Elsevier

Toxicology Letters

Volume 266, 15 January 2017, Pages 32-41
Toxicology Letters

Tetrabromobisphenol A activates the hepatic interferon pathway in rats

https://doi.org/10.1016/j.toxlet.2016.11.019Get rights and content

Highlights

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 1000 mg/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 (1000 mg/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.

Introduction

Tetrabromobisphenol A (TBBPA) is a high production volume brominated flame retardant (Malkoske et al., 2016), used in printed circuit boards, paper, and textiles (U. S. EPA, 2015, Zhou et al., 2014). TBBPA exposure occurs from breast milk (Carignan et al., 2012, Harrad and Abdallah, 2015, Nakao et al., 2015), food ingestion (e.g. fish (Svihlikova et al., 2015)), industrial exposures (Zhou et al., 2014), dust in the home (Di Napoli-Davis and Owens, 2013), and at waste sites (Liu et al., 2016). TBBPA also accumulates in marine life and may be toxic to various fish species (He et al., 2015, Tang et al., 2015).

TBBPA caused clear evidence of uterine adenocarcinomas in female Wistar Han rats [Crl:WI(Han)] in a 2-year study (Dunnick et al., 2015, National Toxicology Program, 2014). These TBBPA-induced uterine tumors were highly malignant with metastases to the liver, pancreas, kidney, thyroid and other organ systems. Other TBBPA carcinogenic findings occurred in the liver, lower intestine, and vascular systems of male mice (National Toxicology Program, 2014). TBBPA has been classified as probably carcinogenic to humans (Group 2a) by the Interagency for Research on Cancer (IARC) based on sufficient evidence for carcinogenicity found in the 2-year rodent studies and mechanistic information reported in the literature (Grosse et al., 2016).

In this study we looked for TBBPA-induced transcriptomic changes in the liver because this organ is a primary site for metabolism of hormones and other chemicals (Tsuchiya et al., 2005), and in the uterus, a target site for TBBPA-induced tumors in rats (National Toxicology Program, 2014). The TBBPA carcinogenic effect in the uterus is of concern because endometrial tumors are a common malignancy in women with an estimated 50,000 new cases per year in the U.S. (Siegel et al., 2013), and one million new cases per year worldwide (Webb, 2015). Uterine cancer is predicted to be one of the three leading cancers in women by 2030 (Rahib et al., 2014). The majority of human uterine tumors are endometrial carcinomas (George et al., 2015); the same type of uterine tumors seen in rats after TBBPA exposure (National Toxicology Program, 2014). Environmental factors are thought to play a role in the development of uterine cancer (Lichtenstein et al., 2000), including chemical and hormone effects (e.g. tamoxifen and estrogen) (IARC, 2012).

TBBPA is a nongenotoxic chemical, and toxicokinetic studies of TBBPA in the female rat did not reveal any specific accumulation of the parent compound or metabolites in the uterus (compared to that in other organ systems) (Knudsen et al., 2014). Thus, these 13-week TBBPA studies were undertaken to identify molecular alterations in the liver and/or uterus to help characterize early changes along the pathway to cancer.

Section snippets

Experimental design

Tetrabromobisphenol A (CAS No. 79-94-7; Albemarle Corporation (Baton Rouge, LA), lot M032607 K) (Fig. 1) was prepared for oral gavage administration in corn oil to deliver TBBPA at doses of 0, 25, 250, or 1000 mg/kg body weight in a volume of 5 mL/kg body weight. Female Wistar Han IGS rats (Crl:WI(Han)) (25 animals/dose level) were obtained from Charles River (Raleigh, NC). 1000 mg/kg was a dose at which TBBPA induced uterine tumors in the female rat (National Toxicology Program, 2014), and

Body and organ weights and histopathologic findings

There was little or no treatment-related toxicity after 13 weeks of TBBPA exposure using conventional toxicity endpoints. This included no treatment-related effects on survival, body weight, or organ weights (Table 1). There were no treatment-related microscopic lesions in the liver or uterus.

Liver transcriptomic alterations

Using a false discovery rate threshold of 0.05, there were 159 differentially expressed liver transcript probes (Table 2). These 159 transcripts corresponded to expression level changes in 132 genes (6

Discussion

In this study we found that TBBPA induced molecular changes in the liver after 13-weeks of exposure (1000 mg/kg), while there were few altered transcripts in the uterus. TBBPA caused liver expression changes in 159 significant Affymetrix probes (relative to controls [FDR  0.05]) which mapped to 132 genes. The TBBPA hepatic transcriptome included transcripts with functions in the IFN pathway (Noureddin et al., 2015, Sathish and Yuan, 2011, Schmeisser et al., 2010, Schneider et al., 2014) and in

Conflict of interest

There is no conflict of interest.

Acknowledgements

This research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank M. Cesta, NIEHS, and G. Knudson, NCI for their review of this manuscript.

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