Nearly 20% of U.S. children are reported to have neurobehavioral deficits in part linked to environmental exposure to industrial chemicals like polychlorinated biphenyls (PCBs). PCB exposure is associated with neurotoxicity including both reduced IQ and response inhibition. PCBs may affect normal brain development by acting on the thyroid hormone (TH) system, either by reducing serum TH levels and/or by interfering with TH receptors (TRs). A critical endpoint, dependent upon sufficient TH, is maturation of oligodendrocytes during development and therefore subject to disruption by PCBs. Due to the complexity of the brain we used both in vitro and in vivo approaches to understand the mechanism of PCBs interfering with TH action. Previous work in our lab has demonstrated that metabolism of PCB congeners is necessary for them to act on the TR in vitro . In neonatal rat livers, we evaluated the TR-agonistic properties of PCBs on TR-dependent gene expression in the presence and absence of metabolism. We found that expression of TH target genes in PCB-exposed livers varied between different congener combinations and was independent of the PCB-induced reduction in circulating T 4 levels. Further evaluation of global changes in gene expression between a commercial PCB mixture A1254 and hypothyroidism revealed that only 25% of TH-responsive genes also respond to PCB exposure. Individual congeners accounted for only half of the A1254 effects on TH-regulated genes, suggesting that unidentified congeners or metabolites are affecting TH action. In the neonatal brain, we evaluated the congener-specific effects on a TH- sensitive endpoint during development, the white matter cell numbers in the corpus callosum (CC). In the CC, hypothyroidism decreased oligodendrocytes by about 80%. A1254 achieved a 35% reduction in oligodendrocytes; an effect mediated by a mixture of individual congeners. Hypothyroidism and A1254 exposure increased astrocyte numbers by 30%, but the effect of A1254 seems to be mediated by yet another subset of PCB congeners independent of the TH serum levels. PCB exposure has a differential effect on glial cell differentiation in the CC compared to hypothyroidism that is congener-specific as well as region-specific. Both changes in glia cells during development are not observed in adulthood. The disruption of glia cell ratio in the CC by PCBs could lead to diminished CNS functionality during a critical window of neonatal development.