DNA Microarray Data Analysis

作为NTPs努力表征多溴联苯醚（PBDE）毒性的一部分，我以前帮助评估转录反应PBDE混合物（DE-71）在雄性和雌性大鼠幼仔和雄性大鼠的肝脏样本，在一项研究中，DE-71诱导的肝脏基因转录变化与脂质和代谢途径。随后，我们研究了出生后第4天和出生后第22天子宫内暴露/出生后暴露后DE-71及其同系物2，2，4，4-四溴二苯醚（BDE-47）的转录组学变化。我们还比较了三个传统的和六个新兴的溴化阻燃剂在雄性Sprague-Dawley大鼠暴露五天后的影响。一份单独的出版物描述了生成的大型毒理基因组学数据集，以统计学方式比较9种阻燃化学品的多个剂量组的对照反应，并对每种化学品进行基因组基准剂量计算。暴露于多溴二苯醚-47后，Nrf 2抗氧化途径的转录本上调幅度最大，但暴露于十溴二苯醚、六溴环十二烷、三丁基溴化铵和六溴代一氧化碳后，该途径也上调。该项目通过整合最近发表的三项研究的毒理基因组学数据继续进行，以探索接触多溴二苯醚如何影响生命周期不同阶段（PND 4、PND 22和成人）的肝脏转录组变化。我们发现，多溴二苯醚暴露诱导肝脏基因表达的变化，在所有三个生命周期阶段和激活的途径，包括癌症，膜功能，和Nrf 2抗氧化途径。这些结果表明，与更传统的13周研究相比，对于暴露期为5天的多溴二苯醚，转录组学终点可能会减少确定毒性和致癌潜力所需的时间，同时使用更少的动物。 在另一个项目中，我们将B6 C3 F1/N小鼠暴露于三氧化二锑（AT），这是一种用于织物和塑料的阻燃剂。长期暴露于AT导致肺泡/细支气管癌（ABC）的发病率和肿瘤多样性增加。突变分析显示小鼠肺肿瘤中Kras和Egfr热点突变增加，Kras和Egfr突变的ABC中丝裂原活化蛋白激酶（MAPK）（Erk 1/）蛋白增加。转录组学分析也表明MAPK信号传导，并且AT暴露导致的小鼠ABC的转录组学应答与来自人肺腺癌数据的数据之间存在显著重叠。

As part of NTPs efforts to characterize polybrominated diphenyl ether (PBDE) toxicity, I previously helped to evaluate the transcriptional response to a PBDE mixture (DE-71) in liver samples of male and female rat pups, and male rats, in a study that associated DE-71-induced liver gene-transcript changes with lipid and metabolic pathways. We later investigated the transcriptomic changes in response to DE-71 and its congener, 2,2,4,4-tetra-bromodiphenyl ether (BDE-47), on postnatal day 4 and postnatal day 22 after in utero exposure/postnatal day exposure. We also compared the effects of three legacy and six emerging brominated flame retardants in male Sprague-Dawley rats following five-day exposure. A separate publication describes the large toxicogenomics data set generated to statistically compare control responses to those from multiple dose groups across the nine flame retardant chemicals and perform genomic benchmark dose calculations for each chemical. Transcripts underlying the Nrf2 antioxidant pathway were upregulated to the greatest extent after exposure to PBDE-47, but this pathway was also upregulated after decaBDE, HBCD, TBB and HCBCO exposure. This project was continued by integrating recently published toxicogenomics data from three recent studies to explore how exposure to PBDE affected liver transcriptomic changes at different life cycle stages (PND 4, PND 22, and adult). We found that PBDE exposure induced liver gene expression changes in all three life cycle stages and activated pathways including cancer, membrane function, and the Nrf2 antioxidant pathway. These results indicate that for PBDEs with a 5-day exposure period, transcriptomic endpoints could potentially reduce the amount of time needed to identify toxic and carcinogenic potential compared to a more traditional 13-week study while using fewer animals. In another project, we exposed B6C3F1/N mice to antimony trioxide (AT), which is used as a flame retardant in fabrics and plastics. Chronic exposure to AT resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). Mutational analysis revealed increased Kras and Egfr hotspot mutations in mouse lung tumors, and increased mitogen-activated protein kinase (MAPK)(Erk1/) protein in ABCs with Kras and Egfr mutations. Transcriptomic analysis also indicated in MAPK signaling, and there was significant overlap between transcriptomic response from mouse ABCs resulting from AT exposure and data from human pulmonary adenocarcinoma data.