Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, China.
Faculty of Preventive Medicine, A Key Laboratory of Guangzhou Environmental Pollution and Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
Toxicol Sci. 2017 Dec 1;160(2):299-314. doi: 10.1093/toxsci/kfx182.
1,2-Dichloroethane (1,2-DCE) is a widely used chlorinated organic toxicant but little is known about the reproductive disorders induced by its excessive exposure. To reveal 1,2-DCE-induced male reproductive toxicity and to elucidate the underlying mechanisms, we exposed male National Institutes of Health Swiss mice to 1,2-DCE by inhalation at 0, 100, 350, and 700 mg/m3 for 6 h/day, for 1 and 4 weeks. Our findings showed a significant decrease in body weight with increased testis/body weight ratio, reduced sperm concentration and induced malformation of spermatozoa, and vacuolar degeneration of germ cells in the seminiferous tubules of testes in mice exposed to 1,2-DCE. Cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) and cAMP-response element modulator (CREM) were significantly inhibited by 1,2-DCE. This is consistent with the declines in the transducer of regulated CREB activity 1 and activator of CREM in testis, which results in the decrease in lactate dehydrogenase C and testis-specific kinase 1 in the testes. Moreover, the activation of p53 and Bax with the inhibition of Bcl-2 might be the reason for the upregulation of caspase-3 in the apoptosis, as detected by TdT-mediated dUTP nick-end labeling assay in the testes induced by 1,2-DCE. Finally, elevated testosterone levels were found along with increased levels of gonadotropin-releasing hormone, cAMP, luteinizing hormone (LH), and LH receptors in the testes. These findings suggest that 1,2-DCE inhibits CREM/CREB signaling cascade and subsequently induces apoptosis associated with p53 activation and mitochondrial dysfunction. This also results in induced malformation of spermatozoa, reduced sperm concentration, and pathological impairment of the testes.
1,2-二氯乙烷（1,2-DCE）是一种广泛使用的氯化有机有毒物质，但对于其过度暴露引起的生殖障碍知之甚少。为了揭示 1,2-DCE 引起的雄性生殖毒性，并阐明其潜在机制，我们通过吸入方式使雄性 NIH 瑞士小鼠暴露于 1,2-DCE 中，浓度分别为 0、100、350 和 700mg/m3，每天 6 小时，持续 1 或 4 周。我们的研究结果表明，暴露于 1,2-DCE 的雄性小鼠体重显著下降，睾丸/体重比降低，精子浓度降低，精子畸形，睾丸曲细精管中的生殖细胞出现空泡变性。环磷酸腺苷反应元件结合蛋白（CREB）和环磷酸腺苷反应元件调节蛋白（CREM）被 1,2-DCE 显著抑制。这与睾丸中调节 CREB 活性的转导器 1 和 CREM 激活剂的下降一致，导致乳酸脱氢酶 C 和睾丸特异性激酶 1 的减少。此外，p53 和 Bax 的激活以及 Bcl-2 的抑制可能是凋亡中 caspase-3 上调的原因，这是通过 TdT 介导的 dUTP 缺口末端标记法在 1,2-DCE 诱导的睾丸中检测到的。最后，在睾丸中发现睾酮水平升高，同时促性腺激素释放激素、cAMP、黄体生成素（LH）和 LH 受体水平升高。这些发现表明，1,2-DCE 抑制 CREM/CREB 信号级联，随后诱导与 p53 激活和线粒体功能障碍相关的细胞凋亡。这也导致精子畸形、精子浓度降低和睾丸病理损伤。
