skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

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,more » 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. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward cAMP-specific PDEs was indicated by no changes in cGMP. ► Rolipram, a specific PDE4 inhibitor, also prevents stimulatory effects of atrazine. ► Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific PDE4.« less

Authors:
 [1]; ;  [2];  [1];  [2]
  1. Section on Cellular Signaling, Program in Developmental Neuroscience, NICHD, NIH, Bethesda, MD (United States)
  2. Laboratory for Ecotoxicology, Department of Biology and Ecology, University of Novi Sad, Faculty of Sciences, 21000 Novi Sad (Serbia)
Publication Date:
OSTI Identifier:
22215971
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 265; Journal Issue: 1; Other Information: Copyright (c) 2012 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ABUNDANCE; AMP; ANDROGENS; CONCENTRATION RATIO; ECOLOGICAL CONCENTRATION; INHIBITION; LTH; MESSENGER-RNA; PHOSPHODIESTERASES; RATS; SECRETION; TESTES; ATRAZINE

Citation Formats

Kucka, Marek, Pogrmic-Majkic, Kristina, Fa, Svetlana, Stojilkovic, Stanko S., and Kovacevic, Radmila, E-mail: radmila.kovacevic@dbe.uns.ac.rs. Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4. United States: N. p., 2012. Web. doi:10.1016/J.TAAP.2012.09.019.
Kucka, Marek, Pogrmic-Majkic, Kristina, Fa, Svetlana, Stojilkovic, Stanko S., & Kovacevic, Radmila, E-mail: radmila.kovacevic@dbe.uns.ac.rs. Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4. United States. doi:10.1016/J.TAAP.2012.09.019.
Kucka, Marek, Pogrmic-Majkic, Kristina, Fa, Svetlana, Stojilkovic, Stanko S., and Kovacevic, Radmila, E-mail: radmila.kovacevic@dbe.uns.ac.rs. Thu . "Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4". United States. doi:10.1016/J.TAAP.2012.09.019.
@article{osti_22215971,
title = {Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific phosphodiesterase-4},
author = {Kucka, Marek and Pogrmic-Majkic, Kristina and Fa, Svetlana and Stojilkovic, Stanko S. and Kovacevic, Radmila, E-mail: radmila.kovacevic@dbe.uns.ac.rs},
abstractNote = {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. -- Highlights: ► Atrazine stimulates cAMP accumulation in pituitary and Leydig cells. ► Atrazine also stimulates PRL and androgens secretion. ► Stimulatory effects of atrazine were abolished in cells with IBMX-inhibited PDEs. ► Atrazine specificity toward cAMP-specific PDEs was indicated by no changes in cGMP. ► Rolipram, a specific PDE4 inhibitor, also prevents stimulatory effects of atrazine. ► Atrazine acts as an endocrine disrupter by inhibiting cAMP-specific PDE4.},
doi = {10.1016/J.TAAP.2012.09.019},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 1,
volume = 265,
place = {United States},
year = {2012},
month = {11}
}