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首页> 外文期刊>Toxicology and Applied Pharmacology >A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling
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A dioxin-like compound induces hyperplasia and branching morphogenesis in mouse mammary gland, through alterations in TGF-β1 and aryl hydrocarbon receptor signaling

机译：二恶英样化合物在小鼠乳腺中诱导增生和分支形态发生，通过TGF-β1和芳基烃受体信号传导的改变

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Abstract Hexachlorobenzene (HCB) is a widespread environmental pollutant and a dioxin-like compound that binds weakly to the aryl hydrocarbon receptor (AhR). Because AhR and transforming growth factor β1 (TGF-β1) converge to regulate common signaling pathways, alterations in this crosstalk might contribute to developing preneoplastic lesions. The aim of this study was to evaluate HCB action on TGF-β1 and AhR signaling in mouse mammary gland, through AhR+/+ and AhR?/? models. Results showed a differential effect in mouse mammary epithelial cells (NMuMG), depending on the dose: 0.05μM HCB induced cell migration and TGF-β1 signaling, whereas 5μM HCB reduced cell migration, promoted cell cycle arrest and stimulated the dioxin response element (DRE) -dependent pathway. HCB (5μM) enhanced α-smooth muscle actin expression and decreased TGF-β receptor II mRNA levels in immortalized mouse mammary fibroblasts AhR+/+, resembling the phenotype of transformed cells. Accordingly, their conditioned medium was able to enhance NMuMG cell migration. Assays in C57/Bl6 mice showed HCB (3mg/kg body weight) to enhance ductal hyperplasia, cell proliferation, estrogen receptor α nuclear localization, branch density, and the number of terminal end buds in mammary gland from AhR+/+ mice. Primary culture of mammary epithelial cells from AhR+/+ mice showed reduced AhR mRNA levels after HCB exposure (0.05 and 5μM). Interestingly, AhR?/? mice exhibited an increase in ductal hyperplasia and mammary growth in the absence of HCB treatment, thus revealing the importance of AhR in mammary development. Our findings show that environmental HCB concentrations modulate AhR and TGF-β1 signaling, which could contribute to altered mammary branching morphogenesis, likely leading to preneoplastic lesions and retaining terminal end buds. Highlights ? 0.05μM HCB induces migration and TGF-β1 signaling in mammary epithelial cells NMuMG. ? 5μM HCB reduces migration, and promotes cell cycle arrest and AhR nuclear pathway in NMuMG. ? HCB enhances α-SMA and decreases TGF-β receptor II expression in fibroblasts AhR+/+. ? Conditioned medium from fibroblasts AhR+/+ exposed to HCB enhances NMuMG migration. ? HCB increases hyperplasia and branching morphogenesis in AhR+/+ mice mammary gland.
机译：摘要六氯苯（HCB）是一种广泛存在的环境污染物，是一种与芳香烃受体（AhR）结合较弱的二恶英类化合物。由于AhR和转化生长因子β1（TGF-β1）共同调节共同的信号通路，这种串扰的改变可能有助于发展成癌前病变。本研究的目的是通过AhR+/+和AhR？/？模型。结果显示，不同剂量的HCB对小鼠乳腺上皮细胞（NMuMG）有不同的作用：0.05μM HCB诱导细胞迁移和TGF-β1信号传导，而5μM HCB减少细胞迁移，促进细胞周期阻滞，并刺激二恶英反应元件（DRE）依赖途径。在永生化小鼠乳腺成纤维细胞AhR+/+中，HCB（5μM）增强了α-平滑肌肌动蛋白的表达，降低了TGF-β受体II mRNA水平，类似于转化细胞的表型。因此，他们的条件培养基能够增强NMuMG细胞的迁移。对C57/Bl6小鼠的检测显示，HCB（3mg/kg体重）可增强AhR+/+小鼠乳腺导管增生、细胞增殖、雌激素受体α核定位、分支密度和末端芽数。来自AhR+/+小鼠的乳腺上皮细胞的原代培养在HCB暴露（0.05和5μM）后显示AhR mRNA水平降低。有趣的是，AhR？/？在没有HCB治疗的情况下，小鼠表现出导管增生和乳腺生长的增加，从而揭示了AhR在乳腺发育中的重要性。我们的研究结果表明，环境HCB浓度调节AhR和TGF-β1信号，这可能有助于改变乳腺分支的形态发生，可能导致癌前病变和保留末端芽。亮点？0.05μmHCB诱导乳腺上皮细胞迁移和TGF-β1信号传导？在NMuMG中，5μM HCB减少迁移，促进细胞周期阻滞和AhR核途径？HCB增强α-SMA并降低成纤维细胞AhR+/+中TGF-β受体II的表达？来自成纤维细胞的条件培养基AhR+/+暴露于HCB可增强NMuMG迁移？HCB增加AhR+/+小鼠乳腺的增生和分支形态发生。

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