Tetrabromobisphenol A activates the hepatic interferon pathway in rats
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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