title: Endocrine disrupting chemical atrazine causes degranulation through Gq/11 protein-coupled neurosteroid receptor in mast cells.
abstract: 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 microM 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 Galpha(q/11), pertussis toxin, phospholipase C inhibitor U-73122, inositol 1,4,5-triphosphate receptor inhibitor xestospongin C and Ca(2+) channel blocker lanthanum chloride. These analyses revealed that the degranulation is mediated by putative metabotropic neurosteroid receptor, G(q/11), phospholipase C and Ca(2+) 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.
authors.affiliation: Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Mizota
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000818:Animals; D001280:Atrazine / Q000633:toxicity*; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D052244:Endocrine Disruptors / Q000633:toxicity*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006540:Herbicides / Q000633:toxicity*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: D052244:Endocrine Disruptors; D006540:Herbicides; D043562:Receptors, G-Protein-Coupled; D001619:beta-N-Acetylhexosaminidases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D001280:Atrazine