Cognitive dysfunction is one of the most prevalent persisting adverse effects reported in epidemiological studies of environmental toxicant exposure. Cognitive as well as emotional dysfunction have been found in children after developmental exposure to a wide variety of toxicants including pesticides, heavy metals and polycyclic and polyhalogenated hydrocarbons. Cognitive and emotional impairment are also seen in experimental animal models of developmental neurotoxic exposures, showing the cause-and-effect relationships between developmental toxicant exposure and persisting deficits in learning, memory, attention and anxiety. In our previous research in the Duke University Superfund Research Center (DUSRC) we have demonstrated the adverse effects of organophosphate (OP) pesticide exposures and persisting cognitive as well as emotional effects in rat models. These have been found to be related to OP induced disruptions of the transmitter systems acetylcholine (ACh) as well as the monoamines, dopamine (DA) and serotonin (5HT). These neurotransmitter systems have been shown in a wide variety of studies to play important roles in the neural bases of cognitive and emotional function. In the next phase of research with rats, we will determine how disruptions of ACh, DA and 5HT across different toxicant classes can impair cognitive and emotional function. We hypothesize that the persisting impacts of pesticides, flame retardants and polycyclic hydrocarbons on cognitive and emotional function involve an adverse outcome pathway converging on this neurotransmitter triad. Pharmacological challenges will determine causative relationships between ACh, DA and 5HT disruption and behavioral impairments. The neurochemical and pharmacological studies will inform our innovative development of therapeutic treatments of persistent cognitive and emotional deficits, directly helping people who have cognitive and emotional dysfunction due to early life neurotoxic exposure. We will complement the classic rat model with the innovative higher throughput zebrafish neurobehavioral model. We will determine conserved neurobehavioral pathways for the neurotoxic induction of cognitive and emotional impairment across toxicant classes. Showing that the ACh, DA and 5HT triad is conserved in the zebrafish model will establish a higher-throughput model to expand the number of chemical exposures that can be evaluated and related to mechanistic changes that underlie behavioral dysfunction. Understanding the neurotransmitter involvement in neurotoxicant induced cognitive and emotional dysfunction will not only provide a common basis for understanding the functional impairments caused by diverse toxicants, it also provides a basis for devising effective therapeutics for neurotoxic damage. This will bring generalized advances to the understanding of neurobehavioral toxicology based on underlying synaptic mechanisms rather than on the behavioral effects of individual chemicals. This multi-component biologically-based investigation progresses beyond classic adverse outcome pathways to an adverse outcome interacting systems approach.

Public Health Relevance

Project 1, ?Cholinergic and Monoaminergic Mechanisms of Persistent Neurobehavioral Toxicity? will provide important mechanistic information concerning the common neurobiological mechanism by which developmental toxicant exposure can cause persisting impairments in cognition and emotional function. This will provide the foundation for our development of therapeutic treatments using the rat model to help people overcome the persisting behavioral impairments from early life neurotoxicity. The zebrafish model will help in the more efficient screening of chemical for neurobehavioral risk, helping future generations to avoid such impairment.

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)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Oliveri, Anthony N; Ortiz, Erica; Levin, Edward D (2018) Developmental exposure to an organophosphate flame retardant alters later behavioral responses to dopamine antagonism in zebrafish larvae. Neurotoxicol Teratol 67:25-30
Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J (2018) Developmental neurotoxicity resulting from pharmacotherapy of preterm labor, modeled in vitro: Terbutaline and dexamethasone, separately and together. Toxicology 400-401:57-64
Lefèvre, Emilie; Bossa, Nathan; Gardner, Courtney M et al. (2018) Biochar and activated carbon act as promising amendments for promoting the microbial debromination of tetrabromobisphenol A. Water Res 128:102-110
Kollitz, Erin M; Kassotis, Christopher D; Hoffman, Kate et al. (2018) Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor ? Signaling. Environ Sci Technol :
Hartman, Jessica H; Smith, Latasha L; Gordon, Kacy L et al. (2018) Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci Rep 8:8359
Luz, Anthony L; Kassotis, Christopher D; Stapleton, Heather M et al. (2018) The high-production volume fungicide pyraclostrobin induces triglyceride accumulation associated with mitochondrial dysfunction, and promotes adipocyte differentiation independent of PPAR? activation, in 3T3-L1 cells. Toxicology 393:150-159
Day, D B; Xiang, J; Mo, J et al. (2018) Combined use of an electrostatic precipitator and a high-efficiency particulate air filter in building ventilation systems: Effects on cardiorespiratory health indicators in healthy adults. Indoor Air 28:360-372
Slotkin, Theodore A; Ko, Ashley; Seidler, Frederic J (2018) Does growth impairment underlie the adverse effects of dexamethasone on development of noradrenergic systems? Toxicology 408:11-21
Rock, Kylie D; Horman, Brian; Phillips, Allison L et al. (2018) EDC IMPACT: Molecular effects of developmental FM 550 exposure in Wistar rat placenta and fetal forebrain. Endocr Connect 7:305-324
Weinhouse, Caren; Truong, Lisa; Meyer, Joel N et al. (2018) Caenorhabditis elegans as an emerging model system in environmental epigenetics. Environ Mol Mutagen 59:560-575

Showing the most recent 10 out of 291 publications