Impact of 5‐azacytidine on rat decidual cell proliferation

Abstract

The DNA demethylating agent 5-azacytidine (5-azaC) has a teratogenic influence during rat development influencing both the embryo and the placenta. Our aim was to investigate its impact on early decidual cell proliferation before the formation of placenta. Thus, female Fischer rats received 5-azaC (5 mg/kg, i.p.) on the 2nd, 5th or 8th day of gestation and the decidual tissues were harvested on gestation day 9. They were then analysed immunohistochemically for expression of cell proliferation marker proliferating cell nuclear antigen (PCNA) in decidual cells and for global DNA methylation using the coupled restriction enzyme digestion, random amplification and pyrosequencing assays. We found that 5-azaC administered on the 5th and 8th (but not on 2nd) day of gestation led to increased PCNA expression in decidual cells compared with untreated controls. No significant changes in DNA methylation were detected, with either method, in any of the treated rat groups compared with untreated controls. Thus, we conclude that 5-azaC can stimulate decidual cell proliferation without simultaneously changing global DNA methylation level in treated cells.

A Free Radical Scavenger Ameliorates Teratogenic Activity of a DNA Hypomethylating Hematological Therapeutic

“…The reason for such improvement may be the known robustness to perturbations of the network structure that regulates early limb development [55]. Sometimes, 5azaC did not change DNA methylation level, although it changed developmental parameters such as proliferation [61]. Indeed, a recent review discusses many reasons why DNA methylation is still not a marker predictive of response to DNA hypomethylating therapy [62].…”

PregPred: an In-Silico Alternative to Animal Testing for Predicting Developmental Toxicity Potential

“…The models developed in this study are available within the PregPred web application In order to carry out an additional statistical validation of the PregPred app, we compiled and prepared a list of 6 additional drugs (not included in any of the QSAR datasets) with developmental toxicity data from various studies. [82][83][84][85][86] These were compounds with known developmental toxicity effects from studies that adhered to the criteria listed under "Merging the datasets and verification of nontoxic compounds." Then, we used PregPred to predict the developmental toxicity potential of these compounds (Fig 4).…”