title: Individual polychlorinated biphenyl (PCB) congeners produce tissue- and gene-specific effects on thyroid hormone signaling during development.
abstract: Polychlorinated biphenyls (PCB) are industrial chemicals linked to developmental deficits that may be caused in part by disrupting thyroid hormone (TH) action by either reducing serum TH or interacting directly with the TH receptor (TR). Individual PCB congeners can activate the TR in vitro when the metabolic enzyme cytochrome P4501A1 (CYP1A1) is induced, suggesting that specific PCB metabolites act as TR agonists. To test this hypothesis in vivo, we compared two combinations of PCB congeners that either activate the TR (PCB 105 and 118) or not (PCB 138 and 153) in the presence or absence of a PCB congener (PCB 126) that induces CYP1A1 in vitro. Aroclor 1254 was used as a positive control, and a group treated with propylthiouracil was included to characterize the effects of low serum TH. We monitored the effects on TH signaling in several peripheral tissues by measuring the mRNA expression of well-known TH-response genes in these tissues. Aroclor 1254 and its component PCB 105/118/126 reduced total T(4) to the same extent as that of propylthiouracil but increased the expression of some TH target genes in liver. This effect was strongly correlated with CYP1A1 expression supporting the hypothesis that metabolism is necessary. Effects were gene and tissue specific, indicating that tissue-specific metabolism is an important component of PCB disruption of TH action and that PCB metabolites interact in complex ways with the TR. These are essential mechanisms to consider when evaluating the health risks of contaminant exposures, for both PCB and other polycyclic compounds known to interact with nuclear hormone receptors.
authors.affiliation: Molecular and Cellular Biology Program, University of Massachusetts Amherst, Amherst, Massachusetts 01003, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Giera
authors.forename: Ruby
authors.initials: R
authors.lastname: Bansal
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Ortiz-Toro
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Taub
authors.forename: R Thomas
authors.initials: RT
authors.lastname: Zoeller
mesh_terms: D000818:Animals; D013956:Antithyroid Agents / Q000737:chemistry / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000235:genetics; D004785:Environmental Pollutants / Q000737:chemistry / Q000633:toxicity*; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D007774:Lactation; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D009928:Organ Specificity; D011078:Polychlorinated Biphenyls / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D013963:Thyroid Hormones / Q000097:blood; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D013956:Antithyroid Agents; D004785:Environmental Pollutants; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; C501478:Thrsp protein, rat; D013963:Thyroid Hormones; D014157:Transcription Factors; D011078:Polychlorinated Biphenyls; D019363:Cytochrome P-450 CYP1A1