IMMUNE FUNCTION ASSAYS AS BIOMARKERS OF METAL EXPOSURE

免疫功能测定作为金属暴露的生物标志物

• 批准号: 3840777
• 负责人: CARROLL A. SNYDER
• 金额: --
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3840777
• 关键词: T lymphocyte; biomarker; cadmium; chromium; clone cells; environmental toxicology; human tissue; immunologic assay /test; immunotoxicity; industrial waste; interleukin 1; interleukin 2; laboratory mouse; laboratory rat; lymphocyte proliferation; mixed lymphocyte reaction test; occupational hazard; tissue /cell culture; toxicant interaction; toxicant screening; water pollution; water supply

Work in this component has focused on determining whether immune-function assays can be used as biomarkers of exposure for a variety of toxicants and whether these assays can be modified to detect exposure to specific toxicants. Eight different toxicants were used to test the applicability of these assays, four metals (Hg, Cd, chromate and Ni) and four organics (benzoquinone, hydroquinone, styrene oxide and aroclor, a PCB). Applicability was assessed using both B-cell and T-cell mitogen assays and the mixed lymphocyte culture (MLC), a T-cell assay. Dose/response exposures were conducted in vitro with all eight toxicants using concentrations that spanned five orders of magnitude (100 ppm - 10 ppb). At the lowest concentration tested (10 ppb), all of the toxicants induced changes in at least one assay and all of the metals induced changes in at least two assays. Moreover at 10 ppb, all of the metals enhanced the proliferation of T-cells in the MLC. Because of the success with the metals in these dose/response studies, our next series of experiments focused on modifying these proliferation assays to detect in vivo exposures to specific metals and on understanding the mechanisms whereby metals alter lymphocyte proliferation. For these studies we employed rats exposed in vivo to either chromate or to cadmium. Using variants of the mitogen and MLC assays, cells isolated from rats exposed to chromate responded differently than cells isolated from rats exposed to cadmium. Moreover, in vivo cadmium exposure but not in vivo chromate exposure enhanced the antigenicity of splenocytes taken from exposed rats toward allogeneic splenocytes. Our results indicate that variants of these proliferation assays may be useful for detecting low-level exposures to chromate or cadmium and perhaps other metals as well. In the coming grant period we will focus on applying these assays (both the original assays and our variants) to humans exposed to chromate and to cadmium. In addition, we will continue investigations into how variants of these assays can be used as biomarkers of exposure for a wide variety of metals. We will also attempt to clone metal-responsive T-cells from both humans and animals exposed to chromate and cadmium. This has already been done with nickel- exposed individuals and we have evidence that chromate, and perhaps other metals, induce a subpopulation of metal responsive T-cells. Should the cloning experiments be successful, it would represent a powerful biomarker of metal exposure.

该组件中的工作重点是确定免疫功能是否 测定可以用作各种有毒物质和 这些测定是否可以修改以检测到特定的暴露 有毒物质。 使用八种不同的毒物测试适用性 在这些测定中，四种金属（Hg，CD，Chomate和Ni）和四个有机物 （苯喹酮，氢喹酮，氧化苯乙烯和Aroclor，PCB）。 使用B细胞和T细胞有丝分裂原分析以及 混合淋巴细胞培养（MLC），一种T细胞测定。 剂量/反应 使用所有八种有毒物质在体外进行暴露 跨越五个数量级的浓度（100 ppm -10 ppb）。 在测试的最低浓度（10 ppb）下，所有有毒物质诱导 至少一种测定法的变化，所有金属都会引起AT的变化 至少有两个测定法。 此外，在10 ppb时，所有金属都增强了 T细胞在MLC中的增殖。 因为 这些剂量/响应研究中的金属，我们的下一系列实验 专注于修改这些扩散测定以检测体内暴露 特定金属以及理解金属改变的机制 淋巴细胞增殖。 对于这些研究，我们采用了暴露于 体内铬酸盐或镉。 使用有丝分裂原和 MLC分析，从暴露于铬酸盐的大鼠中分离出的细胞反应 与暴露于镉的大鼠分离的细胞不同。 而且，在 体内镉暴露但不体内铬酸盐暴露增强了 从暴露的大鼠杀菌细胞的抗原性向同种异体 脾细胞。 我们的结果表明这些扩散的变体 测定可能有助于检测低级暴露于铬酸盐或 镉，也许还有其他金属。 在未来的赠款期内我们 将专注于应用这些测定（原始测定和我们的 变体），暴露于铬酸盐和镉。 另外，我们 将继续调查如何使用这些测定的变体 作为各种金属的暴露生物标志物。 我们也会 尝试从人类和动物中克隆金属响应性T细胞 暴露于铬酸盐和镉。 镍已经完成了 暴露个人，我们有证据表明铬酸盐，也许是其他的 金属诱导金属反应性T细胞的亚群。 应该 克隆实验成功，它将代表强大的生物标志物 金属暴露。