Developmental neurotoxicity is one of the most sensitive outcomes of environmental chemical exposures. In past grant periods, we showed how exposures to otherwise unrelated agents can nevertheless produce similar outcomes because of convergence on adverse effects targeted towards specific neurotransmitter pathways, particularly acetylcholine (ACh) and serotonin (5HT). These are the same transmitters affected by common prenatal exposures to nicotine in maternal smoking, or dexamethasone as used in the therapy of preterm infants, raising the likelihood that these exposures create a subpopulation that will be sensitive to developmental neurotoxicants. In the current study, we will examine the ability of such treatments to sensitize the developing brain to subsequent exposure to chlorpyrifos, an organophosphate pesticide, and will then extend the approach to agents being evaluated in other projects and cores within the Center (polybrominated flame retardants, polyaromatic hydrocarbons). There are three aims: 1. To determine how fetal exposure to nicotine, in a model simulating nicotine levels in human smokers, sensitizes the developing brain to subsequent postnatal chlorpyrifos exposure. Neurotransmitter pathways and behavioral outcomes will be assessed in the rat. Mechanisms will be evaluated in three neural cell culture models (PCI2, mixed fetal neuronal and glial cultures, neural stem cell cultures). 2. To determine how fetal exposure to dexamethasone, in a model simulating its use in preterm labor, sensitizes the developing brain to subsequent postnatal chlorpyrifos exposure. The same approach is used as in Aim 1: studies in rats to determine neurotransmitter pathways underlying effects on behavioral outcomes, along with cell culture models to identify cellular mechanisms of injury. 3. To extend this approach to two suspected neurotoxicants of different classes, identified in other projects within the Center. PBDE99 as a representative of the polybrominated flame retardants and benzo[a]pyrene as a representative of the polycyclic aromatic hydrocarbons.
Environmental chemical exposures contribute to the increased incidence of neurodevelopmental disorders. This project explores sensitive subpopulations created by prenatal exposure to nicotine, modeling the effects of maternal smoking, and dexamethasone, the consensus treatment in preterm delivery. We will determine how otherwise unrelated neurotoxicants can converge on similar functional and behavioral outcomes.
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