Polychlorinated biphenyls (PCBs), and in particular neuroactive non-dioxin-like PCBs, remain a significant children's health concern because of their persistence and inadvertent production by various industrial processes that continue to contaminate food and indoor air, especially in schools across the United States. PCBs have been identified as probable environmental risk factors for neurodevelopmental disorders (NDD), which affect 1 in 10 children born in the United States. Most NDD have complex etiologies that likely involve multiple genetic loci interacting with exposures to environmental factors during critical periods of neurodevelopment. While many genes have been associated with increased risk of NDD, there remains a huge gap in understanding how multiple genes interact to modify neurodevelopment and even less clarity as to how genetic susceptibilities interact with environmental factors to amplify NDD risk. We will address these questions by testing the hypothesis that exposure during critical window(s) of neurodevelopment to a mixture of PCBs found in mothers at risk for having a child with NDD will potently disrupt neuronal connectivity via ryanodine receptor (RyR)-dependent mechanisms and the net outcome will be influenced by heritable mutations that alter the fidelity of Ca2+ signals essential for activity-dependent dendriic growth. This hypothesis derives from data generated during the previous funding cycle demonstrating sensitization of the ryanodine receptor (RyR) by PCB 95 activates calcium-dependent signaling pathways that promote dendritic arborization, and increased dendritic arborization is associated with impaired cognitive behavior in weanling mice exposed to PCB 95 in the maternal diet. The studies described in this application will use a PCB mixture that is relevant to human NDD based on data of PCB levels in the plasma of mothers participating in the MARBLES study at UC Davis, a longitudinal study for pregnant women with increased risk for having a child with NDD. This MARBLES mix will be tested for effects on morphometric, biochemical and functional indices of neuronal connectivity in unique mouse models that express an expansion repeat in the FMR1 gene, the single most frequent monogenetic cause of neurodevelopmental impairments, and a human RyR1 gain of function mutation, singly or in combination. These studies will address the critical need to better understand mechanisms by which non-dioxin-like PCBs cause developmental neurotoxicity, and will provide among the first mechanistic data regarding relevant interactions among genes and environment that increase NDD risk. This information will inform rational strategies for minimizing NDD risk by mitigating relevant exposures and will facilitate the development of mechanistically based screening platforms for identifying other gene-environment interactions likely to amplify adverse neurodevelopmental outcomes.

Public Health Relevance

Polychlorinated biphenyls (PCBs) remain a significant children's health concern because of the persistence of neuroactive congeners and their inadvertent production by various industrial processes that continue to contaminate indoor air, especially in schools across the United States. PCBs have been identified as probable environmental risk factors for neurodevelopmental disorders (NDD), but whether and how PCBs interact with genetic susceptibility factors to amplify vulnerability to NDD remains unanswered. We will address these questions by testing how a mixture of PCBs that mimics the profile of PCBs found in the plasma of women at increased risk for having a child with NDD influences neurodevelopment in unique mouse models that express heritable mutations associated with NDD. These studies will address the critical need to better understand mechanisms by which non-dioxin-like PCBs cause developmental neurotoxicity, and they will provide among the first mechanistic data regarding relevant interactions among genes and environment that increase NDD risk.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES014901-10
Application #
9600699
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Lawler, Cindy P
Project Start
2006-07-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
10
Fiscal Year
2019
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
Keil, Kimberly P; Miller, Galen W; Chen, Hao et al. (2018) PCB 95 promotes dendritic growth in primary rat hippocampal neurons via mTOR-dependent mechanisms. Arch Toxicol 92:3163-3173
Zheng, Jing; McKinnie, Shaun M K; El Gamal, Abrahim et al. (2018) Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum Ca2+ Dynamics. Environ Sci Technol 52:5469-5478
Chen, Xiaopeng; Walter, Kyla M; Miller, Galen W et al. (2018) Simultaneous quantification of T4, T3, rT3, 3,5-T2 and 3,3'-T2 in larval zebrafish (Danio rerio) as a model to study exposure to polychlorinated biphenyls. Biomed Chromatogr 32:e4185
Miller, Galen W; Chandrasekaran, Vidya; Yaghoobi, Bianca et al. (2018) Opportunities and challenges for using the zebrafish to study neuronal connectivity as an endpoint of developmental neurotoxicity. Neurotoxicology 67:102-111
Li, Xueshu; Holland, Erika B; Feng, Wei et al. (2018) Authentication of synthetic environmental contaminants and their (bio)transformation products in toxicology: polychlorinated biphenyls as an example. Environ Sci Pollut Res Int 25:16508-16521
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; Harvey, Danielle J et al. (2018) Bifenthrin causes transcriptomic alterations in mTOR and ryanodine receptor-dependent signaling and delayed hyperactivity in developing zebrafish (Danio rerio). Aquat Toxicol 200:50-61
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
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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