Disruption of estrogen homeostasis as a mechanism for uterine toxicity in Wistar Han rats treated with tetrabromobisphenol A

Abstract

Chronic oral treatment of tetrabromobisphenol A (TBBPA) to female Wistar Han rats resulted in increased incidence of cell proliferation at 250 mg/kg and tumor formation in the uterus at higher doses. The present study was designed to test the hypothesis that disruption of estrogen homeostasis was a major mode-of-action for the observed effects. Biological changes were assessed in serum, liver, and the proximal (nearest the cervix) and distal (nearest the ovaries) sections of the uterine horn of Wistar Han rats 24 hours following administration of the last of five daily oral doses of 250 mg/kg. Expression of genes associated with receptors, biosynthesis, and metabolism of estrogen was altered in the liver and uterus. TBBPA treatment also resulted in changes in expression of genes associated with cell division and growth. Changes were also observed in the concentration of thyroxine in serum and in expression of genes in the liver and uterus associated with thyroid hormone receptors. Differential expression of some genes was tissue-dependent or specific to tissue location in the uterus. The biological responses observed in the present study support the hypothesis that perturbation of estrogen homeostasis is a major mode-of-action for TBBPA-mediated cell proliferation and tumorigenesis previously observed in the uterus of TBBPA-treated Wistar Han rats.

Gene expression changes in immune response pathways following oral administration of tetrabromobisphenol A (TBBPA) in female Wistar Han rats

“…The present laboratory has demonstrated altered expression of genes involved in cell proliferation and biosynthesis and metabolism of estrogen in liver and uterine tissue of female Wistar Han rats treated with five daily doses of 250 mg/kg of TBBPA by gavage (Sanders et al , 2016). Changes in expression of target genes such as Cyp1b1 , Comt , Esr1, Hsd17b2, Igf1, Ppara, Sult2a1, and Ugt1a1 support the hypothesis that disruption of estrogen homeostasis is a major mode-of-action for the increased incidence of uterine lesions in the TBBPA-treated rats of the NTP bioassay.…”

“…RNA for use in the microarray analysis was prepared from liver and uterus tissues as described previously (Sanders et al , 2016). In brief, frozen tissue samples (50–60 mg) were weighed and minced in Qiagen (Germantown, MD) RLT buffer containing β-mercaptoethanol (1:100).…”

“…Previous studies have observed decreased thyroxine (T4) levels and other endocrine effects after TBBPA exposures (Cope et al , 2015; Hamers et al , 2006; Sanders et al , 2016; Van der Ven et al , 2008). TBBPA has some structural similarity to T4 and may compete with the hormone for binding to transthyretin (Meerts et al , 2000).…”

“…Changes in expression of target genes such as Cyp1b1 , Comt , Esr1, Hsd17b2, Igf1, Ppara, Sult2a1, and Ugt1a1 support the hypothesis that disruption of estrogen homeostasis is a major mode-of-action for the increased incidence of uterine lesions in the TBBPA-treated rats of the NTP bioassay. In this study global gene expression changes were investigated by microarray analysis to search for additional affected biological pathways in liver and uterine tissue from the same five-day TBBPA-exposed rats previously studied in Sanders et al (2016).…”

Tetrabromobisphenol A activates the hepatic interferon pathway in rats

“…Upregulation of interferon pathways by TBBPA and tamoxifen could affect estrogen signaling and ultimately the development of uterine cancer. The ability of TBBPA to interact with sulfotransferase (Gosavi et al, 2013) could disrupt estrogen homeostasis (Sanders et al, 2016). In addition, TBBPA can cause oxidative damage and disruption of thyroid hormone signaling (He et al, 2016; Iakovleva et al, 2016).…”