Abstract
Evidence from previous studies suggests that the male reproductive system can be disrupted by fetal or neonatal exposure to diethylstilbestrol (DES). However, the molecular basis for this effect remains unclear. To evaluate the effects of DES on mouse spermatocytes and to explore its potential mechanism of action, the levels of DNA methyltransferases (DNMTs) and DNA methylation induced by DES were detected. The results showed that low doses of DES inhibited cell proliferation and cell cycle progression and induced apoptosis in GC-2 cells, an immortalized mouse pachytene spermatocyte-derived cell line, which reproduces primary cells responses to E2. Furthermore, global DNA methylation levels were increased and the expression levels of DNMTs were altered in DES-treated GC-2 cells. A total of 141 differentially methylated DNA sites were detected by microarray analysis. Rxra, an important component of the retinoic acid signaling pathway, and mybph, a RhoA pathway-related protein, were found to be hypermethylated, and Prkcd, an apoptosis-related protein, was hypomethylated. These results showed that low-dose DES was toxic to spermatocytes and that DNMT expression and DNA methylation were altered in DES-exposed cells. Taken together, these data demonstrate that DNA methylation likely plays an important role in mediating DES-induced spermatocyte toxicity in vitro.
Highlights
Diethylstilbestrol (DES) is an active synthetic estrogen that was used to prevent miscarriage and premature deliveries between 1947–1971[1]
The present study has provided several lines of evidence demonstrating that low doses of DES induce spermatocyte toxicity by triggering apoptosis, inhibiting proliferation, and affecting cell cycle progression
We have further found that DNA methylation might play an important role in DES-induced spermatocyte toxicity
Summary
Diethylstilbestrol (DES) is an active synthetic estrogen that was used to prevent miscarriage and premature deliveries between 1947–1971[1]. Almost immediately after uterine dysfunction and reproductive tissue cancers were discovered in young individuals exposed to DES in utero, the U.S Food and Drug Administration (FDA) banned its use for pregnancy support[2]. DES continues to be used to treat prostate and breast cancers[3]. It has been used as a feed supplement or subcutaneous implantation for cattle, sheep, and poultry to improve weight gain and produce leaner meat. As a result, it was present as a contaminant in food sources for years after the FDA banned its use in humans[4]. In addition to exposure to PLOS ONE | DOI:10.1371/journal.pone.0143143 November 20, 2015
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