Individual Polychlorinated Biphenyl (PCB) Congeners Interact to Disrupt Thyroid Hormone Action During Development

Giera, Stefanie

Publication:
Individual Polychlorinated Biphenyl (PCB) Congeners Interact to Disrupt Thyroid Hormone Action During Development

dc.contributor.advisor	R. Thomas Zoeller
dc.contributor.advisor	Kelly J. Gauger
dc.contributor.advisor	Jerrold S. Meyer
dc.contributor.author	Giera, Stefanie
dc.contributor.department	University of Massachusetts - Amherst
dc.date	2023-09-23T09:24:25.000
dc.date.accessioned	2024-04-26T14:21:53Z
dc.date.available	2014-06-17T00:00:00Z
dc.date.issued	2012-09-01
dc.description.abstract	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.
dc.description.degree	Doctor of Philosophy (PhD)
dc.description.department	Molecular and Cellular Biology
dc.identifier.doi	https://doi.org/10.7275/5694863
dc.identifier.uri	https://hdl.handle.net/20.500.14394/14121
dc.relation.url	https://scholarworks.umass.edu/cgi/viewcontent.cgi?article=1382&context=dissertations_1&unstamped=1
dc.source.status	published
dc.subject	Biological sciences
dc.subject	Health and environmental sciences
dc.subject	Endocrine disruptors
dc.subject	Polychlorinated biphenyls
dc.subject	Thyroid hormones
dc.subject	Developmental Biology
dc.subject	Endocrinology
dc.subject	Molecular Biology
dc.title	Individual Polychlorinated Biphenyl (PCB) Congeners Interact to Disrupt Thyroid Hormone Action During Development
dc.type	campus
dc.type	article
dc.type	dissertation
digcom.contributor.author	Giera, Stefanie
digcom.date.embargo	2014-06-17T00:00:00-07:00
digcom.identifier	dissertations_1/385
digcom.identifier.contextkey	5694863
digcom.identifier.submissionpath	dissertations_1/385
dspace.entity.type	Publication