DNA Microarray Data Analysis

作为NTPs表征多溴联苯醚（PBDE）毒性的一部分，我之前在一项将DE-71诱导的肝脏基因转录变化与脂质和代谢途径联系起来的研究中，帮助评估了雄性和雌性大鼠幼崽和雄性大鼠肝脏样本中PBDE混合物（DE-71）的转录反应。我们随后研究了DE-71及其同系物2,2,4,4-四溴联苯醚（BDE-47）在出生后第4天和出生后第22天的转录组学变化。我们还比较了三种遗留的溴化阻燃剂和六种新出现的溴化阻燃剂在雄性Sprague-Dawley大鼠暴露五天后的效果。另一份出版物描述了生成的大型毒物基因组学数据集，该数据集用于统计比较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PBDE-47后，Nrf2抗氧化通路的转录本上调幅度最大，但暴露于十溴二苯醚、HBCD、TBB和HCBCO后，Nrf2抗氧化通路也上调。该项目通过整合最近发表的三项最新研究的毒物基因组学数据继续进行，以探索暴露于多溴二苯醚如何影响不同生命周期阶段（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在所有三个生命周期阶段发生变化，并激活包括癌症、膜功能和Nrf2抗氧化途径在内的途径。这些结果表明，对于暴露期为5天的多溴二苯醚，与使用较少动物的传统13周研究相比，转录组终点可能潜在地减少识别毒性和致癌潜力所需的时间。

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.