ECE2009 Symposia Environmental pollutants as endocrine disruptors (4 abstracts)
Environmental chemical and thyroid signalling
Hongyan Dong 1 , Carole Yauk 1 , Mike Wade 1 , Andrew Williams 1 , Andrea Rowan-Carroll 1 , Alice Lee 1 , Priya Panchal 1 , Seo-Hee You 2 , R Thomas Zoeller 2 & Iain Lambert 3
1Health Canada, Ottawa, Ontario, Canada; 2University of Massachusetts, Amherst, Massachusetts, USA; 3Carleton University, Ottawa, Ontario, Canada.
Despite the recognized importance of thyroid hormones (TH) for normal brain development, little is known about the critical molecular events underlying this role. We investigated the molecular basis of TH action on the developing brain by: (1) comparing genome-wide gene expression patterns in the cerebellum of euthyroid, hypothyroid and hyperthyroid juvenile mice treated with 6-propyl thiouracil or mercapto-methylimidazole /perchlorate using DNA microarrays; and (2) investigating genes associated with TH receptor-binding sites in post-natal day 15 mouse cerebellum using chromatin immunoprecipitation combined with customized microarrays (ChIP-on-chip). The vast majority of genes that were altered in animals rendered hyper- or hypothyroid were involved in metabolism, apoptosis and REST (RE1-silencing transcription factor). The effect of TH on gene expression differed between males and females; hypothyroidism had a greater effect in male relative to female pups. Sex-specific effects were confirmed in rats treated with PTU. ChIP-on-chip identified 91 genes associated with TH receptor (TR) binding sites in their promoter regions or other genomic locations; 10 of the 13 binding fragments were confirmed with ChIP-PCR. A TRβ binding site upstream of the coding region of myelin associated glycoprotein was demonstrated to be TH responsive using a luciferase expression system. Motif searches did not identify any classical binding elements, indicating that not all TR binding sites conform to variations of the classical form. Genes that are directly-regulated by TH-TR may provide useful biomarkers of exposure to chemicals that operate through the TH-TR pathway (e.g., polychlorinated biphenyls or benzo(a)pyrene). These findings provide mechanistic insight into impaired neurodevelopment resulting from TH deficiency and a rich bioinformatics resource for developing a better understanding of TH function.
Volume 20
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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