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Dongren Yang,^1* Kyung Ho Kim,^2* Andrew Phimister,² Adam D. Bachstetter,³ Thomas R. Ward,⁴ Robert W. Stackman,⁵ Ronald F. Mervis,³ Amy B. Wisniewski,⁶ Sabra L. Klein,⁷ Prasada Rao S. Kodavanti,⁴ Kim A. Anderson,⁸ Gary Wayman,⁹ Isaac N. Pessah,² and Pamela J. Lein^{1, 2,10}

¹Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon, USA; ²Veterinary Molecular Biosciences and Center for Children’s Environmental Health, University of California, Davis, California, USA; ³Neurostructural Research Labs and Center for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida, USA; ⁴Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA; ⁵Department of Psychology, Florida Atlantic University, Boca Raton, Florida, USA; ⁶Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA; ⁷Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA; ⁸Department of Environmental & Molecular Toxicology, Oregon State University, Corvallis, Oregon; USA; ⁹Department of Veterinary and Comparative Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Washington State University, Pullman, Washington, USA; ¹⁰Department of Environmental Health Science, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Abstract
Background: Neurodevelopmental disorders are associated with altered patterns of neuronal connectivity. A critical determinant of neuronal connectivity is the dendritic morphology of individual neurons, which is shaped by experience. The identification of environmental exposures that interfere with dendritic growth and plasticity may, therefore, provide insight into environmental risk factors for neurodevelopmental disorders.

Objective: We tested the hypothesis that polychlorinated biphenyls (PCBs) alter dendritic growth and/or plasticity by promoting the activity of ryanodine receptors (RyRs) .

Methods and results: The Morris water maze was used to induce experience-dependent neural plasticity in weanling rats exposed to either vehicle or Aroclor 1254 (A1254) in the maternal diet throughout gestation and lactation. Developmental A1254 exposure promoted dendritic growth in cerebellar Purkinje cells and neocortical pyramidal neurons among untrained animals but attenuated or reversed experience-dependent dendritic growth among maze-trained littermates. These structural changes coincided with subtle deficits in spatial learning and memory, increased [³H]-ryanodine binding sites and RyR expression in the cerebellum of untrained animals, and inhibition of training-induced RyR upregulation. A congener with potent RyR activity, PCB95, but not a congener with negligible RyR activity, PCB66, promoted dendritic growth in primary cortical neuron cultures and this effect was blocked by pharmacologic antagonism of RyR activity.

Conclusions: Developmental exposure to PCBs interferes with normal patterns of dendritic growth and plasticity, and these effects may be linked to changes in RyR expression and function. These findings identify PCBs as candidate environmental risk factors for neurodevelopmental disorders, especially in children with heritable deficits in calcium signaling.

Key words: dendrite, neurodevelopmental disorders, developmental neurotoxicity, PCBs, plasticity, ryanodine receptor. Environ Health Perspect 117:426–435 (2009) . doi:10.1289/ehp.11771 available via http://dx.doi.org/ [Online 12 September 2008]

Address correspondence to P.J. Lein, University of California Davis, Department of Molecular Biosciences, 1120 Haring Hall, One Shields Ave., Davis, CA 95616 USA. Telephone: (530) 752-1970. Fax: (530) 752-4698. E-mail: pjlein@ucdavis.edu

Supplemental Material is available online at http://www.ehponline.org/members/2008/11771/suppl.pdf

*These authors contributed equally to this work.

We thank L. Calizo, J. Girouard, and B. McKinney for assistance with the Morris water maze ; D. Sethajintanin, L. Quarles, and A. Ackerman for congener-specific PCB analyses ; and J. Harry and N. Zawia for comments on an earlier version of the manuscript.

The U.S. Environmental Protection Agency approved this work for publication ; however, contents do not necessarily reflect the agency’s views and policies nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

Support was provided by the National Institutes of Health (HD40936 and NS046649 to P.J.L., 1PO1ES11269 to I.N.P. and GM041292 to G.A.W.) , Autism Speaks (I.N.P.) , and the UC Davis M.I.N.D. Institute.

The authors declare they have no competing financial interests.

Received 7 June 2008 ; accepted 11 September 2008.