Epigenetic inheritance of 5-Aza-2'-deoxycytidine (5-Aza-CdR) induced alterations.

摘要

The aim of this study were: (1) to investigate if 5-AZA-CdR would induce heritable alterations in development; (2) to determine 5-AZA-CdR effects on post-natal development and reproductive capacity; (3) to confirm if these effects were due to alterations in energy metabolism or in circulating IGF-I levels; and (4) to analyze the nature of the effect on male reproductive capacity.; To determine if 5-AZA-CdR would induce heritable alterations in development, pregnant mice were administered 1 mg/kg of 5-AZA-CdR, and three subsequent generations were examined. Leg and tail abnormalities, abnormal male mating behavior, retarded post-natal body development, cleft palate and global DNA hypermethylation were observed in exposed F1 mice. In the F2, cleft palate and increased levels of global DNA methylation were observed, while in the F3, cleft palate was evident.; Previous work determined genes whose expression is altered in developing limb buds exposed in utero by 5-AZA-CdR. Methylation status in abnormal palate tissue was determined to clarify if methylation of the promoter regions of developmentally related genes were affected. Statistically significant differences were not observed.; To elucidate the effects of 5-AZA-CdR on post-natal development and reproductive capacity, pregnant mice were administered 1 mg/kg of 5-AZA-CdR. Lower weights in treated F1 males and females were observed every recorded time. Effects were more pronounced with age.; 5-AZA-CdR F1 males and females and control mice were killed and levels of serum IGF-1, corticosterone and glucose were determined to investigate if growth retardation was a consequence of altered energy metabolism or serum IGF-1 levels induced by the treatment. However, statistically reduced levels of IGF-1 were observed in 5-AZA-CdR F1 males only.; To understand the effects on reproductive capacity, 5-AZA-CdR F1 males and females were mated with control females and males respectively. Reproductive capacity of in utero exposed male mice was adversely affected. However, testis histology, daily sperm production and testosterone levels were not. To clarify if the altered reproductive capacity was a behavioral phenomenon, a male sexual behavior test was conducted. A significantly decreased number of mounts and a significant increase of mount latency were observed in exposed mice. Additionally, although the treatment affected the male:female offspring ratio, presence of Sry gene (an indicator of Y chromosome presence) in exposed male mice was not affected by the treatment. (Abstract shortened by UMI.)