RESUMO
This study explores the effects of prenatal and postnatal (until weaning period) arsenic exposure given via pregnant females on Wistar rat neonates. Pregnant female rats were divided in four groups - control, low dose, moderate dose and high dose groups of sodium arsenite exposure during gestation and weaning period. Half of the neonates were sacrificed at day 1 of birth and other half at day 21 of birth. Cell cycle analysis in epidermal keratinocytes using flowcytometer revealed that there was a consistent increase in number of cells in G2/M phase from 0.04% in control group to 0.88%, 1.59% and 2.77% in low, moderate and high dose groups respectively for neonates sacrificed at day-1. Whereas, the increase in number of cells with increasing doses in G2/M phase of neonates sacrificed at day-21 was from 3.44% to 5.1%, 6.82%, and 9.17%. At postnatal day 21, mRNA expression of Cyclin A and B1, p53, Caspases 3, 7 and 9, and Bax were found to be up-regulated. Whereas that of Cyclin E, CDK 1 and 2 and Bcl2 were down regulated consistently in skin tissues of arsenic exposed groups.
Assuntos
Arsênio , Gravidez , Ratos , Feminino , Animais , Arsênio/toxicidade , Ratos Wistar , Pele , Ciclo Celular , Divisão CelularRESUMO
6-n-propyl-2-thiouracil (PTU), a thioamide drug, is used as an effective anti-thyroid agent to treat hyperthyroidism and Graves' disease. However, acute liver oxidative damage is an important side effect of the drug. In the present study, we report that PTU administration to rat induces hepatic epigenetic changes by upregulating expression of DNMT1, DNMT3a, DNMT3b, MBD4, MeCP2, p53 and Gadd45a and down-regulation of PCNA and C/EBP-ß. This is accompanied by decrease in the cell population and augmentation of cellular lipid peroxidation, an index of oxidative stress, in liver. On the other hand, co-administration of curcumin, a polyphenol extract from the rhizome of Curcuma longa L, along with PTU ameliorates PTU- induced oxidative stress and epigenetic parameters except for the expression of MBD4. Also, co-administration of curcumin with PTU resulted in restoration of hepatic cell population and histoarchitecture. The protective effect of curcumin to PTU-induced hepatotoxicity is attributed to its antioxidative properties.
Assuntos
Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteínas de Ciclo Celular/metabolismo , Curcumina/administração & dosagem , DNA (Citosina-5-)-Metiltransferases/metabolismo , Endodesoxirribonucleases/metabolismo , Epigênese Genética/efeitos dos fármacos , Hipotireoidismo/tratamento farmacológico , Proteínas Nucleares/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteínas de Ciclo Celular/genética , Curcuma/química , DNA (Citosina-5-)-Metiltransferases/genética , Endodesoxirribonucleases/genética , Humanos , Hipotireoidismo/induzido quimicamente , Hipotireoidismo/genética , Hipotireoidismo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas Nucleares/genética , Antígeno Nuclear de Célula em Proliferação/genética , Propiltiouracila/efeitos adversos , RatosRESUMO
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.
RESUMO
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 ß (C/EBP-ß). Catalase promoter region (-185 to +52) that contains binding sites for C/EBP-ß 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-ß 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.