Reversal of chlorpyrifos neurobehavioral teratogenicity in mice by nicotine administration and neural stem cell transplantation.

Identifying the mechanisms underlying the adverse effects of developmental neurotoxicants enables the design of therapies that can potentially reverse neurobehavioral deficits in adulthood. We administered chlorpyrifos (CPF), a model organophosphate pesticide to pregnant mice and identified visuospatial deficits in adult offspring using performance in the Morris maze. We then evaluated two strategies to reverse the effects, nicotine administration and transplantation of neural stem cells. Daily administration of nicotine prior to behavioral testing did not alter maze performance by itself, but completely reversed the deficits evoked by prenatal CPF exposure. Similarly, control animals grafted with neural stem cells in adolescence did not show any alterations in behavioral performance as adults, but the grafts completely reversed the effects of prenatal CPF treatment. This study thus provides a model for the development and application of both pharmacologic and cell-based therapies to offset the effects of neurobehavioral teratogens.

Mechanism-based approaches for the reversal of drug neurobehavioral teratogenicity.

Understanding the mechanism of neurobehavioral teratogenicity is the primary prerequisite for reversal of the defect. Progress in such studies can be best achieved if the investigation focuses on behaviors related to a specific brain region and innervation. Our model focused on teratogen-induced deficits in hippocampus-related eight-arm and Morris maze behaviors. Different "cholinergic" teratogens, mainly heroin, induced both pre- and postsynaptic hyperactivity in the hippocampal cholinergic innervation that terminated in desensitization of Protein Kinase C (PKC) isoforms to cholinergic receptor stimulation. Understanding this mechanism enabled its reversal with a pharmacological therapy-nicotine infusion. Studies by others provided similar findings by targeting the deficits respective to the model investigated. Consistently, destruction of the A10-septal dopaminergic pathways that downregulate the septohippocampal cholinergic innervation ameliorated maze performance. Grafting of embryonic differentiated cholinergic cells or neural progenitors similarly reversed the biochemical/molecular alterations and the resulting deficits. Reversal therapies offer a model for the understanding of neurobehavioral teratogenicity and, clinically, offer a model for potential treatment of these deficits. Whereas neural progenitor grafting appears to be the most effective treatment, pharmacological reversal with nicotine infusion seems to possess the most feasible and immediate therapy for neurobehavioral birth defects produced by various teratogens, including drugs. This is true even though the effect of pharmacological therapies is diffuse, affecting multiple areas of the brain. "Everybody is talking about the weather but nobody does anything about it." (Mark Twain).