Disruption of Thyroid Hormone Receptor–Mediated Transcription and Thyroid Hormone–Induced Purkinje Cell Dendrite Arborization by Polybrominated Diphenyl Ethers

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Abstract

Background

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants and are becoming a ubiquitous environmental contaminant. Adverse effects in the developing brain are of great health concern.

Objective

We investigated the effect of PBDEs/hydroxylated PBDEs (OH-PBDEs) on thyroid hormone (TH) receptor (TR)-mediated transcription and on TH-induced dendrite arborization of cerebellar Purkinje cells.

Methods

We examined the effect of PBDEs/OH-PBDEs on TR action using a transient transfection-based reporter gene assay. TR–cofactor binding was studied by the mammalian two-hybrid assay, and TR–DNA [TH response element (TRE)] binding was examined by the liquid chemiluminescent DNA pull-down assay. Chimeric receptors generated from TR and glucocorticoid receptor (GR) were used to identify the functional domain of TR responsible for PBDE action. The change in dendrite arborization of the Purkinje cell in primary culture of newborn rat cerebellum was also examined.

Results

Several PBDE congeners suppressed TR-mediated transcription. The magnitude of suppression correlated with that of TR–TRE dissociation. PBDEs suppressed transcription of chimeric receptors containing the TR DNA binding domain (TR-DBD). We observed no such suppression with chimeras containing GR-DBD. In the cerebellar culture, PBDE significantly suppressed TH-induced Purkinje cell dendrite arborization.

Conclusions

Several PBDE congeners may disrupt the TH system by partial dissociation of TR from TRE acting through TR-DBD and, consequently, may disrupt normal brain development.

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Most cited references 42

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Brominated flame retardants: cause for concern?

Linda S. Birnbaum, Daniele F Staskal (2004)

Brominated flame retardants (BFRs) have routinely been added to consumer products for several decades in a successful effort to reduce fire-related injury and property damage. Recently, concern for this emerging class of chemicals has risen because of the occurrence of several classes of BFRs in the environment and in human biota. The widespread production and use of BFRs; strong evidence of increasing contamination of the environment, wildlife, and people; and limited knowledge of potential effects heighten the importance of identifying emerging issues associated with the use of BFRs. In this article, we briefly review scientific issues associated with the use of tetrabromobisphenol A, hexabromocyclododecane, and three commercial mixtures of polybrominated diphenyl ethers and discuss data gaps. Overall, the toxicology database is very limited; the current literature is incomplete and often conflicting. Available data, however, raise concern over the use of certain classes of brominated flame retardants.

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Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations.

Ronald Hites (2004)

Polybrominated diphenyl ethers (PBDEs) are used as flame retardants in many types of consumer products. Perhaps as a result of their widespread use and their lipophilicity, these compounds have become ubiquitous in the environment and in people. This review summarizes PBDE concentrations measured in several environmental media and analyzes these data in terms of relative concentrations, concentration trends, and congener profiles. In human blood, milk, and tissues, total PBDE levels have increased exponentially by a factor of approximately 100 during the last 30 yr; this is a doubling time of approximately 5 yr. The current PBDE concentrations in people from Europe are approximately 2 ng/g lipid, but the concentrations in people from the United States are much higher at approximately 35 ng/g lipid. Current PBDE concentrations in marine mammals from the Canadian Arctic are very low at approximately 5 ng/g lipid, but they have increased exponentially with a doubling time of approximately 7 yr. Marine mammals from the rest of the world have current PBDE levels of approximately 1000 ng/g lipid, and these concentrations have also increased exponentially with a doubling time of approximately 5 yr. Some birds' eggs from Sweden are also highly contaminated (at approximately 2000 ng/g lipid) and show PBDE doubling times of approximately 6 yr. Herring gull eggs from the Great Lakes region now have PBDE concentrations of approximately 7000 ng/g lipid, and these levels have doubled every approximately 3 yr. Fish from Europe have approximately 10 times lower PBDE concentrations than fish from North America. From these and other data, it is clear that the environment and people from North America are very much more contaminated with PBDEs as compared to Europe and that these PBDE levels have doubled every 4-6 yr. Analyses of the relative distributions of the most abundant PBDE congeners (using category averages and principal component analysis) indicated that these patterns cannot yet be used to assign sources to these pollutants.

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Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption.

Tong Zhou, Michele M Taylor, Michael Devito … (2002)

The objective of the current study was to characterize the effects of DE-71 (a commercial polybrominated diphenyl ether mixture containing mostly tetra- and penta-bromodiphenyl ethers) on thyroid hormones and hepatic enzyme activity in offspring, following perinatal maternal exposure. Primiparous Long-Evans rats were orally administered DE-71 (0, 1, 10, and 30 mg/kg/day) in corn oil from gestation day (GD) 6 to postnatal day (PND) 21. Serum and liver samples obtained from dams (GD 20 and PND 22), fetuses (GD 20), and offspring (PNDs 4, 14, 36, and 90) were analyzed for circulating total serum thyroxine (T(4)) and triiodothyronine (T(3)), or hepatic microsomal ethoxy- and pentoxy-resorufin-O-deethylase (EROD and PROD), and uridine diphosphoglucuronosyl transferase (UDPGT) activity. There were no significant effects of treatment on maternal body weight gain, litter size, or sex ratio, nor were there any effects on any measures of offspring viability or growth. Serum T(4) was reduced in a dose-dependent manner in fetuses on GD 20 (at least 15%) and offspring on PND 4 and PND 14 (50 and 64% maximal in the 10 and 30 mg/kg/day groups, respectively), but recovered to control levels by PND 36. Reduction in serum T(4) was also noted in GD 20 dams (48% at highest dose), as well as PND 22 dams (44% at highest dose). There was no significant effect of DE 71 on T(3) concentrations at any time in the dams or the offspring. Increased liver to body weight ratios in offspring were consistent with induction of EROD (maximal 95-fold), PROD (maximal 26-fold) or UDPGT (maximal 4.7-fold). Induction of PROD was similar in both dams and offspring; however, EROD and UDPGT induction were much greater in offspring compared to dams (EROD = 3.8-fold; UDPGT = 0.5-fold). These data support the conclusion that DE-71 is an endocrine disrupter in rats during development.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Print): February 2011

Publication date (Electronic): 22 September 2010

Volume: 119

Issue: 2

Pages: 168-175

Affiliations

[1 ] Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, Japan

[2 ] Department of Developmental Morphology, Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan

[3 ] Laboratory of Environmental Health Sciences, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

Author notes

Address correspondence to T. Iwasaki, Department of Integrative Physiology, Division of Biological Regulations, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. Telephone: 81-27-220-7923. Fax: 81-27-220-7926. E-mail: tiwasaki@ 123456med.gunma-u.ac.jp

The authors declare they have no actual or potential competing financial interests.

Article

Publisher ID: ehp-119-168

DOI: 10.1289/ehp.1002065

PMC ID: 3040602

PubMed ID: 20870570

SO-VID: f0a6eca2-a116-4018-a8aa-b13c6157e1d3

Copyright © This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.

Disruption of Thyroid Hormone Receptor–Mediated Transcription and Thyroid Hormone–Induced Purkinje Cell Dendrite Arborization by Polybrominated Diphenyl Ethers

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Abstract

Background

Objective

Methods

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Conclusions

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Global Health Next Generation Network

Most cited references 42

Brominated flame retardants: cause for concern?

Polybrominated diphenyl ethers in the environment and in people: a meta-analysis of concentrations.

Developmental exposure to brominated diphenyl ethers results in thyroid hormone disruption.

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