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: β-adrenergic receptors (βARs) 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 βARs and m 2 -muscarinic receptors; the only change in the cerebellum was a decrease in βARs. 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.

Developmental neurotoxicity targeting hepatic and cardiac sympathetic innervation: Effects of organophosphates are distinct from those of glucocorticoids

“…Importantly, these effects are distinct from those of glucocorticoids, ruling out the possibility that they represent actions secondary to stress or disruption of the HPA axis. Further, the critical period, tissue selectivity and sex-specificity of the organophosphate effects on noradrenergic innervation seen here differ from those reported earlier for postsynaptic cell signaling [2,4,25,40]. Accordingly, hyperresponsiveness to hepatic gluconeogenic signals is not simply a compensation for presynaptic defects, nor are the effects on norepinephrine an adaptation to abnormalities in postsynaptic function.…”

“…Developing animals appear to be even more sensitive, showing persistent and late-emerging metabolic abnormalities after otherwise nonsymptomatic, early-life exposures; these culminate in deficits in carbohydrate and lipid metabolism resembling prediabetes, and in sensitization to the adverse effects of elevated dietary fat intake [19,20,36,40,42]. We were able to show that one of the triggers for the metabolic effects was the emergence of abnormal hepatic cell signaling, reflecting a potentiation of gluconeogenic signals mediated by β-adrenergic receptors (βARs) and glucagon receptors [2,4,25,40]. Further, we found that the magnitude of the organophosphate effects on hepatic function were as large as those seen after comparable developmental exposures to the glucocorticoid, dexamethasone [3]; excess glucocorticoids are considered to be among the most definitive contributors to the cardiovascular and metabolic components comprising the “fetal origins of adult disease” [6,11].…”

Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity?

“…We recently conducted comparative studies of the effects of diazinon and parathion to elicit long-term changes in hepatic adenylyl cyclase, paralleling our work on chlorpyrifos [37–40, 45]. We designed the dose regimens to produce a toxicodynamic match to the effects of chlorpyrifos, straddling the threshold for barely-detectable cholinesterase inhibition as the benchmark for dosing-equivalents.…”

“…Given recent concerns about human dietary choices, we focused on the role of saturated fat. In these studies, we exposed the animals to diazinon or parathion immediately after birth, using the same nonsymptomatic, low-level exposures as in our previous work; then, in adulthood, we switched half the animals to a diet where the 58% of the calories came from fat, and with a high proportion of saturated fat [45–48]. Animals exposed to either of the organophosphates showed much greater weight gain on the high-fat diet than did unexposed animals given the same dietary manipulation, again in association with prediabetic metabolic profiles; this did not reflect differences in food consumption, indicating a difference in fat metabolism between the exposed and unexposed groups.…”

Environmental chemical risk factors for Type 2 diabetes: an update

“…There is little known about possible mechanisms of long-term health effects of organophosphates, although laboratory studies provide some suggestive evidence. Rats exposed to organophosphates diazinon and parathion in the neonatal period demonstrated persistent changes in metabolism resembling prediabetes [137][138][139], and also exhibited greater weight gain on a high-fat diet compared with unexposed rats [139].…”