The aryl hydrocarbon receptor (AHR) is a nuclear transcription factor widely expressed in various organisms. Since its discovery in the 1970s, it has received significant attention for its important role in multiple physiological functions (Rothhammer and Quintana, 2019). Recent studies have revealed that AHR's roles in physiological and pathological processes extend far beyond initial hypotheses, encompassing many biological processes such as immune regulation (Gutiérrez-Vázquez and Quintana, 2018), tumorigenesis (Huang et al., 2023), and reproduction (Shi et al., 2021). Furthermore, the complex interplay between AHR and steroid hormone receptors—specifically its interaction with estrogen receptors unveil a critical regulatory network for endocrine signaling (Beischlag and Perdew, 2005). AHR has also been shown to interfere with the homeostasis of the hypothalamic-pituitary-gonadal (HPG) axis. Activation of AHR after exposure to environmental pollutants can disrupt the secretion patterns of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby affecting the HPG axis (Pocar et al., 2005).

In reproduction, systemic AHR knockout models exhibit sex-specific phenotypes. In males, slight delay in the development of the anterior lateral and dorsal lateral prostate were observed in mice lacking AHR (Lin et al., 2001). In females, AHR also has a significant impact on reproduction (Hernández-Ochoa et al., 2009). The ovaries from AHR-deficient mice exhibited reduced numbers of antral follicles, smaller follicular diameters, and slower growth rate (Barnett et al., 2007; Benedict et al., 2000). AHR deletion also altered the mRNA or protein levels of estrogen receptors, leading to reduced follicular responsiveness to E2 (Benedict et al., 2003). However, the excessive activation of AHR, such as exposure to pollutants with AHR agonistic activity, has been shown to impair reproduction in both males and females. For instance, the AHR agonist diuron and its metabolites exhibit reproductive toxicity in medaka by disrupting the HPG axis (Zhou et al., 2022). Long-term exposure to AHR agonist neburon induced reproductive toxicity through upregulating the apoptosis and oxidative stress in male zebrafish (Zhang et al., 2024). Additionally, the activation of AHR might be linked to the onset of polycystic ovary syndrome or premature ovarian failure in females (Gregoraszczuk and Ptak, 2013). The previous studies using systemic knockout models failed to fully elucidate the distinct physiological roles of AHR in different germ cells and conditional knockout (cKO) models can directly clarify AHR's role in these different cells.

The ovary mainly contains oocytes, granulosa cells (GCs) and theca cells (Gong et al., 2022). Oocytes are responsible for generating fertilizable gametes. They develop from primordial follicles undergoing complex processes of division and maturation to ultimately become a fertilizable gamete (Jiang et al., 2023; MacLennan et al., 2015). The GCs are crucial for female ovarian reserve, as these cells provide metabolic and hormonal support for developing oocytes (Huang et al., 2022). The activation or suppression of AHR affects oocyte development, particularly in follicle formation and maturation (Barreiro et al., 2011).

In this study, in order to investigate the role of AHR role in oocytes, we constructed oocyte-specific AHR cKO mice. It was found that AHR knockout in oocytes disrupted the mRNA level of key growth factors (Gdf9 and Bmp15), triggered GCs apoptosis and subsequently affected follicular development. Furthermore, this disruption led to altered serum hormone levels and estrous cycle in mice. These findings provided valuable insights into the mechanisms regulating fertility and ovarian function, and offered potential treatment strategy for reproductive diseases.