Borghoff SJ, Wikoff D, Rager JE, Haws LC. 2016. Tetrabromobisphenol A (TBBPA); Dose- and time-dependent changes in plasma TBBPA and its conjugates over 28 days of administration. Presented at the Society of Toxicology’s 55th Annual Meeting, March 13-17, 2016. New Orleans, LA.
TBBPA, a nongenotoxic flame retardant, causes uterine tumors in female rats. A proposed mode of action (MoA) for these tumors involves disruption of estrogen-signaling pathways due to increased bioavailability of estradiol. This is thought to occur though the molecular initiating event (MIE) of binding and inhibition of SULT1E1, the sulfotransferase responsible for inactivating and enhancing the elimination of estradiol. The MIE is proposed to occur under high doses conditions. The objective of this study was to evaluate the effect of dose on the level of TBBPA, TBBPA-glucuronide (GA) and TBBPA-sulfate (S) conjugates in female Wistar Han rat plasma following 28-days of exposure to TBBPA (50, 100, 250, 500 or 1000 mg/kg), thus characterizing conjugation at the high doses (such as those used in the cancer bioassay). Blood samples were collected at 4- and 8- hrs post-dosing on study day 7, 14 and 28; plasma was analyzed for TBBPA, TBBPA-GA and TBBPA-S by LC/MS-MS. There was an increase in TBBPA, TBBPA-GA, and TBBPA-S plasma concentrations at 4-hrs post dose on day 7, 14 and 28; by 8-hrs post dose, plasma concentrations of all three analytes were decreased compared to the 4-hr time point. However, there was still an increase in plasma concentration of TBBPA-GA and TBBPA-S at 28 days compared to concentrations on day 7 and 14 at doses ≥ 250 mg/kg suggesting induction of glucuronidation and sulfation. At all TBBPA doses and time points, there was a lower plasma concentration of TBBPA-S compared to TBBPA-GA; with the S/GA ratio decreasing with dose. This effect was most apparent at 28-days of administration. Together these data show that administration of the high doses of TBBPA associated with the induction of uterine tumors results in a decrease in the sulfation of TBBPA compared to glucuronidation. A decrease in TBBPA sulfation pathway supports in vitro data of TBBPA inhibition of SULT1E1 activity. Furthermore, findings suggest that the proposed MoA involving increased estradiol bioavailability via inhibition of estradiol sulfation by TBBPA is plausible.