DNA Microarray Data Analysis

National Institute Of Environmental Health Sciences

Investigators

Linked publications & trials

Abstract

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.