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。这项研究的数据已发表在另一份出版物中。我正在合作综合从这些出版物中获得的信息，以发现在多溴二苯醚暴露反应中持续激活的途径和基因。这个项目正在进行中。

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. The data for this study has been deposited in a separate publication. I am collaborating to synthesize the information obtained from these publications to discover the pathways and genes that are consistently activated in response to PBDE exposure. This project is ongoing. In another project, we exposed B6C3F1/N mice to cobalt metal dust (CMD) by inhalation to investigate rodent alveolar/bronchiolar carcinomas (ABCs). At a false discovery rate threshold of 0.05, a total of 11,557 transcripts were changed in spontaneous ABCs compared to controls, and 12,420 transcripts were changed in CMD exposed ABCs compared to controls.8,520 transcript changes were shared between spontaneous and CMD exposed changes. Transcriptomic analysis of ABCs that formed spontaneously or due to CMD exposure contained changes related to MAPK signaling and oxidative stress. The genes encoding Nox4 and Ereg was upregulated in CMD-exposed mice. The data here suggest that oxidative stress plays a significant role in CMD-induced pulmonary carcinogenesis in rodents, which may also be relevant in humans.