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【6h】Evaluation of the mode of action and human relevance of peroxisome proliferator activated receptor gamma agonist-induced hemangiosarcomas in mice.

机译评价过氧化物酶体增殖物激活受体γ激动剂诱导的小鼠血管肉瘤的作用方式和人类相关性。

【摘要】Chemical-induced hemangiosarcomas (HS), malignant tumors of endothelial cells (ECs), have become important in evaluating the potential human risk of several agents. Spontaneous HS frequently occur in mice, less in rats, and are rare in humans. Peroxisome proliferator activated receptor gamma (PPARgamma) agonists are non-genotoxic pharmaceuticals for the treatment of type II diabetes mellitus. Many produced HS in multiple tissues in mice, including liver and adipose tissue, but not rats in 2-year bioassays. Our research objective was to understand how PPARgamma agonists induce HS in mice, using the prototypical sarcomagenic troglitazone (TG) and non-sarcomagenic pioglitazone (P1O). Understanding the mechanism of PPARgamma agonist-induced tumorigenesis is critical to evaluate human risk. Since TG does not react with DNA, we hypothesized that increased EC proliferation was involved in TG-induced hemangiosarcomagenesis in mice. Increased EC proliferation can lead to increased DNA replications due to the increased cell number, resulting in the increased possibility of genetic errors. We showed that TG increased EC proliferation in liver and brown (BAT) and white (WAT) adipose tissue in mice at sarcomagenic doses. PIO increased EC proliferation in BAT only. TG directly increased DNA synthesis, inhibited apoptosis, and activated IGF signaling in mouse ECs in vitro . PIO increased DNA synthesis but did not inhibit apoptosis. These results indicate: (1) increased EC proliferation contributes to TG-induced hemangiosarcomagenesis in mice, at least in liver and WAT; (2) a direct proliferative effect of TG on mouse ECs in vitro may be involved in TG-increased EC proliferation in vivo; and (3) TG likely increases the total number of DNA replications greater than PIO since TG inhibits apoptosis. In addition to a direct proliferative effect, we demonstrated that TG-increased hypoxic conditions might be involved in TG-increased EC proliferation, but only in liver. Oxidative stress does not likely play a role. In human ECs, TG did not elevate proliferation or induce gene expression changes observed in TG-treated mouse ECs, indicating a species difference. Further investigation to determine the mechanism of TG-induced HS in mice and identify the biological similarities and species differences will contribute to understanding the possible human relevance of TG-induced HS in mice.

【摘要机译】化学诱导的血管肉瘤(HS)是内皮细胞(EC)的恶性肿瘤,在评估几种药物对人类的潜在危险中已经变得很重要。自发性HS常见于小鼠,少见于大鼠,在人类中很少见。过氧化物酶体增殖物激活受体γ(PPARgamma)激动剂是用于治疗II型糖尿病的非遗传毒性药物。在2年的生物测定中,许多小鼠在肝脏和脂肪组织等多种组织中产生HS,但在老鼠中却未产生。我们的研究目标是使用典型的肉瘤性曲格列酮(TG)和非肉瘤性吡格列酮(P10)了解PPARγ激动剂如何在小鼠中诱导HS。了解PPARγ激动剂诱导的肿瘤发生的机制对于评估人类风险至关重要。由于TG不与DNA反应,因此我们推测增加的EC增殖与TG诱导的小鼠血管肉瘤形成有关。由于细胞数量增加,增加的EC增殖会导致DNA复制增加,从而导致遗传错误的可能性增加。我们显示,在肉瘤发生剂量下,TG可增加小鼠肝脏和棕色(BAT)和白色(WAT)脂肪组织中的EC增殖。 PIO仅在BAT中增加EC增殖。 TG可直接增加小鼠EC中的DNA合成,抑制细胞凋亡并激活IGF信号传导。 PIO增加DNA合成,但不抑制细胞凋亡。这些结果表明:(1)EC增殖的增加至少在肝脏和WAT中有助于TG诱导的小鼠血管肉瘤形成; (2)TG在体外对小鼠EC的直接增殖作用可能与TG在体内增加EC的增殖有关; (3)由于TG抑制细胞凋亡,因此TG可能使DNA复制的总数大于PIO。除了直接的增殖作用外,我们证明了TG升高的低氧状态可能与TG升高的EC增殖有关,但仅在肝脏中。氧化应激不太可能起作用。在人类EC中,TG并未提高增殖或诱导在TG处理的小鼠EC中观察到的基因表达变化,表明物种差异。进一步的研究以确定小鼠中TG诱导的HS的机制并鉴定生物学相似性和物种差异,将有助于理解小鼠中TG诱导的HS与人类的可能相关性。

【作者】Kakiuchi-Kiyota, Satoko.;

【作者单位】University of Nebraska Medical Center.;

【年(卷),期】2010(),

【年度】2010

【页码】258 p.

【总页数】258

【原文格式】PDF

【正文语种】eng

【中图分类】;

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