Aberrant methylation of multiple imprinted genes in embryos of tamoxifen-treated male rats

Abstract

Genomic imprinting is an epigenetic phenomenon known to regulate fetal growth and development. Studies from our laboratory have demonstrated that treatment of adult male rats with tamoxifen increased postimplantation loss around mid gestation. Further studies demonstrated the aberrant expression of transcripts of several imprinted genes in the resorbing embryos at days 11 and 13 of gestation including IGF2. In addition, decreased methylation at the Igf2-H19 imprint control region was observed in spermatozoa and in resorbing embryos sired by tamoxifen-treated males. In this study, methylation analysis of the imprinted genes, which were found to be differentially expressed, was done using EpiTYPER in the spermatozoa of tamoxifen-treated rats and in postimplantation embryos sired by tamoxifen-treated rats. Differentially methylated regions (DMRs) for most imprinted genes have not been identified in the rats. Hence, initial experiments were performed to identify the putative DMRs in the genes selected for the study. Increased methylation at CpG islands present in the putative DMRs of a number of imprinted genes was observed in the resorbing embryos sired by tamoxifen-treated male rats. This increase in methylation is associated with the downregulation of most of these genes at the transcript level in resorbing embryos. No change in the methylation status of these genes was observed in spermatozoa. These observations suggest that a deregulation of mechanisms protecting unmethylated alleles from a wave of de novo methylation occurs following implantation. Reproduction (2013) 146 155-168

Differential DNA methylation of the meiosis‐specific gene FKBP6 in testes of yak and cattle–yak hybrids

“…DNA methylation is an important epigenetic regulation influencing chromatin structure, DNA conformation, chromatin stability and the interaction between DNA and protein, which regulates gene expression and thus affects protein function (Jones, ; Kedia‐Mokashi, Kadam, Ankolkar, Dumasia, & Balasinor, ). Recently, research has focused on the relationship between DNA methylation and interspecific crosses leading to reproductive isolation, the generation of species and heterosis (Brown, Piccuillo, & O' Neill, ; Wang et al., ).…”

Sex-associated autosomal DNA methylation differences are wide-spread and stable throughout childhood

“…For example, injection of testosterone into female mice at birth induces male-associated methylation patterns in the bed nucleus of the stria terminalis (18). Fluctuations in estradiol levels and exposure to estradiol-imitating compounds like Bisphenol A (BPA) have also been linked to DNA methylation changes (19-21). The speed of these methylation changes suggests that sex hormones may interact directly with biological pathways responsible for creating and maintaining methylation marks (for a review, see (22)).…”

Counselling regarding paternal exposures: Can we do better?

“…Epigenetic changes have been confirmed in humans, with levels of DNA methylation reported to be raised in children conceived by intracytoplasmic sperm injection (ICSI) and also implicated in fetal alcohol spectrum disorders . Further to this, animal studies have shown a decrease in genomic methylation levels in epididymal sperm following chronic exposure to 5‐azacytidine, (a drug that alters DNA methylation), cyclophosphamide and tamoxifen . Despite these theoretical concerns, there is no human data supporting the premise that paternal exposure before or during pregnancy can increase the risk of birth defects or other adverse pregnancy outcomes (apart from infertility as outlined above).…”