Neonatal Organophosphorus Pesticide Exposure Alters the Developmental Trajectory of Cell-Signaling Cascades Controlling Metabolism: Differential Effects of Diazinon and Parathion

Abstract

BackgroundOrganophosphorus pesticides (OPs) are developmental neurotoxicants but also produce lasting effects on metabolism.Objectives/methodsWe administered diazinon (DZN) or parathion (PRT) to rats on postnatal days 1–4 at doses straddling the threshold for systemic signs of exposure and assessed the effects on hepatic and cardiac cell signaling mediated through the adenylyl cyclase (AC) cascade.ResultsIn the liver, DZN elicited global sensitization, characterized by parallel up-regulation of AC activity itself and of the responses to stimulants acting at β-adrenergic receptors, glucagon receptors, or G-proteins. The effects intensified over the course from adolescence to adulthood. In contrast, PRT elicited up-regulation in adolescence that waned by adulthood. Superimposed on these general patterns were effects on glucagon receptor coupling to AC and on responses mediated through the Gi inhibitory protein. The effects on the liver were more substantial than those in the heart, which displayed only transient effects of DZN on AC function in adolescence and no significant effects of PRT. Furthermore, the hepatic effects were greater in magnitude than those in a brain region (cerebellum) that shares similar AC cascade elements.ConclusionsThese findings indicate that OPs alter the trajectory of hepatic cell signaling in a manner consistent with the observed emergence of prediabetes-like metabolic dysfunction. Notably, the various OPs differ in their net impact on peripheral AC signaling, making it unlikely that the effects on signaling reflect their shared property as cholinesterase inhibitors.

Environmental Endocrine Disruption of Energy Metabolism and Cardiovascular Risk

“…Catecholamines play a critical role in regulating blood pressure through their action on adrenergic G-protein coupled receptors, some of which signal through adenylate cyclase. 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].…”

“…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.…”

Toxic influence of organophosphate, carbamate, and organochlorine pesticides on cellular metabolism of lipids, proteins, and carbohydrates

“…In signaling cascade level, diazinon up-regulated adenyle cyclase activity, which is a response to stimulants acting on beta-adrenergic, glucagon, or G-protein receptors. 86 Hepatic injury. Histochemical alteration in the liver can affect metabolism of carbohydrates, lipids, and particularly proteins.…”

Diazinon and parathion diverge in their effects on development of noradrenergic systems

“…Although the determinations presented here are entirely new, the tissue samples were archived from several earlier studies (Adigun et al, 2010; Slotkin et al, 2008a, b, 2009a), so that no additional animals were actually used. All experiments were carried out humanely and with regard for alleviation of suffering, with protocols approved by the Institutional Animal Care and Use Committee and in accordance with all federal and state guidelines.…”