Tetrabromobisphenol A activates the hepatic interferon pathway in rats

Abstract

Tetrabromobisphenol A (TBBPA) is a widely used flame retardant in printed circuit boards, paper, and textiles. In a two-year study, TBBPA showed evidence of uterine tumors in female Wistar-Han rats and liver and colon tumors in B6C3F1 mice. In order to gain further insight into early gene and pathway changes leading to cancer, we exposed female Wistar Han rats to TBBPA at 0, 25, 250, or 1000mg/kg (oral gavage in corn oil, 5×/week) for 13 weeks. Because at the end of the TBBPA exposure period, there were no treatment-related effects on body weights, liver or uterus lesions, and liver and uterine organ weights were within 10% of controls, only the high dose animals were analyzed. Analysis of the hepatic and uterine transcriptomes showed TBBPA-induced changes primarily in the liver (1000mg/kg), with 159 transcripts corresponding to 132 genes differentially expressed compared to controls (FDR=0.05). Pathway analysis showed activation of interferon (IFN) and metabolic networks. TBBPA induced few molecular changes in the uterus. Activation of the interferon pathway in the liver occurred after 13-weeks of TBBPA exposure, and with longer term TBBPA exposure this may lead to immunomodulatory changes that contribute to carcinogenic processes.

Keywords: Interferon response transcripts; Microarray; Pathway analysis; Tetrabromobisphenol A; Toxicogenomics.

Fig. 1

TBPPA structure.

Fig. 2

TBBPA (1000 mg/kg) liver transcript heat map.

Fig. 3

Selected Liver TBBPA (1000 mg/kg) transcripts confirmed by Nanostring analysis.

Fig. 4

Plots of selected TBBPA (1000 mg/kg) induced-liver transcripts. The gene expression value shown refers to the RMA normalized gene expression measure described in the methods.

Fig. 5

Proposed Mechanism for TBBPA activation of interferon pathway.