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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Hazardous Substances Basic Research Grants Program (NIEHS) (P42)
Project #
Application #
Study Section
Special Emphasis Panel (ZES1-SET-V)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Brown, Daniel R; Clark, Bryan W; Garner, Lindsey V T et al. (2015) Zebrafish cardiotoxicity: the effects of CYP1A inhibition and AHR2 knockdown following exposure to weak aryl hydrocarbon receptor agonists. Environ Sci Pollut Res Int 22:8329-38
Slotkin, Theodore A; Card, Jennifer; Seidler, Frederic J (2014) Prenatal dexamethasone, as used in preterm labor, worsens the impact of postnatal chlorpyrifos exposure on serotonergic pathways. Brain Res Bull 100:44-54
Levin, Edward D; Cauley, Marty; Johnson, Joshua E et al. (2014) Prenatal dexamethasone augments the neurobehavioral teratology of chlorpyrifos: significance for maternal stress and preterm labor. Neurotoxicol Teratol 41:35-42
Pillai, Hari K; Fang, Mingliang; Beglov, Dmitri et al. (2014) Ligand binding and activation of PPAR? by Firemaster® 550: effects on adipogenesis and osteogenesis in vitro. Environ Health Perspect 122:1225-32
Bess, Amanda S; Ryde, Ian T; Hinton, David E et al. (2013) UVC-induced mitochondrial degradation via autophagy correlates with mtDNA damage removal in primary human fibroblasts. J Biochem Mol Toxicol 27:28-41
Dong, Wu; Macaulay, Laura J; Kwok, Kevin W H et al. (2013) Using whole mount in situ hybridization to examine thyroid hormone deiodinase expression in embryonic and larval zebrafish: a tool for examining OH-BDE toxicity to early life stages. Aquat Toxicol 132-133:190-9
Slotkin, Theodore A; Cooper, Ellen M; Stapleton, Heather M et al. (2013) Does thyroid disruption contribute to the developmental neurotoxicity of chlorpyrifos? Environ Toxicol Pharmacol 36:284-7
Clark, Bryan W; Cooper, Ellen M; Stapleton, Heather M et al. (2013) Compound- and mixture-specific differences in resistance to polycyclic aromatic hydrocarbons and PCB-126 among Fundulus heteroclitus subpopulations throughout the Elizabeth River estuary (Virginia, USA). Environ Sci Technol 47:10556-66
Garner, Lindsey V T; Brown, Daniel R; Di Giulio, Richard T (2013) Knockdown of AHR1A but not AHR1B exacerbates PAH and PCB-126 toxicity in zebrafish (Danio rerio) embryos. Aquat Toxicol 142-143:336-46
Zhao, Bin; Bohonowych, Jessica E S; Timme-Laragy, Alicia et al. (2013) Common commercial and consumer products contain activators of the aryl hydrocarbon (dioxin) receptor. PLoS One 8:e56860

Showing the most recent 10 out of 198 publications