Neonatal parathion exposure and interactions with a high-fat diet in adulthood: Adenylyl cyclase-mediated cell signaling in heart, liver and cerebellum

Abstract

Organophosphates are developmental neurotoxicants but recent evidence points to additional adverse effects on metabolism and cardiovascular function. One common mechanism is disrupted cell signaling mediated through cyclic AMP, targeting neurohumoral receptors, G-proteins and adenylyl cyclase (AC) itself. Earlier, we showed that neonatal parathion evokes later upregulation of the hepatic AC pathway in adolescence but that the effect wanes by young adulthood; nevertheless metabolic changes resembling prediabetes persist. Here, we administered parathion to neonatal rats (postnatal days 1-4, 0.1 or 0.2 mg/kg/day), straddling the threshold for cholinesterase inhibition, but we extended the studies to much later, 5 months of age. In addition, we investigated whether metabolic challenge imposed by consuming a high-fat diet for 7 weeks would exacerbate neonatal parathion's effects. Parathion alone increased the expression or function of G(i), thus reducing AC responses to fluoride. Receptors controlling AC activity were also affected: beta-adrenergic receptors (betaARs) in skeletal muscle were increased, whereas those in the heart were decreased, and the latter also showed an elevation of m(2)-muscarinic acetylcholine receptors, which inhibit AC. The high-fat diet also induced changes in AC signaling, enhancing the hepatic AC response to glucagon while impairing the cardiac response to fluoride or forskolin, and suppressing betaARs and m(2)-muscarinic receptors; the only change in the cerebellum was a decrease in betaARs. Although there were no significant interactions between neonatal parathion exposure and a high-fat diet, their convergent effects on the same signaling cascade indicate that early OP exposure, separately or combination with dietary factors, may contribute to the worldwide increase in the incidence of obesity and diabetes.

Figure 1

Effects of neonatal parathion exposure and subsequent adult consumption of a high-fat diet on cardiac AC activity: (A) basal AC, (B) isoproterenol-stimulated AC, (C) glucagon-stimulated AC, (D) fluoride-stimulated AC, (E) forskolin-stimulated AC. Data represent means and standard errors obtained from 6 animals in each group. Significant ANOVAs appear at the top of the corresponding panels. Panel (F) shows the simple main effect of diet, collapsed across all the other variables.

Figure 2

Effects of neonatal parathion exposure and subsequent adult consumption of a high-fat diet on hepatic AC activity: (A) basal AC, (B) isoproterenol-stimulated AC, (C) glucagon-stimulated AC, (D) fluoride-stimulated AC, (E) forskolin-stimulated AC. Data represent means and standard errors obtained from 6 animals in each group. Significant ANOVAs appear at the top of the corresponding panels. and, where justified by the interactions, lower-order tests are shown within panels. Panel (F) shows the simple main effects for the two measures showing significant changes, collapsed across all the other variables.

Figure 3

Effects of neonatal parathion exposure and subsequent adult consumption of a high-fat diet on receptor binding: (A) heart βARs, (B) liver βARs, (C) cerebellum βARs, (D) gastrocnemius βARs, (E) heart m₂AChRs. Data represent means and standard errors obtained from 6 animals in each group. Significant ANOVAs appear at the top of the corresponding panels, and, where justified by the interactions, lower-order tests are shown within panels.. Panel (F) shows the simple main effects for the measures showing significant changes, collapsed across all the other variables.