There is considerable public and regulatory concern that developmental exposures to polychlorinated biphenyls (PCBs) cause significant cognitive and behavioral deficits in children, but assessing the risks posed by these compounds has been difficult because the biological mechanisms underlying PCB effects on the developing nervous system have yet to be identified. We have recently demonstrated that developmental exposure of rodents to a commercial PCB mixture impairs dendritic growth and plasticity in vivo coincident with deficits in spatial learning. These effects on neurodevelopment and cognitive function correlate with altered expression and function of ryanodine receptors (RyR) within the central nervous system. RyR regulate calcium-dependent signaling pathways that have been implicated in activity-dependent dendritic growth, which is a critical determinant of neuronal connectivity in the developing brain. The goal of our study is to characterize the mechanisms and structure-activity relationship (SAR) of PCB developmental neurotoxicity by testing the hypothesis that non-coplanar PCBs alter dendritic growth and plasticity by disrupting RyR function.
The specific aims are to: 1. Test the relative contributions of RyR perturbation and thyroid hormone deficits in PCB effects on dendritic growth and plasticity in vivo; 2. Use primary cultures of hippocampal neurons to identify the molecular mechanisms mediating PCB effects on dendritic growth; 3. Determine how non-coplanar PCBs alter the function and expression of proteins that comprise calcium release units in cultured hippocampal neurons; 4. Determine whether heritable mutations in ryr1 and ryr2 that increase sensitivity to halogenated compounds in the human population increase susceptibility to PCB developmental neurotoxicity in mice expressing these mutations. These studies address the critical need to better understand mechanisms underlying PCB developmental neurotoxicity. Results will provide a rational basis for characterizing exposure risks and developing biomarkers of exposure and effect. Since RyR genes exhibit a significant number of expressed mutations and polymorphisms in the human population, data supporting RyR as a molecular target of PCBs in the developing nervous system will provide insights into genetic susceptibilities that magnify environmentally induced neurodevelopmental disorders.

Public Health Relevance

Polychlorinated biphenyls (PCBs) are persistent, widespread environmental contaminants, and there is compelling evidence that exposure of the developing brain to PCBs can cause learning and memory problems in children. But how PCBs cause these effects is not well understood. The goal of the proposed studies is to link known molecular effects of PCBs (activation of ryanodine receptors) to specific changes in brain development (disruption of dendritic growth). Establishing this link will provide a powerful means for predicting which of the 209 possible PCBs present the greatest risk to the developing brain and may provide novel insights into genetic susceptibilities that magnify environmentally induced neurodevelopmental disorders.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
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Special Emphasis Panel (ZRG1-IFCN-A (03))
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Lawler, Cindy P
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University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Wilson, Machelle D; Sethi, Sunjay; Lein, Pamela J et al. (2017) Valid statistical approaches for analyzing sholl data: Mixed effects versus simple linear models. J Neurosci Methods 279:33-43
Holland, Erika B; Goldstone, Jared V; Pessah, Isaac N et al. (2017) Ryanodine receptor and FK506 binding protein 1 in the Atlantic killifish (Fundulus heteroclitus): A phylogenetic and population-based comparison. Aquat Toxicol 192:105-115
Chen, Hao; Streifel, Karin M; Singh, Vikrant et al. (2017) From the Cover: BDE-47 and BDE-49 Inhibit Axonal Growth in Primary Rat Hippocampal Neuron-Glia Co-Cultures via Ryanodine Receptor-Dependent Mechanisms. Toxicol Sci 156:375-386
Zhang, Rui; Pessah, Isaac N (2017) Divergent Mechanisms Leading to Signaling Dysfunction in Embryonic Muscle by Bisphenol A and Tetrabromobisphenol A. Mol Pharmacol 91:428-436
Sethi, S; Chen, X; Kass, P H et al. (2017) Polychlorinated biphenyl and polybrominated diphenyl ether profiles in serum from cattle, sheep, and goats across California. Chemosphere 181:63-73
Aschner, Michael; Ceccatelli, Sandra; Daneshian, Mardas et al. (2017) Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: example lists and criteria for their selection and use. ALTEX 34:49-74
Kania-Korwel, Izabela; Lukasiewicz, Tracy; Barnhart, Christopher D et al. (2017) Editor's Highlight: Congener-Specific Disposition of Chiral Polychlorinated Biphenyls in Lactating Mice and Their Offspring: Implications for PCB Developmental Neurotoxicity. Toxicol Sci 158:101-115
Sethi, Sunjay; Keil, Kimberly P; Chen, Hao et al. (2017) Detection of 3,3'-Dichlorobiphenyl in Human Maternal Plasma and Its Effects on Axonal and Dendritic Growth in Primary Rat Neurons. Toxicol Sci 158:401-411
Bal-Price, Anna; Lein, Pamela J; Keil, Kimberly P et al. (2017) Developing and applying the adverse outcome pathway concept for understanding and predicting neurotoxicity. Neurotoxicology 59:240-255
Holland, Erika B; Feng, Wei; Zheng, Jing et al. (2017) An Extended Structure-Activity Relationship of Nondioxin-Like PCBs Evaluates and Supports Modeling Predictions and Identifies Picomolar Potency of PCB 202 Towards Ryanodine Receptors. Toxicol Sci 155:170-181

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