DNA Microarray Data Analysis

探讨了五溴二苯醚同系物(PBDE-47)和五溴二苯醚混合物(DE-71)暴露对Wistar汉族仔鼠从妊娠6天(GD6)到出生后4天(PND 4)的影响。多溴联苯醚-47是多溴二苯醚混合物(DE-71)的同系物，对多溴二苯醚-47的毒性与DE-71的毒性进行了比较。在宫内和出生后分别以0、0.1、15和50 mg/kg的化学浓度经口灌胃进行暴露。与对照组相比，PND4仔鼠血浆总甲状腺素(T4)降低。肝脏转录变化包括诱导的CYP转录水平，上调的Nrf2抗氧化途径转录，以及上调的ABC膜转运转录。这些转录变化可能是氧化应激和代谢变化的早期指标，长期暴露可能会导致毒性和/或致癌。 在另一个项目中，我们将B6C3F1/N小鼠暴露在银杏叶提取物(GBE)中，以研究调节GBE诱导的肝癌发生的关键microRNAs。将暴露于GBE的肝癌发生与年龄匹配的对照组和自发发生肝癌的样本进行了全球miRNA表达谱比较。与对照组相比，经处理的肝癌发生样本中共有74个miRNAs发生改变，而在自发肝癌发生样本中与对照组相比，共有33个miRNAs发生改变。CDK1mRNA只有在处理组和对照组的比较中才发生变化，并被选择用于功能验证。在小鼠肝癌细胞系HEPA-1中，miR-31和CDK1的蛋白水平呈负相关，而CDK1的mRNA水平没有变化，提示存在转录后效应。与对照组相比，暴露90天组的GBE肝癌和非肿瘤肝脏样本中的一组miRNAs(miRs-411、300、127、134、409-3p和433-3p)发生了改变，因此其中一些miRNAs可能能够作为GBE暴露或肝细胞癌发生的生物标志物。 在另一项单独的研究中，比较了三种传统阻燃剂和六种新出现的溴化阻燃剂在暴露5天后对雄性Spraogue Dawley大鼠的影响。每只大鼠暴露于0.1-1000mol/kg体重范围内的阻燃剂后，评估其对甲状腺和肝细胞的毒性。暴露于PBDE-47、HBCD和HCDBCO阻燃剂后，肝细胞中央小叶肥大和肝脏重量增加。PBDE-47暴露对总甲状腺素(TT4)水平的影响最大。在PBDE-47、DecaBDE和HBCD暴露后，肝脏转录包括与肝脏疾病相关的转录上调和/或代谢转录变化，而对其他阻燃剂(TBB、TBPH、TBBPA-DBPE、BTBPE、DBDPE或HCDBCO)的转录变化较小。在暴露于多溴联苯醚-47后，Nrf2抗氧化途径的转录本在最大程度上上调，但该途径也在十溴二苯醚、六溴联苯、四溴联苯和六氯联苯暴露后上调。这项研究的数据已经保存在另一份出版物上。

We explored the effects of pentabromodiphenyl ether congener (PBDE-47) exposure and pentabromodiphenyl ether mixture (DE-71) exposure on Wistar Han pups from gestation day 6 (GD 6) through postnatal day 4 (PND 4). PBDE-47 is a congener of a PBDE mixture (DE-71) and PBDE-47 toxicity was compared to DE-71 toxicity. In utero and postnatal exposure was performed using chemical concentrations of 0, 0.1, 15, and 50 mg/kg administered by oral gavage. Total plasma thyroxine (T4) was reduced in PND4 pups compared to controls. Liver transcriptomic changes included induced CYP transcript levels, up-regulated Nrf2 antioxidant pathway transcripts, and up-regulated ABC membrane transport transcripts. These transcriptional changes could be early indicators of oxidative stress and metabolic changes, which may lead to toxicity and/or carcinogenicity after long duration exposure. In another project, we exposed B6C3F1/N mice to Ginkgo biloba extract (GBE) in order to investigate key microRNAs that modulate GBE-induced liver carcinogenesis. The global miRNA expression profile of GBE-exposed hepatocarcinogenesis was compared with age-matched controls and spontaneous hepatocarcinogenesis samples. A total of 74 miRNAs were changed in the treated hepatocarcinogenesis samples compared to controls and 33 miRNAs were changed in spontaneous hepatocarcinogenesis samples compared to controls. Cdk1 mRNA was changed only in the treated vs control comparison and was chosen for functional validation. In mouse hepatoma cell line HEPA-1 cells there was an inverse correlation between miR-31 and CDK1 protein levels, but no change in Cdk1 mRNA levels, which suggested a post-transcriptional effect. A set of miRNAs (miRs-411, 300, 127, 134, 409-3p, and 433-3p) were changed in GBE hepatocarcinogenesis samples and non-tumor liver samples for the 90-day GBE-exposed group compared to controls, such that some of these miRNAs might be able to serve as biomarkers for GBE exposure or hepatocellular carcinogenesis. In a separate study, the effects of three legacy and six emerging brominated flame retardants were compared in male Sprague Dawley rats following 5-day exposure. Thyroid toxicity and hepatocellular toxicity were evaluated after the rats were exposed to each of the flame retardants in concentrations that ranged from 0.1 - 1000 mol/kg body weight per day. Centrilobular hypertrophy of hepatocytes and increases in liver weights were found following exposure to PBDE-47, HBCD and HCDBCO flame retardants. Total thyroxine (TT4) levels were reduced most by PBDE-47 exposure. The liver transcriptomes after PBDE-47, decaBDE, and HBCD exposure included upregulation of transcripts related to liver disease and/or metabolic transcriptional changes, while fewer transcriptional changes were seen in response to the other flame retardants (TBB, TBPH, TBBPA-DBPE, BTBPE, DBDPE, or HCDBCO). 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.