State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Medical College, Xiamen University, Xiamen, Fujian, China.
Toxicol Lett. 2014 Mar 21;225(3):413-21. doi: 10.1016/j.toxlet.2014.01.010. Epub 2014 Jan 18.
Tributyltin (TBT), one of the environmental pollutants, has been shown to impact the reproduction of animals. However, due to the lack of appropriate animal model, analysis of the affected molecular pathways in germ cells is lagging and has been particularly challenging. In the present study, we investigated the effects of tributyltin chloride (TBTCL) on the nematode Caenorhabditis elegans germline. We show that exposure of C. elegans to TBTCL causes significantly elevated level of sterility and embryonic lethality. TBTCL exposure results in an increased number of meiotic DNA double-strand breaks in germ cells, subsequently leading to activated DNA damage checkpoint. Exposing C. elegans to TBTCL causes dose- and time-dependent germline apoptosis. This apoptotic response was blocked in loss-of-function mutants of hus-1 (op241), mrt-2 (e2663) and p53/cep-1 (gk138), indicating that checkpoints and p53 are essential for mediating TBTCL-induced germ cell apoptosis. Moreover, TBTCL exposure can inhibit germ cell proliferation, which is also mediated by the conserved checkpoint pathway. We thereby propose that TBT exhibits its effects on the germline by inducing DNA damage and impaired maintenance of genomic integrity.
三丁基锡（TBT）是一种环境污染物，已被证明会影响动物的繁殖。然而，由于缺乏合适的动物模型，对生殖细胞中受影响的分子途径的分析滞后，这一直是一个特别具有挑战性的问题。在本研究中，我们研究了三丁基氯化锡（TBTCL）对线虫秀丽隐杆线虫生殖系的影响。我们发现，TBTCL 暴露会导致线虫的不育率和胚胎致死率显著升高。TBTCL 暴露会导致生殖细胞中减数分裂 DNA 双链断裂的数量增加，随后激活 DNA 损伤检查点。TBTCL 暴露会导致线虫生殖系细胞凋亡，且具有剂量和时间依赖性。在 hus-1（op241）、mrt-2（e2663）和 p53/cep-1（gk138）的功能丧失突变体中，这种凋亡反应被阻断，表明检查点和 p53 对于介导 TBTCL 诱导的生殖细胞凋亡是必需的。此外，TBTCL 暴露还可以抑制生殖细胞的增殖，这也受到保守检查点途径的调控。因此，我们提出 TBT 通过诱导 DNA 损伤和基因组完整性受损来发挥其对线虫生殖系的作用。
