Journal Article

Endocrine Disrupting Chemical Atrazine Causes Degranulation through G<sub>q/11</sub> Protein-Coupled Neurosteroid Receptor in Mast Cells

Kaori Mizota and Hiroshi Ueda

in Toxicological Sciences

Volume 90, issue 2, pages 362-368
Published in print April 2006 | ISSN: 1096-6080
Published online December 2005 | e-ISSN: 1096-0929 | DOI: http://dx.doi.org/10.1093/toxsci/kfj087
Endocrine Disrupting Chemical Atrazine Causes Degranulation through Gq/11 Protein-Coupled Neurosteroid Receptor in Mast Cells

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We studied the effects of representative endocrine-disrupting chemicals on β-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 μM 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 β-hexosaminidase release was characterized by various inhibitors including antisense-oligodeoxynucleotide for Gαq/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, Gq/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 Gq/11-coupled neurosteroid receptor and phospholipase C.

Keywords: degranulation; endocrine-disrupting chemical; extravasation; mast cell; neurosteroid

Journal Article.  4801 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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