Gestational oral low-dose estradiol-17β induces altered DNA methylation of CDKN2D and PSAT1 in embryos and adult offspring

Abstract

Endocrine disrupting chemicals (EDC) interfere with the natural hormone balance and may induce epigenetic changes through exposure during sensitive periods of development. In this study, the effects of short-term estradiol-17β (E2) exposure on various tissues of pregnant sows (F0) and on day 10 blastocysts (F1) were assessed. Intergenerational effects were investigated in the liver of 1-year old female offspring (F1). During gestation, sows were orally exposed to two low doses and a high dose of E2 (0.05, 10, and 1000 µg/kg body weight/day). In F0, perturbed tissue specific mRNA expression of cell cycle regulation and tumour suppressor genes was found at low and high dose exposure, being most pronounced in the endometrium and corpus luteum. The liver showed the most significant DNA hypomethylation in three target genes; CDKN2D, PSAT1, and RASSF1. For CDKN2D and PSAT1, differential methylation in blastocysts was similar as observed in the F0 liver. Whereas blastocysts showed hypomethylation, the liver of 1-year old offspring showed subtle, but significant hypermethylation. We show that the level of effect of estrogenic EDC, with the periconceptual period as a sensitive time window, is at much lower concentration than currently presumed and propose epigenetics as a sensitive novel risk assessment parameter.

Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

“…Previous investigations indicated that CpG islands in breast cancers are more likely to be demethylated in EREs [27]. A great body of evidence suggest that E2 induces gene expression via demethylating promoter or enhancer regions in the genome [27,59,60]. ERα plays a role in passive demethylation, via the ERE-mediated inhibition of DNMT1 expression.…”

Exposure of pregnant sows to low doses of estradiol-17β impacts on the transcriptome of the endometrium and the female preimplantation embryos†

“…Both sexes were affected, including a masculinization of the female offspring [14]. Although, we neither observed changes in genes involved in the process of modifying DNA methylation such as DNA methyltransferases nor obtained a GO term involving epigenetics in the DAVID analyses, a separate analysis of DNA methylation changes in the embryos and offspring showed that epigenetic marks have been affected in both [63]. Three genes were analyzed from which two were significantly affected in the embryos and offspring.…”

“…Due to management reasons, the sows underwent further breeding until this second part started, where the same sows were again allocated to the same treatment group as in the first part. All details about the complete study design have been published by van der Weijden et al [63] in the supplementary information. The second part (here named "study 2") was conducted as follows.…”

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome

“…Although these three modes of epigenetic regulation converge on a common cellular process (i.e., regulating gene expression), the mechanisms may act with different degrees of dynamic effects, strengths, and reversibility (Bintu et al 2016). Moreover, although they are often studied independently, it is becoming increasingly clear that there is extensive cross-talk between DNA methylation, histone modifications, and ncRNAs (Hanly et al 2018;Rose and Klose 2014;Vaissière et al 2008).…”