Persistent exposure of rats to 6-propyl-2-thiouracil (PTU) from birth resulted in decreases in plasma thyroid hormone (TH) levels and hepatic expression of catalase and CCAAT enhancer binding protein β (C/EBP-β). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-β showed an augmentation in the methylation level along with a change in methylation pattern of CpG islands in response to PTU treatment. PTU withdrawal on 30 days of birth restored TH levels and C/EBP-β to control rats in adulthood. Although catalase expression was restored to some extent in adult rats in response to PTU withdrawal, a permanent change in its promoter CpG methylation pattern was recorded. The results suggest that downregulation of adult hepatic catalase gene in response to persistent neonatal PTU exposure may not solely be attributed to thyroid-disrupting properties of PTU. It is possible that besides thyroid-disrupting behavior, PTU may impair expression of hepatic catalase by altering methylation pattern of its promoter.

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Background: Neonatal 6-n-propyl-2-thiouracil (PTU) exposure to male rats is reported to impair liver function in adulthood. However, the mechanism by which the drug impairs liver function is not well known. Objectives: The objectives of the study were to investigate the effects of neonatal exposure of PTU on the expression of DNA methyltransferases (DNMTs), methyl-DNA binding proteins (MBDs), Gadd45a, p53, and proliferating cell nuclear antigen (PCNA) in adult rat liver. Methods: The effects of neonatal transient (from birth to 30 days of age) and persistent (from birth to 90 days of age) treatment of PTU on DNA damage and on the expression of p53, PCNA, DNMTs, and MBDs were investigated at transcriptional and translational levels in male adult liver. Results: Persistent exposure to PTU from birth caused significant downregulation of expression of DNMT1 and DNMT3a and upregulation of DNMT3b, MBD4, and Gadd45a without any damage to DNA. Although MeCp2 transcripts were significantly low in the liver of adult rats after persistent exposure to PTU compared to controls, its translated products were significantly higher than in controls. The expression of p53 and PCNA in PTU-treated rats was significantly higher and lower, respectively, than that in control rats. Conclusion: The results suggest that neonatal exposure of male rats to PTU resulted in alteration in the expression of proteins that are associated with DNA methylation and genome stabilization in adult rat liver.

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