BackgroundExposure to silver is increasing because of silver nanoparticles in consumer products.Objectives and methodsMany biological effects of silver entail actions of Ag+ (monovalent silver ions), so we used neuronotypic PC12 cells to evaluate the potential for silver to act as a developmental neurotoxicant, using chlorpyrifos (CPF), a pesticide known to evoke developmental neurotoxicity, as a positive control for comparison.ResultsIn undifferentiated cells, a 1-hr exposure to 10 μM Ag+ inhibited DNA synthesis more potently than did 50 μM CPF; it also impaired protein synthesis but to a lesser extent than its effect on DNA synthesis, indicating a preferential effect on cell replication. Longer exposures led to oxidative stress, loss of viability, and reduced numbers of cells. With the onset of cell differentiation, exposure to 10 μM Ag+ evoked even greater inhibition of DNA synthesis and more oxidative stress, selectively impaired neurite formation without suppressing overall cell growth, and preferentially suppressed development into the acetylcholine phenotype in favor of the dopamine phenotype. Lowering the exposure to 1 μM Ag+ reduced the net effect on undifferentiated cells. However, in differentiating cells, the lower concentration produced an entirely different pattern, enhancing cell numbers by suppressing ongoing cell death and impairing differentiation in parallel for both neurotransmitter phenotypes.ConclusionsOur results show that silver has the potential to evoke developmental neurotoxicity even more potently than known neurotoxicants, such as CPF, and that the spectrum of effects is likely to be substantially different at lower exposures that do not show signs of outright toxicity.

Developmental exposure of rats to the organophosphate (OP) pesticides leads to altered neurobehavioral function in juvenile and young adult stages. The current study was conducted to determine whether effects of neonatal parathion exposure on cognitive performance persist in older adult and aged rats, and the relationship of behavioral changes to underlying cholinergic and serotonergic mechanisms. We administered parathion to rat pups on postnatal days 1-4, at doses spanning the threshold for the initial signs of systemic toxicity and for barely-detectable cholinesterase inhibition (0.1 or 0.2 mg/kg/day). Beginning at 14 months of age and continuing until 19 months, the rats were trained in the 16-arm radial maze. Controls showed the normal sex difference in this spatial learning and memory task, with the males committing significantly fewer working memory errors than females. Neonatal parathion exposure eliminated the sex difference primarily by causing impairment in males. In association with the effects on cognitive performance, neonatal parathion exposure elicited widespread abnormalities in indices of serotonergic and cholinergic synaptic function, characterized by upregulation of 5HT 2 receptors and the 5HT transporter, deficits in choline acetyltransferase activity and nicotinic cholinergic receptors, and increases in hemicholinium-3 binding to the presynaptic choline transporter. Within-animal correlations between behavior and neurochemistry indicated a specific correlation between working memory performance and hippocampal hemicholinium-3 binding; parathion exposure destroyed this relationship. Like the behavioral effects, males showed greater effects of parathion on neurochemical parameters. This study demonstrates the sex-selective, long-term behavioral alterations caused by otherwise nontoxic neonatal exposure to parathion, with effects persisting into the beginning of senescence.

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.