Environmental toxicants and white matter composition: Understanding the role of thyroid disruption

It is becoming increasingly clear that chemicals present in the environment can interfere with thyroid hormone (TH) action and signaling. This is of great concern because TH is critical for normal brain development and recent evidence suggests that the developing brain is exquisitely sensitive to perturbations in TH action. Developmental exposure to the ubiquitous environmental toxicants, polychlorinated biphenyls (PCBs), is associated with neurological deficits that may be related to ability of these chemicals to alter TH-mediated brain development by interfering with TH action. Thyroid hormone plays an important role of is on the development and maturation of white matter tracts and its glial constituents. Because PCBs are suspected of interfering with thyroid hormone (TH) signaling in the developing brain, and because TH is important in white matter development, this dissertation set-out to critically test the hypothesis that developmental exposure to PCBs alters white matter development by interfering with TH action. In testing this hypothesis, we addressed four main questions: (1) Do PCBs perturb white matter development by causing a relative state of hypothyroidism? (2) Is the severity of TH insufficiency associated with different effects on white matter? (3) Do PCBs have a TH-like effect on white matter composition? (4) Do PCBs and TH insufficiency alter white matter by affecting the same signaling networks? We focused our experiments on postnatal day 15, a time when both myelination and TH levels are at their peak during development, and effects of hypothyroidism on white matter development have been documented. We evaluated the effect of developmental exposure to the commercial PCB mixture Aroclor 1254, TH insufficiency, and TH excess on markers of oligodendrocyte and astrocytes in two white matter tracts, the corpus callosum (CC) and anterior commissure (AC). The results described in this dissertation are consistent with the idea that developmental exposure to PCBs alters white matter composition independent of ability to interfere with TH action. Furthermore, the nature of the experimental designs used in testing our hypothesis provided fundamental information on the role of TH in the differentiation of oligodendrocytes and astrocyte from common precursors