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首页> 外文期刊>Archives of Toxicology >Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis
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Novel insight in estrogen homeostasis and bioactivity in the ACI rat model of estrogen-induced mammary gland carcinogenesis

机译：雌激素态腺癌ACI大鼠雌激素模型中雌激素宿舍和生物活性的新颖洞察力

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Despite being widely used to investigate 17 beta-estradiol (E2)-induced mammary gland (MG) carcinogenesis and prevention thereof, estrogen homeostasis and its significance in the female August Copenhagen Irish (ACI) rat model is unknown. Thus, levels of 12 estrogens including metabolites and conjugates were determined mass spectrometrically in 38 plasmas and 52 tissues exhibiting phenotypes ranging from normal to palpable tumor derived from a representative ACI study using two different diets. In tissues, 40 transcripts encoding proteins involved in estrogen (biotrans)formation, ESR1-mediated signaling, proliferation and oxidative stress were analyzed (TaqMan PCR). Influence of histo(patho)logic phenotypes and diet on estrogen and transcript levels was analyzed by 2-way ANOVA and explanatory variables influencing levels and bioactivity of estrogens in tissues were identified by multiple linear regression models. Estrogen profiles in tissue and plasma and the influence of Hsd17b1 levels on intra-tissue levels of E2 and E1 conclusively indicated intra-mammary formation of E2 in ACI tumors by HSD17B1-mediated conversion of E1. Proliferation in ACI tumors was influenced by Egfr, Igf1r, Hgf and Met levels. 2-MeO-E1, the only oxidative estrogen metabolite detected above 28-42 fmol/g, was predominately observed in hyperplastic tissues and intra-tissue conversion of E1 seemed to contribute to its levels. The association of the occurrence of 2-MeO-E1 with higher levels of oxidative stress observed in hyperplastic and tumor tissues remained equivocal. Thus, the present study provides mechanistic explanation for previous and future results observed in the ACI model.
机译：尽管被广泛用于探测17β-雌二醇（E2）诱导的乳腺发生和预防，但雌激素稳态及其在癌症癌症的雌激素的重要性（ACI）大鼠模型是未知的。因此，在38个血浆和52个组织中，测定包含代谢物和缀合物的12种雌激素和缀合物的雌激素，表现出从正常到源自代表性的ACI研究的表型，其表型测定使用两种不同的饮食。在组织中，分析了在雌激素（Biotrans）形成，ESR1介导的信号，增殖和氧化应激中的40种编码蛋白质的转录物（Taqman PCR）。通过多元线性回归模型通过双向Anova分析Histo（patho）逻辑表型和饮食对雌激素和转录水平的影响，并通过多元线性回归模型鉴定组织中雌激素的影响水平和雌激素的生物活性。组织和血浆中的雌激素曲线以及HSD17b1水平对组织内部和e1内部组织水平的影响得出了通过HSD17b1介导的E1介导的γ2在ACI肿瘤中形成乳腺癌内形成。 ACI肿瘤的增殖受EGFR，IGF1R，HGF和达到的水平影响。 2-MeO-E1，唯一在28-42mmol / g以上检测到的氧化雌激素代谢物，在增生组织中主要观察到E1的组织内转化似乎有助于其水平。在增生和肿瘤组织中观察到具有更高水平的氧化应激的2 MeO-E1的发生仍然是难以置信的。因此，本研究为在ACI模型中观察到的前一个和未来结果提供机械解释。

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