title: Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4.
abstract: Atrazine, one of the most commonly used herbicides worldwide, acts as an endocrine disruptor, but the mechanism of its action has not been characterized. In this study, we show that atrazine rapidly increases cAMP levels in cultured rat pituitary and testicular Leydig cells in a concentration-dependent manner, but less effectively than 3-isobutyl-1-methylxanthine, a competitive non-specific inhibitor of phosphodiesterases (PDEs). In forskolin (an activator of adenylyl cyclase)- and probenecid (an inhibitor of cyclic nucleotide transporters)-treated cells, but not in 3-isobutyl-1-methylxanthine-treated cells, atrazine further increased cAMP levels, indicating that inhibition of PDEs accounts for accumulation of cAMP. In contrast to cAMP, atrazine did not alter cGMP levels, further indicating that it inhibits cAMP-specific PDEs. Atrazine-induced changes in cAMP levels were sufficient to stimulate prolactin release in pituitary cells and androgen production in Leydig cells, indicating that it acts as an endocrine disrupter both in cells that secrete by exocytosis of prestored hormones and in cells that secrete by de novo hormone synthesis. Rolipram abolished the stimulatory effect of atrazine on cAMP release in both cell types, suggesting that it acts as an inhibitor of PDE4s, isoforms whose mRNA transcripts dominate in pituitary and Leydig cells together with mRNA for PDE8A. In contrast, immortalized lacto-somatotrophs showed low expression of these mRNA transcripts and several fold higher cAMP levels compared to normal pituitary cells, and atrazine was unable to further increase cAMP levels. These results indicate that atrazine acts as a general endocrine disrupter by inhibiting cAMP-specific PDE4s.
authors.affiliation: Section on Cellular Signaling, Program in Developmental Neuroscience, NICHD, NIH, Bethesda, MD, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Kucka
authors.forename: Kristina
authors.initials: K
authors.lastname: Pogrmic-Majkic
authors.forename: Svetlana
authors.initials: S
authors.lastname: Fa
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
authors.forename: Radmila
authors.initials: R
authors.lastname: Kovacevic
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000262:Adenylyl Cyclases / Q000378:metabolism; D000728:Androgens / Q000378:metabolism; D000818:Animals; D001280:Atrazine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology; D052244:Endocrine Disruptors; D005089:Exocytosis / Q000187:drug effects; D006540:Herbicides / Q000633:toxicity*; D007985:Leydig Cells / Q000187:drug effects; D008297:Male; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects; D016133:Polymerase Chain Reaction; D011388:Prolactin / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000728:Androgens; D006063:Chorionic Gonadotropin; D052244:Endocrine Disruptors; D006540:Herbicides; D012333:RNA, Messenger; D011388:Prolactin; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; C521385:Pde4a protein, rat; D000262:Adenylyl Cyclases; D020889:Rolipram; D001280:Atrazine