Regulation of Aryl Hydrocarbon Receptor Expression in Rat Granulosa Cells1

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most of the toxic and endocrine-disruptive actions of aromatic compounds in the ovary. Paradoxically, this receptor has been shown to play important roles in normal female reproductive function as well. Although knowledge of AHR expression regulation in the ovary is of crucial significance to understand the receptor biology and its function in reproductive physiology, there are only limited data in this area. The purpose of the present study was to establish the possible regulation that AHR might undergo in ovarian cells. Here we show that the hormones FSH and estradiol are able to reduce AHR protein and transcript levels in granulosa cells in a way that parallels the changes observed in ovarian tissue across the rat estrous cycle. These findings suggest that estradiol and FSH would be cycle-associated endogenous modulators of AHR expression. In addition, we show that in granulosa cells the receptor is rapidly downregulated via proteasomal degradation following treatment with AHR ligands. However, prolonged treatment with an agonist caused an increase in Ahr mRNA levels. These actions would constitute a regulatory mechanism that both attenuates AHR signal rapidly and replenishes the cellular receptor pool in the long term. In conclusion, our results indicate that AHR expression is regulated by classical hormones and by its own ligands in granulosa cells.

Attenuation of cell cycle progression by 2,3,7,8-tetrachlorodibenzo-p-dioxin eliciting ovulatory blockade in gonadotropin-primed immature rats

“…The regulation of AhR expression in the ovary by its own ligands is most likely dependent upon the time allowed for ligand treatment, inhibition by the shorter treatment vs. stimulation by the longer treatment. The AhR protein levels in granulosa cells are decreased by exposure to the AhR agonist ß-naphthoflavone for up to 24 h [34]. It is known that AhR agonists induce rapid degradation of the AhR via The present studies support the hypothesis that TCDD attenuates cell cycle progression during the developmental transition from small antral follicles to mature preovulatory follicles, resulting in a reduced number of ovulating oocytes.…”

“…Therefore, it seems likely that TCDD inhibits granulosa cell proliferation of proteasomal activity [35]. However, prolonged treatment of granulosa cells with ß-naphthoflavone increases AhR mRNA levels [34]. Similarly, treatment of rat granulosa cells with TCDD for 48 h increases AhR mRNA levels [18].…”

“…The expression of AhR in the ovary has been reported in different species, including rat where it is localized to oocytes and granulosa cells [33]. FSH and estradiol reduce AhR levels in granulosa cells in a manner paralleling the changes observed in ovarian tissue across the rat estrous cycle, suggesting they act as cycle-associated endogenous modulators of AhR expression [34]. Such a view is supported by the present finding that AhR levels were gradually decreased after 48 h of PMSG treatment.…”

Comparison of Aryl Hydrocarbon Receptor Gene Expression in Laser Dissected Granulosa Cell Layers of Immature Rat Ovaries

“…Rationale for the decrease in the AhR mRNA is not explained from the present study, however, previous in vitro study has been shown that expression of the AhR protein and mRNA in the granulosa cells is decreased under the control of both FSH and estradiol [3]. During the transition from the preantral to the antral stage, the follicles acquire the ability to secrete more estradiol-17 depending on FSH, and we have demonstrated in immature rat ovaries that P450 aromatase mRNA is expressed more in the granulosa cell layers from antral follicles than those from preantral follicles when dissected by LMD [14].…”

“…73(7): 923-926, 2011 Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates toxicity of AhR agonists, such as the polycyclic aromatic hydrocarbons (PAHs) [2,6,12], and is expressed in mammalian ovaries [2]. Treatment with AhR agonists such as 2,3,7,8-tetrachlorodibenzo-pdioxin [16] and 3,3',4,4', [17] increases cytochrome P450 (CYP) 1A1 mRNA, a phase I enzyme, in rat ovaries, indicating that AhR signaling cascades are activated. Ligand-activated AhR regulates the ovarian atresia in primordial and primary follicles via activation of the Bax signaling pathway [9,10], and ovotoxicity induced by PAH is prevented by the concomitant treatment with AhR antagonists, thus indicating that AhR is the key mediator of ovotoxicity [11].…”