Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein-coupled neurosteroid receptor in mast cells
Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein-coupled neurosteroid receptor in mast cells
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DOI：
10.1093/toxsci/kfj087
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发表时间：
2006-04-01
影响因子：
3.8
通讯作者：
Ueda, H
中科院分区：
文献类型：
--
作者：
Mizota, K;Ueda, H
我们研究了具有代表性的内分泌干扰化学物质对肥大细胞释放β-氨基己糖苷酶的影响及其假定的神经类固醇受体参与。一些内分泌干扰化学品，如阿米三醇，二苯甲酮，双酚A，五氯苯酚和四溴苯酚A没有引起RBL-2 H3细胞的氨基己糖苷酶释放，但他们阻止了硫酸脱氢表雄酮，一种代表性的神经类固醇激动剂的释放。与此相反，阿特拉津，这是一种广泛使用的除草剂，引起快速和浓度依赖性脱粒的范围在10 nM和1 μ M之间的RBL-2 H3和腹膜肥大细胞。阿特拉津诱导的脱粒也通过Alexa 488-膜联蛋白V与磷脂酰丝氨酸的结合来评价，磷脂酰丝氨酸在脱粒过程中被外化，这些作用被BSA结合的（膜不可渗透的）孕酮（PROG-BSA）阻断。阿特拉津诱导的β-氨基己糖苷酶释放的特征在于各种抑制剂，包括G α（q/11）的反义寡核苷酸、百日咳毒素、磷脂酶C抑制剂U-73122、肌醇1，4，5-三磷酸受体抑制剂xestospongin C和Ca 2+通道阻断剂氯化镧。这些分析表明，脱粒是由假定的代谢型神经甾体受体，G（q/11），磷脂酶C和Ca 2+动员从细胞内商店介导的。在记录了孕酮受体调节阿特拉津诱导的肥大细胞脱颗粒体外，这种反应进行了评估，在小鼠中。阿特拉津注射于小鼠足垫引起疼痛反应，局部给予PROG-BSA或苯海拉明可拮抗阿特拉津引起的疼痛反应。阿特拉津还引起PROG-BSA可逆性血浆外渗。所有这些发现都有力地表明，除草剂阿特拉津通过激活假定的G（q/11）偶联神经类固醇受体和磷脂酶C发挥炎症活性。
We studied the effects of representative endocrine-disrupting chemicals on beta-hexosaminidase release from mast cells and their putative neurosteroid receptor involvement. Some endocrine-disrupting chemicals, such as amitrol, benzophenon, bisphenol A, pentachlorophenol, and tetrabromophenol A did not cause hexosaminidase release from RBL-2H3 cells, but they blocked the release by dehydroepiandrosterone sulfate, a representative neurosteroid agonist. On the contrary, atrazine, which is a widely used herbicide, caused a rapid and concentration-dependent degranulation in the range between 10 nM and 1 mu M in RBL-2H3 and peritoneal mast cells. Atrazine-induced degranulation was also evaluated by Alexa 488-annexin V binding to the phosphatidylserine, which is externalized during degranulation, and these actions were blocked by BSA-conjugated (membrane-impermeable) progesterone (PROG-BSA). The atrazine-induced beta-hexosaminidase release was characterized by various inhibitors including antisense-oligodeoxynucleotide for G alpha(q/11), pertussis toxin, phospholipase C inhibitor U-73122, inositol 1,4,5-triphosphate receptor inhibitor xestospongin C and Ca2+ channel blocker lanthanum chloride. These analyses revealed that the degranulation is mediated by putative metabotropic neurosteroid receptor, G(q/11), phospholipase C and Ca2+ mobilization from intracellular stores. Having documented progesterone receptor-modulation of atrazine-induced mast cell degranulation in vitro, this response was evaluated in mice. Atrazine caused pain responses when injected in the foot pads of mice, and they were antagonized by local administration of PROG-BSA or diphenhydramine. Atrazine also caused PROG-BSA-reversible plasma extravasation. All these findings strongly suggest that herbicide atrazine exerts inflammatory activity through activation of putative G(q/11)-coupled neurosteroid receptor and phospholipase C.