Paul H. O'Neill School of Public and Environmental Affairs Indiana University, Bloomington, Indiana 47405, USA.
School of Public Health, Indiana University, Bloomington, Indiana 47405, USA.
Environ Int. 2022 Jan;158:106943. doi: 10.1016/j.envint.2021.106943. Epub 2021 Oct 28.
2,4,6-Tribromophenol (2,4,6-TBP) is a brominated flame retardant that accumulates in human tissues and is a potential toxicant. Previous studies found 2,4,6-TBP levels in human tissues were significantly higher than those of brominated flame retardants measured in the same samples. In contrast, the levels of 2,4,6-TBP in the environment and foodstuff are not elevated, suggesting a low potential for direct intake through environmental exposure or diet. Here, we hypothesized that high levels of 2,4,6-TBP in human tissues are partially from the indirect exposure sources, such as biotransformation of highly brominated substances. We conducted in vitro assays utilizing human and rat liver microsomes to compare the biotransformation rates of four highly brominated flame retardants, which could potentially transform to 2,4,6-TBP, including decabromodiphenyl ethane (DBDPE), 2,4,6-tris-(2,4,6-tribromophenoxy)-1,3,5-triazine (TTBP-TAZ), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), and tetrabromobisphenol A (TBBPA). Our results show that TTBP-TAZ rapidly metabolizes in both human and rat liver microsomes with a half-life of 1.1 and 2.2 h, respectively, suggesting that TTBP-TAZ is a potential precursor of 2,4,6-TBP. In contrast, 2,4,6-TBP was not formed as a result of biotransformation of TBBPA, BTBPE, and DBDPE in both human and rat liver microsomes. We applied suspect and target screening to explore the metabolic pathways of TTBP-TAZ and identified 2,4,6-TBP as a major metabolite of TTBP-TAZ accounting for 87% of all formed metabolites. These in vitro results were further tested by an in vivo experiment in which 2,4,6-TBP was detected in the rat blood and liver at concentrations of 270 ± 110 and 50 ± 14 μg/g lipid weight, respectively, after being exposed to 250 mg/kg body weight/day of TTBP-TAZ for a week. The hepatic mRNA expression demonstrated that TTBP-TAZ significantly activates the aryl hydrocarbon receptor (AhR) and promotes fatty degeneration (18 and 28-fold change compared to control, respectively) in rats.
2,4,6-三溴苯酚（2,4,6-TBP）是一种溴化阻燃剂，在人体组织中积累，是一种潜在的有毒物质。先前的研究发现，人体组织中 2,4,6-TBP 的水平明显高于同一样本中测量的溴化阻燃剂水平。相比之下，环境和食品中的 2,4,6-TBP 水平并没有升高，这表明通过环境暴露或饮食直接摄入的可能性较低。在这里，我们假设人体组织中 2,4,6-TBP 水平较高部分来自间接暴露源，例如高度溴化物质的生物转化。我们利用人肝微粒体和大鼠肝微粒体进行了体外实验，比较了四种可能转化为 2,4,6-TBP 的高溴化阻燃剂，包括十溴二苯醚（DBDPE）、2,4,6-三（2,4,6-三溴苯氧基）-1,3,5-三嗪（TTBP-TAZ）、1,2-双（2,4,6-三溴苯氧基）乙烷（BTBPE）和四溴双酚 A（TBBPA）的生物转化速率。我们的结果表明，TTBP-TAZ 在人肝微粒体和大鼠肝微粒体中迅速代谢，半衰期分别为 1.1 和 2.2 h，这表明 TTBP-TAZ 是 2,4,6-TBP 的潜在前体。相比之下，2,4,6-TBP 并没有在人肝微粒体和大鼠肝微粒体中作为 TBBPA、BTBPE 和 DBDPE 的生物转化产物形成。我们应用可疑和目标筛选方法来探索 TTBP-TAZ 的代谢途径，发现 2,4,6-TBP 是 TTBP-TAZ 的主要代谢产物，占所有形成代谢产物的 87%。这些体外结果通过体内实验进一步验证，在大鼠体内以 250mg/kg 体重/天的剂量暴露于 TTBP-TAZ 一周后，在大鼠血液和肝脏中分别检测到 270±110μg/g 和 50±14μg/g 脂质重量的 2,4,6-TBP。肝 mRNA 表达表明，TTBP-TAZ 显著激活芳香烃受体（AhR），并促进大鼠的脂肪变性（与对照组相比分别增加 18 倍和 28 倍）。
