DNA Microarray Data Analysis

本研究探讨了五溴二苯醚同系物（PBDE-47）暴露和五溴二苯醚混合物（DE-71）暴露对Wistar Han幼鼠妊娠第6天（GD 6）至出生后第4天（PND 4）的影响。PBDE-47是PBDE混合物（DE-71）的同系物，PBDE-47毒性与DE-71毒性进行了比较。在子宫和出生后，通过灌胃给药，使用浓度分别为0、0.1、15和50 mg/kg的化学物质进行暴露。与对照组相比，PND4幼崽血浆总甲状腺素（T4）降低。肝脏转录组变化包括诱导的CYP转录水平、Nrf2抗氧化途径转录上调和ABC膜运输转录上调。这些转录变化可能是氧化应激和代谢变化的早期指标，长期暴露后可能导致毒性和/或致癌性。

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.