cell death are prime targets for the transcriptional regulation by the activated AhR. This hypothesis is supported by Heimler et al. 1998 who demonstrated that TCDD not only disrupts ovarian steroid production but, at the same time, is able to induce apoptosis in human follicular granulosa cells. Moreover, Matikainen and co-workers (2001) have recently reported two XRE binding sites for the AhR–ARNT complex in the promoter of the pro-apoptotic gene, Bax. Production of Bax protein and subsequent Bax-dependent increase in apoptosis are increased in murine oocytes upon exposure to the AhR ligand DMBA, but not with TCDD (Matikainen et al. 2001). Further analyses have shown that substitution of the existing guanine or cytosine to an adenine three bases downstream of the core XRE sequence renders the Bax promoter inducible by TCDD. These data elegantly demonstrate the ligand-dependent discrimination of DNA response elements (Matikainen et al. 2001).

There are only a few studies investigating the impact of AhR-mediated apoptosis in female reproductive tissues other than the ovary. Flaws et al.(1997) demonstrated that in utero exposure to TCDD induces cleft clitoris and vaginal threads of mesenchymal tissue in female rat offspring, indicating a disturbed balance between proliferation and apoptosis during the development of female genitalia.

	AhR and the regulation of the hypothalamopituitary–gonadal (HPG) axis

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
AhR-mediated actions can affect the regulation of the HPG axis by altering the secretion pattern of preovulatory follicle-stimulating hormone (FSH) and luteinizing hormone (LH) secretion in primed female rats exposed to TCDD or related AhR ligands (Li et al. 1995, Gao et al. 1999). Exposure to environmentally relevant concentrations of TCDD induces a significant reduction of FSH and LH during the preovulatory period in rats (Gao et al. 1999), strongly suggesting that the reproductive toxicity of TCDD can in part be related to a dysregulation of the hypothalamo-hypophyseal axis by mechanism(s) not yet completely understood. The observation that treatment with exogenous gonadotropin-releasing hormone (GnRH) partially overcomes the blockage of preovulatory surges of LH and FSH after TCDD exposure (Gao et al. 2000) may indicate insufficient production in and/or release of GnRH from the hypothalamus as a result of TCDD action to the central nervous system (CNS). This TCDD-induced inhibition of gonadotropin surges has been explained by a decreased responsiveness of the hypothalamus to the positive feedback of estrogens, without affecting preovulatory serum estrogen levels (Gao et al. 2001). This hypothesis is confirmed by the observation that tenfold higher than physiological serum concentrations of estrogens completely reverse the TCDD effects on gonadotropin secretion (Gao et al. 2001). This latter effect can be blocked by the partial estrogen antagonist tamoxifen providing further evidence for a functional relationship between both the aryl hydrocarbon- and estrogen-mediated signaling pathways.

Members of the AhR signaling pathway are expressed in the preoptic area of the brain (POA), a region known to control reproductive functions (Petersen et al. 2000). The distribution pattern of AhR gene expression closely overlaps with that of glutamic acid decarboxylase (GAD) 67, the enzyme necessary for gamma-aminobutyric acid (GABA) synthesis. Interestingly, the GAD 67 gene contains multiple canonical XRE sequences (Erlander et al. 1991, Pinal et al. 1997). GAD 67 mRNA levels in the rostral POA/anteroventral periventricular nucleus (rPOA/AVPV) and in the rostral portion of the medial preoptic nucleus (MPN) are higher in females than in males (Hays et al. 2002). GABAergic neurons in the AVPV play a role in onset of puberty, the E2-dependent gonadotropin surge and in ovulation. Developmental exposure to TCDD can specifically down-regulate GAD 67 expression in the rPOA/AVPV in female rats resulting in abolished sexual differentiation of this area. In utero exposure of female rats to TCDD induces delayed onset of puberty and increases the time required to achieve pregnancy in a continuous mating situation (Gray & Ostby 1995, Gray et al. 1997). Thus, sex- and region-specific suppression of GABA synthesis in the CNS adds to the multiple cellular actions by which TCDD can disrupt female reproductive functions.

	Evidence for a physiological role of AhR in reproduction

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
Many attempts have been made to identify endogenous ligands that could trigger AhR-dependent signaling under physiological conditions. However, with the exception of the tryptophane analogs indirubin and indigo, which have been recently identified in human urine (Adachi et al. 2001), and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester in the porcine lung (Song et al. 2002), the nature of endogenous AhR ligands remains elusive. The attempt to assess the role of the AhR in the absence of activation by xenobiotic compounds led to the production of AhR-deficient mice from three independent research groups (Fernandez-Salguero et al. 1995, Schmidt et al. 1996, Mimura et al. 1997). Those AhR-knockout animal models demonstrated a range of complex reproductive deficiencies in female mice in the absence of AhR gene expression. These adverse reproductive parameters included deaths of the –/– females during pregnancy and lactation, small litter size at birth, poor survival of pups during the first 2 weeks after birth, and death of –/– pups after weaning. The poor reproductive success in these AhR-null animals possibly reflects the disruption of multiple biological processes. A more extensive analysis of older AhR –/– animals showed hypertrophic uteri displaying thrombosis and mineralization of the serosal vessels coinciding with a reduction of the litter size (Fernandez-Salguero et al. 1997). In addition, increased numbers of primordial follicles were detected in 2- to 3- or 4-day-old AhR –/– females (Benedict et al. 2000, Robles et al. 2000). Female AhR-null mice at 53 days of age displayed a decreased number of antral follicles (Benedict et al. 2000) and a resistance of germ cells to undergo apoptosis (Robles et al. 2000). These results indicate that the decreased number of antral follicles observed in the AhR –/– mice may be insufficient to support the hormone synthesis needed during pregnancy and lactation. Furthermore, a recent study by Benedict et al.(2003) suggested that AhR deletion impairs follicular growth and, concomitantly, reduces the number of follicles that ovulate and become corpora lutea. This would implicate AhR as a novel regulator of ovulation. In agreement with this hypothesis, the ovulatory gonadotropin surge has been shown to induce the expression of AhR gene activity in the macaque ovary (Chaffin et al. 1999) and we have recently demonstrated the AhR-mediated induction of CYP1A1 in the absence of exogenous ligands in in-vitro matured bovine oocytes, suggesting a direct role of the AhR signaling pathway in the resumption of meiosis in mammalian oocytes (Pocar et al. 2004).

Thus, the bHLH transcription factor AhR appears to have a prominent functional role in female reproduction that deserves further attention.

	Conclusions

Top Abstract Introduction AhR cross-talk with steroid... Cell cycle and apoptosis AhR and the regulation... Evidence for a physiological... Conclusions References

 
It is clear now that the many complex reproductive effects of dioxins and related compounds observed in mammals reflect four important findings:

1. Although the biological effects of dioxin-like compounds require the AhR, the role of this bHLH transcription factor extends beyond the activation of the AhR gene battery and includes also non-genomic pathways.
   
2. There exists an intricate network of interactions, direct and indirect, between sex steroid receptors and the AhR–ARNT system which can modify reproductive processes.
   
3. AhR-mediated actions affect all levels of a reproductive system, from the HPG axis to the reproductive organs themselves, causing adaptive short-term and irreversible long-term effects on the reproductive system.
   
4. Developmental and transgenic mouse studies have clearly demonstrated that the AhR transcription factor is more than just a xenobiotic sensor but potentially an integral key component of normal reproductive physiology.
   

The complex role of the AhR in female reproduction is still largely elusive. A multidisciplinary approach with areas of expertise in toxicology, pathology, endocrinology and molecular/developmental biology will be required to further unveil the secrets of the role of AhR in reproduction of the female.

	Footnotes

 
Received 28 April 2004
First decision 22 July 2004
Revised manuscript received 7 December 2004
Accepted 7 December 2004

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