College of Pharmacy, Chung-Ang University, Seoul, Korea.
PLoS One. 2012;7(9):e44856. doi: 10.1371/journal.pone.0044856. Epub 2012 Sep 12.
Simazine is a triazine herbicide that is being widely applied worldwide and commonly detected in surface and groundwater. Despite its popular use in controlling weeds and algae, very limited information is available regarding its toxicity. In the present study, pregnant mice were orally exposed to low doses (0, 5, 50, or 500 µg/kg body weight per day) of simazine during gestation and lactation, during which no overt maternal toxic response was detected, and their offspring was assessed. Simazine-exposed male offspring showed decreased body, testicular, and epididymis weight, increased testicular apoptosis, and decreased sperm concentrations. Differentially-expressed genes in the testes of male offspring exposed to simazine were identified by DNA microarray, revealing 775 upregulated and 791 downregulated genes; among these, the relaxin-family peptide receptor 1 (Rxfp1), which is the receptor for relaxin hormone, was significantly downregulated. In addition, the expression of target genes in the relaxin pathway, including nitric oxide synthase 2 (Nos2) and Nos3, was significantly decreased in simazine-exposed F1 testes. Moreover, simazine inhibited NO release, and knockdown of Rxfp1 blocked the inhibitory action of simazine on NO production in testicular Leydig cells. Therefore, the present study provides a better understanding of the toxicities associated with the widely used herbicide simazine at environmentally relevant doses by demonstrating that maternal exposure interferes with the pleotropic relaxin-NO signaling pathway, impairing normal development and reproductive activity of male offspring.
西玛津是一种三嗪类除草剂，在世界范围内广泛应用，常被检测到存在于地表水和地下水中。尽管它在控制杂草和藻类方面被广泛使用，但关于其毒性的信息非常有限。在本研究中，怀孕的老鼠在妊娠期和哺乳期经口暴露于低剂量（0、5、50 或 500μg/kg 体重/天）的西玛津，在此期间未检测到明显的母体毒性反应，并对其后代进行了评估。暴露于西玛津的雄性子代的体重、睾丸和附睾重量降低，睾丸细胞凋亡增加，精子浓度降低。通过 DNA 微阵列鉴定暴露于西玛津的雄性子代睾丸中的差异表达基因，发现 775 个上调和 791 个下调基因；其中，松弛素家族肽受体 1（Rxfp1），即松弛素激素的受体，显著下调。此外，西玛津暴露的 F1 睾丸中松弛素通路的靶基因，包括一氧化氮合酶 2（Nos2）和 Nos3 的表达也显著降低。此外，西玛津抑制 NO 的释放，并且 Rxfp1 的敲低阻断了西玛津对睾丸间质细胞中 NO 产生的抑制作用。因此，本研究通过证明母体暴露干扰了广泛使用的除草剂西玛津在环境相关剂量下的多效性松弛素-NO 信号通路，提供了对其毒性的更好理解，从而损害了雄性子代的正常发育和生殖活动。
