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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.
Highlights
The environment can critically influence the complex regulation of the human body
25 genes were found to be differentially expressed in various tissues and treatment groups as compared to the control group (Fig. 2). These included 11 cell cycle regulators (CDKN2D, CDC42EP4, GADD45A, MGMT, GADD45B, CCDC34, CDC42EP3, CDKN1B, CCN1, CDC42BPA, and CDKN2C), 10 tumour suppressor genes (HIC1, BGN, RB1, Ras Association Domain Family Member 1 (RASSF1), LATS1, PTEN, P53, ITIH5, Phosphoserine Aminotransferase 1 (PSAT1), and ACTG2), two methylation specific genes (DNMT3a and MeCP2), one gene associated with aberrant expression in cancer (BPGM), and one gene functionally associated with the biosynthesis of sex steroids (HSD17B7)
The most downregulated differentially expressed genes (DEG) (12.5-fold) was the tumour suppressor gene hypermethylated in cancer 1 (HIC1), in skeletal muscle in the no observed effect level (NOEL) dose group
Summary
The environment can critically influence the complex regulation of the human body. Several environmentally present exogenous compounds are able to interfere with the endocrine system, possibly leading to adverse consequences to human health[1,2]. To explain observed cell proliferation and tumour initiation upon exposure to estrogenic substances, gene expression and epigenetic changes of cell cycle regulators, tumour suppressors, and methylation specific enzymes have been widely studied[11,12,13,14,15,16,17]. When a pregnant female F0 is exposed, the subsequent two generations, namely the F1 and F2, are directly exposed in utero or through the germline, respectively, and may exhibit intergenerational epigenetic www.nature.com/scientificreports/. A far greater concern than direct effects of EDC - with large implications for human health - is that alterations to the epigenome may not cause immediate phenotypic effects, but remain as molecular fingerprints; only leading to a phenotype long after exposure or in subsequent generations[23,24]. The current understanding of the link between E2 exposure during critical periods of early development and intergenerational epigenetic changes is limited
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