State Key Lab of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, Nanjing, Jiangsu, P.R.China.
PLoS One. 2013 Jun 7;8(6):e66301. doi: 10.1371/journal.pone.0066301. Print 2013.
2,2',4,4'-tetrabromodiphenyl ether (BDE47) is the dominant PBDE congener in humans, wildlife, and the environment. It has been reported to be metabolized by cytochrome P450 (CYP) enzymes. Still, the effects of BDE47 on spermatogenesis failure are attracting an increasing amount of attention. However, it is unclear whether CYP-mediated metabolism contributes to BDE47-induced reproductive toxicity.
The role of cytochrome P450 3A1 (CYP3A1) in the formation of oxidative metabolites of BDE47 and its induced spermatogenesis failure was investigated in SD rats. BDE47 significantly increased the expression and activity of CYP3A1 in rat liver, and 3-OH-BDE47, the major oxidative metabolite of BDE47, dose-dependently increased in rat liver, serum, and testis, which was aggravated by dexamethasone (DEX), an inducer of CYP3A1. Additionally, testicular 3-OH-BDE47 and reactive oxygen species (ROS) in seminiferous tubules increased especially when BDE47 was administered in combination with DEX, which was confirmed in GC-1 and GC-2 cells that 3-OH-BDE47 induced more ROS production and cell apoptosis via the upregulation of FAS/FASL, p-p53 and caspase 3. As a result, daily sperm production dose-dependently decreased, consistent with histological observations in giant cells and vacuolar spaces and increase in TUNEL-positive apoptotic germ cells.
CYP3A1-mediated metabolic activation of BDE47 and the active metabolite 3-OH-BDE47 and consequent ROS played an important role in reduction of spermatogenesis by germ cell apoptosis. Our study helps provide new insights into the mechanism of reproductive toxicity of environmental chemicals.
2,2',4,4'-四溴二苯醚（BDE47）是人类、野生动物和环境中主要的多溴二苯醚同系物。据报道，它可以被细胞色素 P450（CYP）酶代谢。尽管如此，BDE47 对精子发生失败的影响引起了越来越多的关注。然而，CYP 介导的代谢是否有助于 BDE47 诱导的生殖毒性尚不清楚。
本研究在 SD 大鼠中研究了细胞色素 P450 3A1（CYP3A1）在 BDE47 形成氧化代谢物及其诱导的精子发生失败中的作用。BDE47 显著增加了大鼠肝脏中 CYP3A1 的表达和活性，并且 BDE47 的主要氧化代谢物 3-OH-BDE47 剂量依赖性地增加在大鼠肝脏、血清和睾丸中，这一现象在 CYP3A1 诱导剂地塞米松（DEX）存在下更为严重。此外，睾丸 3-OH-BDE47 和生精小管中的活性氧（ROS）增加，尤其是当 BDE47 与 DEX 联合给药时，这在 GC-1 和 GC-2 细胞中得到证实，3-OH-BDE47 通过上调 FAS/FASL、p-p53 和 caspase 3 诱导更多的 ROS 产生和细胞凋亡。结果，每日精子生成剂量依赖性降低，与巨细胞和空泡的组织学观察一致，并增加 TUNEL 阳性凋亡生殖细胞。
CYP3A1 介导的 BDE47 代谢激活及其活性代谢物 3-OH-BDE47 以及随后的 ROS 通过生殖细胞凋亡在精子发生减少中起重要作用。我们的研究有助于提供对环境化学物质生殖毒性机制的新见解。
