期刊
ENVIRONMENTAL HEALTH PERSPECTIVES
卷 120, 期 7, 页码 997-1002出版社
US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE
DOI: 10.1289/ehp.1104832
关键词
dendrites; developmental neurotoxicity; hippocampal neurons; neuronal connectivity; non-dioxin-like PCBs; ryanodine receptor
资金
- National Institutes of Health [R01 ES014901, R01 ES017425, P42 ES04699, R01 MH086032, P01 ES011269, T32 ES007060]
- U.S. Environmental Protection Agency [R833292, R829388]
- Hope for Depression Research Foundation
- J.B. Johnson Foundation
BACKGROUND: Aroclor 1254 (A1254) interferes with normal dendritic growth and plasticity in the developing rodent brain, but the mechanism(s) mediating this effect have yet to be established. Non-dioxin-like (NDL) polychlorinated biphenyls (PCBs) enhance the activity of ryanodine receptor (RyR) calcium ion (Ca2+) channels, which play a central role in regulating the spatiotemporal dynamics of intracellular Ca2+ signaling. Ca2+ signaling is a predominant factor in shaping dendritic arbors, but whether PCB potentiation of RyR activity influences dendritic growth is not known. OBJECTIVE: We determined whether RyR activity is required for PCB effects on dendritic growth. METHODS AND RESULTS: Golgi analysis of hippocampi from weanling rats confirmed that developmental exposure via the maternal diet to NDL PCB-95 (2,2',3,5'6-pentachlorobiphenyl), a potent RyR potentiator, phenocopies the dendrite-promoting effects of A1254. Dendritic growth in dissociated cultures of primary hippocampal neurons and in hippocampal slice cultures is similarly enhanced by PCB-95 but not by PCB-66 (2,3,4',4-tetrachlorobiphenyl),a congener with negligible effects on RyR activity. The dendrite-promoting effects of PCB-95 are evident at concentrations as low as 2 pM and are inhibited by either pharmacologic blockade or siRNA knockdown of RyRs. CONCLUSIONS: Our findings demonstrate that environmentally relevant levels of NDL PCBs modulate neuronal connectivity via RyR-dependent effects on dendritic arborization. In addition, these findings identify RyR channel dysregulation as a novel mechanism contributing to dysmorphic dendritogenesis associated with heritable and environmentally triggered neurodevelopmental disorders.
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