The aryl hydrocarbon receptor (AhR) has been extensively characterized as an environmental sensor with major roles in xenobiotic-induced toxicity. Evidence is accumulating that these functions serve as adaptive mechanisms overlapping its physiological roles. We previously described a critical role of constitutive AhR activation for the correct progress of mammalian oocyte maturation but the signaling pathway through which AhR controls maturation remains unclear. The aim of this study was to investigate whether the AhR interacts with the epidermal growth factor receptor (EGFR) and p42/44 extracellular regulated kinases (ERK1/2), both key factors in the signaling network that finely regulates the oocyte maturation. As experimental model we used bovine cumulus-oocyte complexes (COCs) during in vitro maturation (IVM). Blocking ERK1/2 signaling in COCs during IVM with the specific EGFR inhibitor AG1478 or the mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 downregulated the expression of the AhR-target gene Cyp1a1. Inhibition of AhR activity was associated with a reduction in the oocytes' ability to progress in meiosis resumption. In contrast, exposure to the AhR antagonist resveratrol reduced both CYP1A1 expression and the oocytes' maturation competence, without affecting ERK1/2 signaling. These findings strongly indicate the EGFR/ERKs signaling network as an upstream regulator of the AhR activation in COCs, offering a new understanding of the finely tuned physiological mechanism leading to oocyte maturation. This information may provide fresh opportunities for improving oocyte in vitro maturation, and therefore boosting the efficiency of assisted reproduction techniques in mammals.

中文翻译：

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体外成熟过程中牛卵丘-卵母细胞复合物中芳烃受体活性的调节：EGFR 和 EGFR 后 ERK1/2 信号级联的作用

芳烃受体 (AhR) 已被广泛表征为一种环境传感器，在异生物质诱导的毒性中具有重要作用。越来越多的证据表明，这些功能是与其生理作用重叠的适应性机制。我们之前描述了组成型 AhR 激活对于哺乳动物卵母细胞成熟的正确进展的关键作用，但 AhR 控制成熟的信号通路仍不清楚。本研究的目的是调查 AhR 是否与表皮生长因子受体 (EGFR) 和 p42/44 细胞外调节激酶 (ERK1/2) 相互作用，这两个信号网络中的关键因素都可以精细调节卵母细胞成熟。作为实验模型，我们在体外成熟 (IVM) 期间使用牛卵丘-卵母细胞复合物 (COC)。在 IVM 期间用特异性 EGFR 抑制剂 AG1478 或丝裂原活化蛋白激酶 (MEK) 抑制剂 PD98059 阻断 COC 中的 ERK1/2 信号传导可下调 AhR 靶基因 Cyp1a1 的表达。AhR 活性的抑制与卵母细胞在减数分裂恢复中进展的能力降低有关。相比之下，暴露于 AhR 拮抗剂白藜芦醇会降低 CYP1A1 的表达和卵母细胞的成熟能力，而不影响 ERK1/2 信号传导。这些发现有力地表明 EGFR/ERKs 信号网络作为 COCs 中 AhR 激活的上游调节因子，提供了对导致卵母细胞成熟的微调生理机制的新理解。这些信息可能为改善卵母细胞体外成熟提供新的机会，