Environmental chemical exposure may contribute to uterine cancer development: studies with tetrabromobisphenol A

Abstract

Tetrabromobisphenol A (TBBPA), a widely used flame retardant, caused uterine tumors in rats. In this study, TBBPA was administered to male and female Wistar Han rats and B6C3F1/N mice by oral gavage in corn oil for 2 years at doses up to 1,000 mg/kg. TBBPA induced uterine epithelial tumors including adenomas, adenocarcinomas, and malignant mixed Müllerian tumors (MMMTs). In addition, endometrial epithelial atypical hyperplasia occurred in TBBPA-treated rats. Also found to be related to TBBPA treatment, but at lower incidence and at a lower statistical significance, were testicular tumors in rats, and hepatic tumors, hemangiosarcomas (all organs), and intestinal tumors in male mice. It is hypothesized that the TBBPA uterine tumor carcinogenic mechanisms involve altered estrogen levels and/or oxidative damage. TBBPA treatment may affect hydroxysteroid-dehydrogenase-17β (HSD17β) and/or sulfotransferases, enzymes involved in estrogen homeostasis. Metabolism of TBBPA may also result in the formation of free radicals. The finding of TBBPA-mediated uterine cancer in rats is of concern because TBBPA exposure is widespread and endometrial tumors are a common malignancy in women. Further work is needed to understand TBBPA cancer mechanisms.

Keywords: flame retardants; malignant mixed Müllerian tumors (MMMT); tetrabromobisphenol A; uterine tumors.

Figure 1

a: An example of the epithelium of normal endometrial glands consisting of a single layer of well differentiated cuboidal to columnar epithelium without stratification and surrounded by a delicate fibrous stroma. b: A uterine adenocarcinoma composed of neoplastic epithelium with enlarged pleomorphic epithelial cells. These cells are arranged in poorly configured acinar structures, within and supported by a fibrovascular stroma. These cells may also be arranged in solid nests, cords, and papillary structures. c: A MMMT composed of a mixture of neoplastic epithelial and mesenchymal cells arranged in interweaving bundles. There is marked nuclear atypia with variation in size and shape and prominent, sometimes multiple nucleoli. d an 1e: Cytokeratin (Figure 1d) and vimentin (Figure 1e) immunohistochemical stains revealed cytoplasmic staining of neoplastic epithelial and mesenchymal cells, respectively, in order to better characterize the MMMTs. f: An example of atypical glandular endometrial hyperplasia characterized by clusters of enlarged glands separated by little to no stroma and lined by tall, stratified, disorganized epithelium. The epithelium blebs into the lumen and there is cellular proliferation, atypia, and loss of nuclear polarization.

Figure 2

Proposed TBBPA metabolism in rats. Adapted from: (Chignell et al., 2008, Hakk et al., 2000, Knudsen et al., 2014a, Kuester et al., 2007, Schauer et al., 2006)