Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis
Triazine herbicides inhibit relaxin signaling and disrupt nitric oxide homeostasis
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DOI：
10.1016/j.taap.2016.07.010
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发表时间：
2016-09-15
影响因子：
3.8
通讯作者：
Bae, Jeehyeon
中科院分区：
文献类型：
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作者：
Park, Si Eun;Lim, Sa Rang;Bae, Jeehyeon
三嗪类除草剂在世界范围内广泛使用，我们以前观察到小鼠母体暴露于西玛津（50或500 μ g/kg）导致其雌性后代的卵巢和子宫变小。在这里，我们调查了潜在的机制，可能占西玛津引起的生殖功能障碍。我们发现，母亲暴露后，西玛津被传递给后代，其存在于后代卵巢证明。对暴露于西玛津的后代的分析显示，松弛素激素受体，松弛素家族肽受体1（RXFP 1）的表达在卵巢和子宫中显著下降。此外，松弛素途径的下游靶基因，包括一氧化氮（NO）合酶2（Nos 2），Nos 3，基质金属肽酶9（Mmp 9），和血管内皮生长因子（Vegf）在他们的卵巢下调。此外，AKT和细胞外信号调节激酶（ERR）的水平和它们的磷酸化活性形式减少西玛津暴露的卵巢。在体外暴露的人卵巢颗粒细胞（KGN）和子宫内膜细胞（Hec-1A），以非常低的浓度（0.001至1 nM）的三嗪类药物，包括阿特拉津，特丁津，和丙嗪抑制NO的生产，同时减少RXFP 1，NOS 2和NOS 3。三嗪类化合物对NO释放的抑制作用依赖于RXFP 1、磷酸肌醇3-激酶（PI 3 K）/AKT和ERR。放射性配体结合实验也证实三嗪类化合物竞争性抑制松弛素与其受体的结合。因此，本研究表明，三嗪类除草剂作为内分泌干扰物通过干扰松弛素激素信号。因此，必须进一步评价其对人类健康的影响。(C)2016 Elsevier Inc. All rights reserved.
Triazines are herbicides that are widely used worldwide, and we previously observed that the maternal exposure of mice to simazine (50 or 500 mu g/kg) resulted in smaller ovaries and uteri of their female offspring. Here, we investigated the underlying mechanism that may account for the reproductive dysfunction induced by simazine. We found that following maternal exposure, simazine is transmitted to the offspring, as evidenced by its presence in the offspring ovaries. Analyses of the simazine-exposed offspring revealed that the expression of the relaxin hormone receptor, relaxin-family peptide receptor 1 (RXFP1), prominently decreased in their ovaries and uteri. In addition, downstream target genes of the relaxin pathway including nitric oxide (NO) synthase 2 (Nos2), Nos3, matrix metallopeptidase 9 (Mmp9), and vascular endothelial growth factor (Vegf) were downregulated in their ovaries. Moreover, AKT and extracellular signal-regulated kinases (ERR) levels and their phosphorylated active forms decreased in simazine-exposed ovaries. In vitro exposure of the human ovarian granulosa cells (KGN) and uterine endometrium cells (Hec-1A) to very low concentrations (0.001 to 1 nM) of triazines including atrazine, terbuthylazine, and propazine repressed NO production with a concurrent reduction in RXFP1, NOS2, and NOS3. The inhibitory action of triazines on NO release was dependent on RXFP1, phosphoinositol 3-kinase (PI3K)/AKT, and ERR. Radioligand-binding assay also confirmed that triazines competitively inhibited the binding of relaxin to its receptor. Therefore, the present study suggests that triazine herbicides act as endocrine disrupters by interfering with relaxin hormone signaling. Thus, further evaluation of their impact on human health is imperative. (C) 2016 Elsevier Inc. All rights reserved.