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Polychiorinated Biphenyls 105 and 118 Form Thyroid Hormone Receptor Agonists after Cytochrome P4501A1 Activation in Rat Pituitary GH3 Cells.

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Title: Polychiorinated Biphenyls 105 and 118 Form Thyroid Hormone Receptor Agonists after Cytochrome P4501A1 Activation in Rat Pituitary GH3 Cells.
Authors: Kelly J. Gauger1,2, Giera, Stefanie1,3, Sharlin, David S.1, Bansal, Ruby4, Iannacone, Eric1,5, Zoeller, R. Thomas1,4 tzoeller@bjo.umass.edu
Source: Environmental Health Perspectives. Nov2007, Vol. 115 Issue 11, p1623-1630. 8p. 1 Diagram, 4 Charts, 5 Graphs.
Subject Terms: *Polychlorinated biphenyls, Thyroid hormones, Rats, Hormone receptors, Derivatization, Cytochrome P-450
Abstract: BACKGROUND: Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) signaling by reducing TH levels in blood, by exerting direct effects on TH receptors (TRs), or both. OBJECTIVE: Our objective was to identify individual PCBs that directly affect TH signaling by acting on the TR. METHODS: We administered a mixture of six PCB congeners based on their ortho substitution pattern, including PCBs 77 and 126 (non-ortho), PCBs 105 and 118 (mono-ortho), and PCBs 138 and 153 (di-ortho), to pregnant Sprague-Dawley rats from gestational days (G) 6 to 16. This mixture, or various combinations of the components, was also evaluated in a transient transfection system using GH3 cells. RESULTS: The mixture reduced serum TH levels in pregnant rats on G16 but simultaneously up-regulated the expression of malic enzyme in liver. It also functioned as a TR agonist in vitro; however, none of the individual PCB congeners comprising this mixture were active in this system. Using the aryl hydrocarbon receptor (AhR) antagonist cc-naphthoflavone, and the cytochrome P450 (CYP)1A1 antagonist ellipticine, we show that the effect of the mixture on the thyroid hormone response element required AhR and CYP1A1. CONCLUSIONS: We propose that PCB 126 induces CYP1A1 through the AhR in GH3 cells, and that CYP1A1 activates PCB 105 and/or 118 to a form a compound that acts as a TR agonist. These data suggest that some tissues may be especially vulnerable to PCBs interfering directly with TH signaling due to their capacity to express CYP1A1 in response to coplanar PCBs (or other dioxin-like molecules) if sufficient mono-ortho PCBs are present. [ABSTRACT FROM AUTHOR]
Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Polychiorinated Biphenyls 105 and 118 Form Thyroid Hormone Receptor Agonists after Cytochrome P4501A1 Activation in Rat Pituitary GH3 Cells.
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. Nov2007, Vol. 115 Issue 11, p1623-1630. 8p. 1 Diagram, 4 Charts, 5 Graphs.
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  Data: *<searchLink fieldCode="DE" term="%22Polychlorinated+biphenyls%22">Polychlorinated biphenyls</searchLink><br /><searchLink fieldCode="DE" term="%22Thyroid+hormones%22">Thyroid hormones</searchLink><br /><searchLink fieldCode="DE" term="%22Rats%22">Rats</searchLink><br /><searchLink fieldCode="DE" term="%22Hormone+receptors%22">Hormone receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Derivatization%22">Derivatization</searchLink><br /><searchLink fieldCode="DE" term="%22Cytochrome+P-450%22">Cytochrome P-450</searchLink>
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  Data: BACKGROUND: Polychlorinated biphenyls (PCBs) may interfere with thyroid hormone (TH) signaling by reducing TH levels in blood, by exerting direct effects on TH receptors (TRs), or both. OBJECTIVE: Our objective was to identify individual PCBs that directly affect TH signaling by acting on the TR. METHODS: We administered a mixture of six PCB congeners based on their ortho substitution pattern, including PCBs 77 and 126 (non-ortho), PCBs 105 and 118 (mono-ortho), and PCBs 138 and 153 (di-ortho), to pregnant Sprague-Dawley rats from gestational days (G) 6 to 16. This mixture, or various combinations of the components, was also evaluated in a transient transfection system using GH3 cells. RESULTS: The mixture reduced serum TH levels in pregnant rats on G16 but simultaneously up-regulated the expression of malic enzyme in liver. It also functioned as a TR agonist in vitro; however, none of the individual PCB congeners comprising this mixture were active in this system. Using the aryl hydrocarbon receptor (AhR) antagonist cc-naphthoflavone, and the cytochrome P450 (CYP)1A1 antagonist ellipticine, we show that the effect of the mixture on the thyroid hormone response element required AhR and CYP1A1. CONCLUSIONS: We propose that PCB 126 induces CYP1A1 through the AhR in GH3 cells, and that CYP1A1 activates PCB 105 and/or 118 to a form a compound that acts as a TR agonist. These data suggest that some tissues may be especially vulnerable to PCBs interfering directly with TH signaling due to their capacity to express CYP1A1 in response to coplanar PCBs (or other dioxin-like molecules) if sufficient mono-ortho PCBs are present. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
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  Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – SubjectFull: Thyroid hormones
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      – TitleFull: Polychiorinated Biphenyls 105 and 118 Form Thyroid Hormone Receptor Agonists after Cytochrome P4501A1 Activation in Rat Pituitary GH3 Cells.
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              Text: Nov2007
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