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Bystander effects due to neutrons, and low-dose hyper-radiosensitivity to gamma rays in human cells using cytogenetics.

机译：中子的旁观者效应，以及使用细胞遗传学对人类细胞中的伽玛射线造成的低剂量超放射敏感性。

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Chapter 2: Micronuclei have been used extensively in studies as an easily-evaluated indicator of DNA damage but little is known about their association with other types of damage such as nucleoplasmic bridges and nuclear buds. Radiation-induced clastogenic events were evaluated via the cytokinesis-block micronucleus assay in two normal human lymphoblastoid cell lines exposed to neutrons or gamma radiation. Micronuclei, nucleoplasmic bridges and nuclear buds were enumerated by recording the coincident presence of these endpoints within individual cells, and the associations among these three endpoints were evaluated for all treatment conditions. The common odds ratios for micronuclei and nucleoplasmic bridges were found to be significantly larger than unity, indicating that the presence of one or more micronuclei in a cell imposes a significant risk for having one or more nucleoplasmic bridges in that same cell, and vice versa. The strength of this association did not change significantly with radiation dose. Common odds ratios for association between micronuclei and buds, and between bridges and buds were also found to be significantly higher than unity. However, associations between micronuclei and buds could not be calculated for some treatments due to heterogeneity in the odds ratios, and hence may depend on radiation dose. This study provides evidence for how paired analyses among genetic endpoints in the cytokinesis-block micronucleus assay can provide information concerning abnormalities of cell division and possibly about structural chromosomal rearrangements induced by radiation.;Chapter 3: Bystander effects have been observed repeatedly in mammalian cells following photon and alpha particle irradiation. However, few studies have been performed to investigate bystander effects arising from neutron irradiation. Here we asked whether neutrons also induce a bystander effect in two normal human lymphoblastoid cell lines. These cells were exposed to fast neutrons produced by targeting a near-monoenergetic 50.5 MeV proton beam at a Be target (17 MeV average neutron energy), and irradiated-cell conditioned media (ICCM) was transferred to unirradiated cells. The cytokinesis-block micronucleus assay was used to quantify genetic damage in radiation-naive cells exposed to ICCM from cultures that received 0 (control), 0.5, 1, 1.5, 2, 3 or 4 Gy neutrons. Cells grown in ICCM from irradiated cells showed no significant increase in the frequencies of micronuclei or nucleoplasmic bridges compared to cells grown in ICCM from sham irradiated cells for either cell line. However, the neutron beam has a photon dose-contamination of 5%, which may modulate a neutron-induced bystander effect. To determine whether these low doses of contaminating photons can induce a bystander effect, cells were irradiated with cobalt-60 at doses equivalent to the percent contamination for each neutron dose. No significant increase in the frequencies of micronuclei or bridges was observed at these doses of photons for either cell line when cultured in ICCM. As expected, high doses of photons induced a clear bystander effect in both cell lines for micronuclei and bridges (p < 0.0001). These data indicate that neutrons do not induce a bystander effect in these cells. Finally, neutrons had a relative biological effectiveness of 2.0 +/- 0.13 for micronuclei and 5.8 +/- 2.9 for bridges compared to cobalt-60. These results may be relevant to radiation therapy with fast neutrons and for regulatory agencies setting standards for neutron radiation protection and safety.;Chapter 4: The shape of the ionizing radiation response curve at very low doses has been the subject of considerable debate. Linear-no-threshold (LNT) models are widely used to estimate risks associated with low dose exposures. However, the low-dose hyper-radiosensitivity (HRS) phenomenon, in which cells are especially sensitive at low doses but then show increased radioresistance at higher doses, provides evidence of nonlinearity in the low dose region. HRS is more prominent in the G2 phase of the cell cycle than the G0/G1 or S phases. Here I provide the first cytogenetic evidence of low-dose hyper-radiosensitivity in human peripheral blood lymphocytes using structural chromosomal aberrations. Human peripheral blood lymphocytes from two normal healthy female donors were acutely exposed to cobalt-60 gamma rays in either G0 or G2 using closely-spaced doses ranging from 0-1.5 Gy. Structural chromosomal aberrations were enumerated and the slopes of the regression lines at low doses (0-0.4 Gy) were compared with doses of 0.5 Gy and above. HRS was clearly evident in both donors for cells irradiated in G2. No HRS was observed in cells irradiated in G0. The radiation effect per unit dose was 2.5-3.5 fold higher for doses ≤0.4 Gy than >0.5 Gy. These data provide the first cytogenetic evidence for the existence of HRS in human cells irradiated in G2 and suggest that LNT models may not always be optimal for making radiation risk assessments at low doses.
机译：第2章：微核已在研究中广泛用作DNA损伤的易于评估的指标，但对它们与其他类型的损伤（如核质桥和核芽）的关联知之甚少。在两个暴露于中子或γ射线的正常人淋巴母细胞系中，通过胞质阻滞微核试验评估了辐射诱发的分裂发生事件。通过记录单个细胞中这些终点的同时存在，来列举微核，核质桥和核芽，并针对所有治疗条件评估这三个终点之间的关联。发现微核和核质桥的常见比值比显着大于1，表明细胞中存在一个或多个微核对在同一细胞中具有一个或多个核质桥构成重大风险，反之亦然。这种关联的强度并没有随辐射剂量而显着变化。还发现微核与芽之间，桥与芽之间缔合的共同优势比明显高于统一性。但是，由于比值比的异质性，对于某些处理无法计算微核与芽之间的关联，因此可能取决于辐射剂量。这项研究提供了证据，证明胞质分裂阻滞微核试验中遗传终点之间的配对分析如何提供有关细胞分裂异常以及可能由辐射诱导的结构染色体重排的信息。;第3章：在哺乳动物细胞中反复观察到旁观者效应光子和α粒子辐照。但是，很少有研究来研究中子辐照引起的旁观者效应。在这里，我们问中子是否还会在两种正常人淋巴母细胞系中诱导旁观者效应。这些细胞暴露于通过将近单能50.5 MeV质子束对准Be目标（17 MeV平均中子能量）产生的快速中子，然后将辐照细胞条件培养基（ICCM）转移到未辐照的细胞中。胞质分裂阻滞微核试验用于量化暴露于接受0（对照），0.5、1、1.5、2、3或4 Gy中子的培养物暴露于ICCM的未辐射细胞的遗传损伤。在ICCM中从受辐照的细胞中生长的细胞与在任何一种细胞系中从深部辐照的细胞在ICCM中生长的细胞相比，均未显示微核或核质桥的频率显着增加。但是，中子束的光子剂量污染为5％，这可能会调节中子引起的旁观者效应。为了确定这些低剂量的污染光子是否能引起旁观者效应，以等于每个中子剂量污染百分数的剂量用60钴辐照细胞。当在ICCM中培养时，对于任一细胞系，在这些剂量的光子剂量下，未观察到微核或桥的频率显着增加。正如预期的那样，高剂量的光子在微核和桥细胞系中均引起明显的旁观者效应（p <0.0001）。这些数据表明中子在这些细胞中不会诱导旁观者效应。最后，与钴60相比，中子对微核的相对生物学有效性为2.0 +/- 0.13，对电桥的相对生物学有效性为5.8 +/- 2.9。这些结果可能与使用快中子的放射疗法以及为中子放射防护和安全性制定标准的监管机构有关。第四章：非常低剂量下的电离辐射响应曲线的形状一直是引起广泛争议的主题。线性无阈值（LNT）模型被广泛用于估计与低剂量暴露相关的风险。但是，出现了低剂量超放射敏感性（HRS）现象，其中细胞在低剂量时特别敏感，但在高剂量时显示出更高的放射抵抗力，提供了低剂量区域非线性的证据。 HRS在细胞周期的G2阶段比G0 / G1或S阶段更为突出。在这里，我提供了使用结构染色体畸变在人外周血淋巴细胞中低剂量超放射敏感性的第一个细胞遗传学证据。来自两个正常健康女性供体的人外周血淋巴细胞以0-1.5 Gy的近距离剂量急性暴露于G0或G2中的钴60γ射线。列举了结构染色体畸变，并比较了低剂量（0-0.4 Gy）和0.5 Gy及以上剂量时回归线的斜率。在两个供体中，在G2中照射的细胞，HRS都明显可见。在G0照射的细胞中未观察到HRS。 ≤0.4Gy的剂量比> 0.5 Gy的剂量的每单位剂量的辐射作用高2.5-3.5倍。这些数据为G2照射的人类细胞中HRS的存在提供了首个细胞遗传学证据，并表明LNT模型对于低剂量辐射风险评估可能并不总是最佳的。

著录项

  • 作者

    Seth, Isheeta.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Cellular biology.;Oncology.;Toxicology.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 125 p.
  • 总页数 125
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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