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.

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

“…Organophosphorus pesticides, including diazinon and parathion, have been shown to up-regulate adenylate cyclase activity in a model of neonatal rat exposure [143]. Additionally, exposure to the herbicide atrazine has been shown to potentiate cAMP signaling in cultured rat pituitary cells [144]. Thus, EDC-induced sensitization of the cAMP pathway to catecholamines may potentiate their effects on blood pressure.…”

“…This suggests that individuals with exposure to these EDCs may experience differential efficacy or enhanced side effects from drugs metabolized by these enzymes, including key CVD drugs such as statins. Evidence that atrazine and organophosphate pesticides can potentiate the action of adenylate cyclase [143,144] may suggest enhanced efficacy for adrenergic blockers in the treatment of hypertension or the use of agents with anti-glucagon effects in the treatment of diabetes in patients exposed to these agents. Patients with known ongoing exposure to EDCs that inhibit 11β-HSD-2 may experience enhanced benefit with agents targeting the mineralocorticoid receptor (e.g.…”

Melatonin Reverses Fas, E2F-1 and Endoplasmic Reticulum Stress Mediated Apoptosis and Dysregulation of Autophagy Induced by the Herbicide Atrazine in Murine Splenocytes

“…As a potent endocrine disruptor, ATR targets endocrine, reproductive and nervous systems [4]–[6]. In addition, it also modulates immunity [7] due to the interaction between endocrine and immune systems [8].…”

Design of molecularly imprinted TiO2/carbon aerogel electrode for the photoelectrochemical determination of atrazine

“…Due to its low reactivity, slow degradation and moderate water solubility, atrazine is reasonably stable, mobile and persistent in the environment for a long period, and commonly found in soil, water and agriculture products [1]. Atrazine is considered as a potential contamination which can cause cancer and do harm to reproductive system, endocrine system, central nervous system and the immune system of human [2].…”