Zhao Tianxin, Tang Xiangliang, Li Dian, Zhao Jinglu, Zhou Rui, Shu Fangpeng, Jia Wei, Fu Wen, Xia Huimin, Liu Guochang
Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
Department of Pediatric Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China; Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China.
J Hazard Mater. 2022 Feb 15;424(Pt B):127547. doi: 10.1016/j.jhazmat.2021.127547. Epub 2021 Oct 20.
Polybrominated diphenyl ethers (PBDEs) are a widely used class of brominated flame retardants. Exposure to PBDEs could induce testicular damage in mammals, but the effects and potential mechanism of action of prenatal exposure to environmentally relevant PBDEs on testicular development remain unclear. For the in vivo study, pregnant ICR mice were exposed to environmentally relevant levels of 2,2',4,4',5-pentabromodiphenyl ether (PBDE-99), a major component of commercial PBDE mixtures. We found that the anogenital index and testicular organ coefficient were significantly decreased, the incidence of cryptorchidism was increased, and testicular histology was disturbed in male offspring. Transcriptomic profiling showed that steroidogenesis disorders were significant in all PBDE-99 exposure groups. The testosterone levels, expressions of testosterone regulators, and the number of CYP11A1-positive and 11β-HSD1-positive Leydig cells were significantly decreased after PBDE-99 exposure. For the in vitro study, TM3 Leydig cells were exposed to PBDE-99 at gradient concentrations. Transcriptomic profiling and validation experiments showed that PBDE-99 upregulated reactive oxygen species, activated the ERK1/2 pathway, inhibited the ubiquitination degradation pathway, and finally induced Leydig cell apoptosis. Cumulatively, these findings revealed that prenatal exposure to environmentally relevant levels of PBDE-99 leads to steroidogenesis disorders by inducing the apoptosis of Leydig cells, causing testicular dysgenesis.
多溴二苯醚（PBDEs）是一类广泛使用的溴化阻燃剂。暴露于PBDEs可导致哺乳动物睾丸损伤，但产前暴露于环境相关水平的PBDEs对睾丸发育的影响及潜在作用机制仍不清楚。在体内研究中，将怀孕的ICR小鼠暴露于环境相关水平的2,2',4,4',5-五溴二苯醚（PBDE-99），这是商用PBDE混合物的主要成分。我们发现，雄性后代的肛门生殖器指数和睾丸器官系数显著降低，隐睾症发病率增加，睾丸组织学受到干扰。转录组分析表明，所有PBDE-99暴露组均存在显著的类固醇生成紊乱。PBDE-99暴露后，睾酮水平、睾酮调节因子的表达以及CYP11A1阳性和11β-HSD1阳性睾丸间质细胞数量均显著降低。在体外研究中，将TM3睾丸间质细胞暴露于梯度浓度的PBDE-99。转录组分析和验证实验表明，PBDE-99上调活性氧，激活ERK1/2通路，抑制泛素化降解通路，最终诱导睾丸间质细胞凋亡。综上所述，这些发现揭示了产前暴露于环境相关水平的PBDE-99通过诱导睾丸间质细胞凋亡导致类固醇生成紊乱，从而引起睾丸发育异常。
