Relevance of Aryl hydrocarbon receptor signalling in the inhibitory effect of environmental pollutant TCDD on promoter-specific aromatase (CYP19A1) expression in granulosa cells

Article

作者: Rani, Payal ; Onteru, Suneel Kumar ; Singh, Dheer ; Sharma, Deeksha

Estrogens are major female reproductive hormones, synthesized in granulosa cells by aromatase (CYP19A1). Aromatase expression is controlled via tissue-specific promoters and dysregulated by endocrine disruptors like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD, a well-known reproductive toxicant, acts through the aryl hydrocarbon receptor (AhR), yet its promoter-specific regulation in buffalo, a key livestock species of major agricultural value, has not been addressed.The effect of TCDD was examined on promoter-specific expression of CYP19A1 and estrogen production in cultured buffalo granulosa cells. Granulosa cells were exposed to TCDD at concentrations of 5, 10, and 15 pg/mL for 6, 12, and 24 h. In parallel, cells were treated with AhR inhibitor CH-223191 alone and in combination. Gene expression analysis showed that TCDD significantly (P < 0.05) decreased CYP19A1 expression at all tested concentrations and time points. Promoter-specific transcript analysis demonstrated that suppression was mediated via downregulation of proximal promoter PII. Chromatin immunoprecipitation followed by qPCR analysis confirmed TCDD downregulated CYP19A1 expression driven by PII. Consistently, estradiol production was significantly reduced in TCDD treated cells as measured by ELISA. TCDD increased the expression of AhR downstream genes, ARNT and CYP1A2. AhR inhibitor treatment alone decreased expression of AhR marker gene (CYP1A1) without affecting CYP19A1. Overall, TCDD disrupts estrogen biosynthesis in buffalo granulosa cells by selectively downregulating proximal promoter-specific (PII)-CYP19A1 expression and estrogen production via AhR signaling. Importantly, these effects were reversed by pharmacological inhibition of AhR, highlighting a mechanistic basis for dioxin-induced toxicity and potential of buffalo granulosa cells as a model for comparative reproductive toxicology.

2025-09-01·BIOCHEMICAL PHARMACOLOGY

Molecular Dissection of the AHR-AREG driven EGFR-ERK1/2-CyclinD1 axis in acquired lenvatinib resistance of Hepatocellular carcinoma

Article

作者: Wang, Ruilin ; An, Lin ; Diao, Jinmei ; Hu, Yuelei ; Sun, Dawei ; Liu, Juan

Lenvatinib serves as a first-line systemic therapy for advanced hepatocellular carcinoma (HCC), yet the development of resistance poses a major clinical challenge. The purpose of this study is to investigate the mechanisms underlying lenvatinib resistance in HCC and identify potential interventions. We established lenvatinib-resistant HuH7 and Hep3B cell lines and conducted in vitro, bioinformatics, and biochemical assays to explore and validate the mechanisms underlying acquired resistance to lenvatinib in HCC. Additionally, cellular xenograft models of lenvatinib-resistant HCC were utilized to assess tumor responses to a novel drug treatment regimen. Our findings revealed a shift from suppression to activation in the expression of p-ERK1/2 and Cyclin D1 in HCC cells as they transitioned from sensitivity to resistance to lenvatinib. Furthermore, we demonstrated that targeting ERK1/2 with ravoxertinib (an ERK1/2 inhibitor) could significantly enhance the sensitivity of resistant HCC cells to lenvatinib therapy. Through transcriptome data analysis and experimental validation, we identified amphiregulin (AREG), induced autocrinely by lenvatinib, as a critical mediator that activates the EGFR-ERK1/2 signaling pathway, leading to increased Cyclin D1 expression in HCC cells. Mechanistically, lenvatinib promotes aryl hydrocarbon receptor (AHR) nuclear translocation, directly activating AREG transcription. Using in vivo models, we further confirmed that inhibiting ERK1/2 with ravoxertinib or AHR with CH-223191 (an AHR inhibitor) could overcome lenvatinib resistance in HCC. Overall, lenvatinib-induced AHR activation promotes AREG expression, which subsequently facilitates the acquisition of drug resistance in HCC via the EGFR-ERK1/2-CyclinD1 signaling axis. Targeting ERK1/2 and AHR effectively improved the response to lenvatinib treatment in resistant HCC.

2025-07-01·TOXICOLOGY LETTERS

Enhancement of cigarette smoke extract-induced goblet cell metaplasia and hyperplasia exerted through IL-13 receptor α1 expression

Article

作者: Ishimori, Kanae ; Matsumoto, Risa ; Mori, Akina ; Ito, Shigeaki ; Ichikawa, Sakuya

Chronic airway inflammation, such as that occurring in chronic obstructive pulmonary disease, induces goblet cell metaplasia and hyperplasia (GCMH) and leads to hyperproduction of mucus and thickening of airway walls, restricting airflow. Cigarette smoke causes chronic inflammation and GCMH in the airways through a complex mechanism involving various factors, including immune cells. Previous studies reported direct effects of cigarette smoke on epithelial cells. Replicating the physiological condition of immune cells, we assessed the interaction between cigarette smoke extract (CSE) and interleukin (IL)-13, a GCMH inducer, on air-liquid interface-cultured normal human bronchial epithelial cells (NHBEs) from a single non-smoking subject. While single exposure to IL-13 or CSE induced mucus production, as previously reported, co-exposure to IL-13 and CSE synergistically enhanced this effect. We also investigated IL-13 receptor expression, which revealed that CSE exposure significantly induced the expression of the functional IL-13 receptor subunit, IL-13Rα1. To analyze the signaling pathway involved, we exposed NHBE cultures to benzo(a)pyrene, an aryl hydrocarbon receptor (AhR) ligand and constituent of CSE, which increased IL-13Rα1 expression in a concentration-dependent manner. Furthermore, treatment with the AhR inhibitor resveratrol erased the effects of CSE on mucus production and IL-13Rα1 expression. Here, we present a novel pathway to GCMH by which cigarette smoke induces IL-13Rα1 expression through AhR stimulation, making epithelial cells sensitive to IL-13. This discovery not only contributes to our understanding of chronic airway inflammation, but also supports the use of in vitro models to reproduce chronic inflammation without co-culture of epithelial cells and immune cells.

100 项与 AhR Inhibitor(Bukwang) 相关的药物交易

登录后查看更多信息