Borghoff SJ, Wikoff D, White MC, Thompson C, Haws LC. 2015. Identification of the molecular initiating event (MIE) for TBBPA induced uterine tumors in the framework of an adverse outcome pathway (AOP). Presented at the Society of Toxicology’s 54th Annual Meeting, March 22-26, San Diego, CA.
Tetrabromobisphenol A (TBBPA), a nongenotoxic flame retardant, was shown to cause uterine tumors in female rats. A proposed mode of action (MOA) for these tumors is disruption of estrogen-signaling pathways. Thus, establishing an AOP for estrogen related uterine tumors would aid in the integration of data for this MOA. As a critical first step, this assessment involved the compilation and strategic review of information on TBBPA within an AOP framework with the objective of identifying the MIE. Two potential MIEs associated with alteration of estrogen signaling were investigated: interaction with estrogen receptors (ER) and inhibition of estradiol sulfotransferase (ES). Results from 27 assays were identified that characterized measures of estrogenicity through interaction with ER. A review of these data showed a lack of interaction between TBBPA and ERs (e.g., TBBPA was inactive in 18 of 19 assays in ToxCast), though in 1 assay (of 8) reported in the literature showed that TBBPA exhibited weak ER agonist/antagonist activity with very low potency compared to known ligands (EC50 TBBPA ~ 19 mM vs. BPA ~ 0.63 mM). Collectively, these data did not provide support for ER binding as the MIE. In contrast, an in silico analysis showed that TBBPA binds to ES, and several in vitro assays reported TBBPA inhibited ES with high potency (IC50 0.012 -0.033 mM), thus demonstrating that the ability of TBBPA to interfere with the metabolism of estradiol to its sulfated conjugate is a plausible MIE. Several data gaps were identified; notably, the quantitation of TBBPA inhibition of ES and its influence on circulating levels of estrogen would provide critical information on the subsequent key events leading to the development of an AOP for altered estrogen signaling and uterine tumors. Identification of the MIE is the first step in mapping an AOP; this can be used to develop an integrative testing strategy to conduct more informed risk assessments for TBBPA, as well as other chemicals.