Polychlorinated biphenyls (PCBs) remain a significant children?s health concern because they continue to contaminate food and indoor air, especially in schools across the United States. Non-dioxin-like (NDL) PCBs are implicated as environmental risk factors for neurodevelopmental disorders, and the parent grant addresses the critical need to understand the mechanisms by which NDL PCBs interact with genetic susceptibility factors to influence risk for developing these disorders. The long-term goal is to identify and understand factors that influence individual susceptibility to environmentally-mediated childhood disorders and, ultimately, to reduce the burden of these disorders to individuals and society. The objective of the proposed transdisciplinary and translational studies is to expand the scope of the current project to investigate a PCB congener (PCB 11), route of exposure (inhalation) and target organ (developing lung) not addressed in the parent grant. Additionally, this project will employ state-of-the art optogenetic techniques to translate in vitro observations of PCB effects on structural connectivity to functional connectivity in living animals. The consortium enables extensive collaborations among the PIs, including sharing of animal models, unique skills (optogenetics) and expertise (PCB toxicity, inhalation exposure, biodistribution, in vivo imaging).
The Specific Aims are to: (1) Test the hypothesis that the disposition and neurotoxicity of PCB 11 differs when maternal exposure occurs via the diet versus inhalation; (2) Use optogenetics to test the hypothesis that developmental exposure to PCB 11 alters sensorimotor learning coincident with changes in neural assemblies and patterns of synaptic connectivity in vivo; and (3) Test the hypothesis that exposure to PCB 11 alters conducting airway epithelial development, airway innervation and airway oxidant stress/responsiveness and that the response is influenced by route of exposure.
Aim 1 will fill a data gap on how the route of exposure influences PCB developmental neurotoxicity.
Aim 2 will determine whether PCB-induced changes in structural connectivity of primary cultured neurons translate to changes in functional connectivity in the intact living brain that impair behavior.
Aim 3 will determine whether PCB 11 interferes with the innervation and function of the developing lung, an understudied target in PCB toxicity. All three aims will generate novel toxicity data for PCB 11, a congener emerging as a prevalent PCB contaminant in complex environmental mixtures, including air and the serum of women at risk for having a child with a NDD. The proposed research is innovative because it uses state-of-the-art methods to: characterize how the route of PCB exposure affects developmental toxicity; confirm that in vitro observations of PCB effects on structural connectivity can be translated to physiological consequences in vivo; and evaluate the developing lung as a target organ for PCBs. These outcomes are significant because they will inform risk assessment for PCB 11, a prevalent environmental contaminant for which there is little toxicity data.

Public Health Relevance

Polychlorinated biphenyls (PCBs) remain a significant children?s health concern because of their in- advertent production by various modern industrial processes, and the persistence of neuroactive congeners in the environment, including in the human food supply, and in indoor air, including schools across the United States. The proposed transdisciplinary studies are relevant to public health because their successful completion will address critical data gaps regarding the influence of route of exposure on developmental toxicity, which will improve assessment of risks that PCBs pose to the de- veloping organism. Therefore, the proposed research is relevant to the NIEHS mission in that it seeks to develop fundamental knowledge about the effect of environmental stressors on living systems to en- hance health and reduce the burden of human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
3R01ES014901-09S1A1
Application #
9449769
Study Section
Special Emphasis Panel (ZES1)
Program Officer
Lawler, Cindy P
Project Start
2008-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Type
University-Wide
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Zheng, Jing; Chen, Juan; Zou, Xiaohan et al. (2018) Saikosaponin d causes apoptotic death of cultured neocortical neurons by increasing membrane permeability and elevating intracellular Ca2+ concentration. Neurotoxicology 70:112-121
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Sethi, Sunjay; Keil, Kimberly P; Lein, Pamela J (2018) 3,3'-Dichlorobiphenyl (PCB 11) promotes dendritic arborization in primary rat cortical neurons via a CREB-dependent mechanism. Arch Toxicol 92:3337-3345
Philippat, Claire; Barkoski, Jacqueline; Tancredi, Daniel J et al. (2018) Prenatal exposure to organophosphate pesticides and risk of autism spectrum disorders and other non-typical development at 3 years in a high-risk cohort. Int J Hyg Environ Health 221:548-555
Frank, Daniel F; Miller, Galen W; Connon, Richard E et al. (2017) Transcriptomic profiling of mTOR and ryanodine receptor signaling molecules in developing zebrafish in the absence and presence of PCB 95. PeerJ 5:e4106

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