Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.
Applications of gene arrays in environmental toxicology: fingerprints of gene regulation associated with cadmium chloride, benzo(a)pyrene, and trichloroethylene.
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DOI：
10.1289/ehp.0110971
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发表时间：
2001-01
影响因子：
10.4
通讯作者：
Buckpitt A
中科院分区：
文献类型：
--
作者：
Bartosiewicz M;Penn S;Buckpitt A
目前，对未知化学品的毒性测试使用了一些短期生物测定法。这些测试成本高，耗时长，需要大量的动物，通常集中在一个单一的终点。最近发展的DNA阵列提供了一个潜在的机制，通过基因调控的全基因组评估，提高标准毒性测试的效率。在这项研究中，我们使用包含148个外源性代谢酶、DNA修复酶、热休克蛋白、细胞因子和管家基因基因的DNA阵列来检查肝脏对氯化镉、苯并（a）芘（BaP）的反应的基因表达模式。和三氯乙烯（TCE）。在小鼠中对每种化学物质进行了剂量反应研究;每种化学物质都产生了独特的基因诱导模式。正如预期的那样，氯化镉显着上调金属硫蛋白酶I和II（5- 10,000倍，在最高剂量）和几个热休克/应激反应蛋白和早期反应基因。相反，施用BaP仅上调Cyp 1a 1和Cyp 1a 2基因，并且在阵列上存在的任何应激反应基因或任何DNA修复基因中没有产生显著增加。同样，TCE诱导的基因诱导具有高度选择性;在最高试验剂量下，仅Hsp 25和86以及Cyp 2a上调。具有高度集中的一组基因的微阵列分析能够区分不同类别的毒物，并且具有区分高度有毒物质与更微妙的有毒物质的潜力。这些数据表明，使用微阵列来评估未知化学品或化学混合物的潜在危害，必须包括多个剂量和时间点，以提供这些物质的潜在毒性的有效评估。
Toxicity testing of unknown chemicals currently uses a number of short-term bioassays. These tests are costly and time consuming, require large numbers of animals, and generally focus on a single end point. The recent development of DNA arrays provides a potential mechanism for increasing the efficiency of standard toxicity testing through genome-wide assessments of gene regulation. In this study, we used DNA arrays containing 148 genes for xenobiotic metabolizing enzymes, DNA repair enzymes, heat shock proteins, cytokines, and housekeeping genes to examine gene expression patterns in the liver in response to cadmium chloride, benzo(a)pyrene (BaP), and trichloroethylene (TCE). Dose-response studies were carried out in mice for each chemical; each produced a unique pattern of gene induction. As expected, CdCl2 markedly up-regulated metallothionine I and II (5- to 10,000-fold at the highest doses) and several of the heat shock/stress response proteins and early response genes. In contrast, administration of BaP up-regulated only Cyp1a1 and Cyp1a2 genes and produced no significant increases in any of the stress response genes or any of the DNA repair genes present on the array. Likewise, TCE-induced gene induction was highly selective; only Hsp 25 and 86 and Cyp2a were up-regulated at the highest dose tested. Microarray analysis with a highly focused set of genes is capable of discriminating between different classes of toxicants and has potential for differentiating highly noxious versus more subtle toxic agents. These data suggest that use of microarrays to evaluate the potential hazards of unknown chemicals or chemical mixtures must include multiple doses and time points to provide effective assessments of potential toxicity of these substances.