title: Changes in the levels of DNA methylation in testis and liver of SD rats neonatally exposed to 5-aza-2'-deoxycytidine and cadmium.
abstract: To investigate the changes in the levels of DNA methylation in the testis during development after neonatal transient exposure to DNA methyltransferase (DNMT) inhibitors, we orally administered Sprague-Dawley (SD) rats with 5-aza-2'-deoxycytidine (5-aza-CdR; 0.025 or 0.25 mg kg(-1)) or cadmium (Cd; 1, 2 or 4 mg kg(-1)) daily from days 3-7 postpartum (pp). Sperm numbers decreased at day 70 pp in all exposure groups. We then used a PCR-based assay, combined bisulfite restriction analysis (COBRA) and pyrosequencing to determine the degrees of DNA methylation. Both 5-aza-CdR and Cd reduced DNMT activity in vivo after 5 days' exposure at day 8 pp but not at day 70 pp. In contrast, the DNA methylation level of LINE-1 was not changed in the testis, either at day 8 pp or at day 70 pp. We observed increased apoptosis and an increase in the p53 mRNA level, accompanied by a decreased DNA methylation level in the p53 gene promoter region, at day 8 pp in testis for the 5-aza-CdR-exposed groups but not in the Cd-exposed group. The Cd-exposed group exhibited a degradation of seminiferous tubules and inhibition of a stepwise change in methylation in the coding region of c-fos in testis at day 70 pp. Because we observed toxic phenotype development accompanied by aberrant DNA methylation, DNA methylation may play a role in chemical induced testis damage, with different DNMT inhibitors affecting DNA methylation levels in gene- or stage-specific manner.
authors: School of Public Health, Fudan University and Key Laboratory of Public Health Safety, Ministry of Education, 130 DongAn Road, Shanghai, 200032, China.
authors: Hongyan
authors: H
authors: Zhu
authors: Keyong
authors: K
authors: Li
authors: Jiren
authors: J
authors: Liang
authors: Jie
authors: J
authors: Zhang
authors: Qing
authors: Q
authors: Wu
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000964:Antimetabolites, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000633:toxicity; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D019256:Cadmium Chloride / Q000633:toxicity*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects*; D000077209:Decitabine; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009929:Organ Size / Q000187:drug effects; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D013076:Sperm Count; D013737:Testis / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D019256:Cadmium Chloride; D001374:Azacitidine