Abstract
Prenatal exposure to diethylstilbestrol (DES) is known to cause increased susceptibility to a wide array of clinical disorders in humans. Previous studies from our laboratory demonstrated that prenatal exposure to DES induces thymic atrophy and apoptosis in thymus. In the current study, we investigated if such effects on the thymus result from alterations in the expression of microRNA (miR). To that end, we exposed pregnant C57BL/6 mice to DES, and miR profiles were studied in thymocytes of both the mother and fetuses on postnatal day 3 (GD17). Of the 609 mouse miRs examined by performing high-throughput miR arrays, we observed that there were 59 miRs that were altered that were common for both mothers and fetuses, whereas there were 107 miRs that were altered, specific to mothers only, and 101 miRs that were altered specific to fetuses only. Upon further analyses in the fetuses, we observed that DES-mediated changes in miRs expression may regulate genes involved in important functions such as apoptosis, autophagy, toxicity, and cancer. Of the miRs that showed decreased expression following DES treatment, miR-18b and miR-23a were found to possess complementary sequences and binding affinity for 3’UTR regions of Fas ligand (FasL) and Fas, respectively. Transfection studies confirmed that DES-mediated down-regulation of miR-18b and miR-23a led to increased expression of FasL and Fas. These data demonstrated that prenatal exposure to DES can cause alterations in miRs leading to changes in the expression of genes, specifically, miR-mediated increased expression in Fas and FasL causing apoptosis and thymic atrophy.
- Alternative splicing/RNA editing
- Acetylation/deacetylation
- Methylation
- Ubiquitination
- Signaling network analyses
- Apoptosis
- The American Society for Pharmacology and Experimental Therapeutics