Thyroid Toxicology: Polychlorinated Biphenyls Exert Thyroid Hormone-Like Effects on Oligodendrocyte DevelopmentEPA Grant Number: FP916424
Title: Thyroid Toxicology: Polychlorinated Biphenyls Exert Thyroid Hormone-Like Effects on Oligodendrocyte Development
Investigators: Sharlin, David S.
Institution: University of Massachusetts - Amherst
EPA Project Officer: Manty, Dale
Project Period: January 1, 2004 through December 31, 2006
Project Amount: $100,096
RFA: STAR Graduate Fellowships (2004) RFA Text | Recipients Lists
Research Category: Fellowship - Toxicology , Academic Fellowships , Economics and Decision Sciences , Health Effects
The objective of this research project is to understand the mechanism by which maternal polychlorinated biphenyl (PCB) exposure can have a toxic effect on the development of oligodendrocytes in neonatal rat brain. Preliminary findings indicate that maternal PCB exposure causes an increase in the number of oligodendrocytes in the internal capsule of the rat brain measured on postnatal day 15 (P15), but a subsequent decline measured in the internal capsule of littermates on P30, relative to controls. It is well accepted that thyroid hormone (TH) acts on oligodendrocyte precursor cells and mature oligodendrocytes directing survival, differentiation, and myelination. Moreover, these developmental processes have been linked to specific thyroid hormone receptor (TR) isoforms. Therefore, these experiments are designed to test the hypothesis that individual PCB congeners can exert TH-like effects by interacting with specific TRs and cause aberrant oligodendrocyte development.
The complexity of TH action mediated through the various receptor isoforms cannot be easily dissected in vivo. Therefore, I plan to utilize the oligodendrocyte cell line, CG-4, and primary oligodendrocyte cultures derived from optic nerves of wildtype, TRα, TRβ knockout mice to investigate the TH-like effects of PCBs on oligodendrocyte development. The CG-4 cell line is a bipotential glial precursor capable of differentiating into either mature oligodendrocytes or type-2 astrocytes depending on the culture medium. These cells will be used to answer the following questions with regard to oligodendrocyte precursor proliferation and differentiation:
- Do PCBs increase proliferation of the oligodendrocyte progenitor population?
- Do PCBs predispose or inhibit bipotential glial precursors from forming oligodendrocytes?
If PCBs interact with TRs and alter TH signaling leading to events identified in initial experiments, then these effects should not be seen in cultures devoid of TRs. The proposed use of oligodendrocyte primary cultures derived from knockout mice will provide a mechanism to delineate specific TRs affected by PCBs. The goal is to determine if the effects of PCBs on oligodendrocyte development require TRs and which TRs may be contributing the deleterious effects. The ability of PCBs to effect oligodendrocyte development by interacting with TRs will be determined by investigating proliferation and differentiation, known endpoints of TH-action. If endpoints of TH-action are altered by PCBs in primary culture, followup experiments will be used to restore the expression of the knocked-out receptor. Full-length cDNA(s) encoding the desired receptor(s) will be transfected back to restore the expression.
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||Sharlin DS, Bansal R, Zoeller RT. Polychlorinated biphenyls exert selective effects on cellular composition of white matter in a manner inconsistent with thyroid hormone insufficiency. Endocrinology 2006;147(2):846-858.||