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Hepatic Gene Expression Changes in Hypothyroid Juvenile Mice: Characterization of a Novel Negative Thyroid-Responsive Element

Environmental and Occupational Toxicology (H.D., C.L.Y., A.L., G.R.D., M.G.W.) and Biostatistics and Epidemiology (A.W.) Divisions, Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada K1A 0L2

Address all correspondence and requests for reprints to: Carole L. Yauk, Environmental and Occupational Toxicology Division, Healthy Environments and Consumer Safety Branch, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0L2. E-mail: carole_yauk{at}hc-sc.gc.ca.

The molecular mechanisms involved in the response of developing mice to disruptions in maternal thyroid hormone (TH) homeostasis are poorly characterized. We used DNA microarrays to examine a broad spectrum of genes from the livers of mice rendered hypothyroid by treating pregnant mice from gestational d 13 to postnatal d 15 with 6-propyl-2-thiouracil in drinking water. Twenty-four individuals (one male and one female pup from six litters of control or 6-propyl-2-thiouracil treatment groups, respectively) were profiled using Agilent oligonucleotide microarrays. MAANOVA identified 96 differentially expressed genes (false discovery rate adjusted P < 0.1 and fold change > 2 in at least one gender). Of these, 72 genes encode proteins of known function, 15 of which had previously been identified as regulated by TH. Pathway analysis revealed these genes are involved in metabolism, development, cell proliferation, apoptosis, and signal transduction. An immediate-early response gene, Nr4a1 (nuclear receptor subfamily 4, group A, member 1), was up-regulated by 3-fold in hypothyroid juvenile mouse liver; treatment of HepG2 cells with T₃ resulted in down-regulation of Nr4a1. A potential thyroid response element –1218 to –1188 bp upstream of the promoter region of Nr4a1 was identified and demonstrated to bind TH receptor (TR)- and TRß. Point mutation or deletion of the sequence containing the potential Nr4a1-thyroid response element in transient gene expression studies resulted in both higher basal expression and loss of T₃ regulatory capacity, suggesting that this site is responsible for the negative regulation of gene expression by TR and TH.

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