Impact of preimplantational oral low‐dose estradiol‐17β exposure on the endometrium: The role of miRNA

Flöter, Veronika L.; Lorenz, Anne-Kathrin; Kirchner, Benedikt; Pfaffl, Michael W.; Bauersachs, Stefan; Ulbrich, Susanne E.

doi:10.1002/mrd.22975

Cited by 10 publications

(11 citation statements)

References 56 publications

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“…Our studies suggested a similar regulatory relationship in the porcine endometrium [23]. However, neither endometrium [47] nor blastocyst [38] miRNAome was shown to be affected on day 10 of pregnancy by E2 administered daily to sows in different doses, even though its concentrations significantly increased in the endometrium.…”

Section: Mirnas At the Embryo-maternal Interfacesupporting

confidence: 55%

MiRNAs in the Peri-Implantation Period: Contribution to Embryo–Maternal Communication in Pigs

Kaczmarek

Najmula

Guzewska

et al. 2020

IJMS

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MicroRNAs (miRNAs) constitute a large family of noncoding RNAs, approximately 22 nucleotides long, which function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathophysiological processes in animals. To date, the regulatory roles of miRNAs in reproduction, such as fertilization, embryo development, implantation, and placenta formation, among others, have been demonstrated in numerous mammalian species, including domestic livestock such as pigs. Over the past years, it appeared that understanding the functions of miRNAs in mammalian reproduction can substantially improve our understanding of the biological challenges of successful reproductive performance. This review describes the current knowledge on miRNAs, specifically in relation to the peri-implantation period when the majority of embryonic mortality occurs in pigs. To present a broader picture of crucial peri-implantation events, we focus on the role of miRNA-processing machinery and miRNA–mRNA infarctions during the maternal recognition of pregnancy, leading to maintenance of the corpus luteum function and further embryo implantation. Furthermore, we summarize the current knowledge on cell-to-cell communication involving extracellular vesicles at the embryo–maternal interface in pigs. Finally, we discuss the potential of circulating miRNAs to serve as indicators of ongoing embryo–maternal crosstalk.

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Section: Mirnas At the Embryo-maternal Interfacesupporting

confidence: 55%

MiRNAs in the Peri-Implantation Period: Contribution to Embryo–Maternal Communication in Pigs

Kaczmarek

Najmula

Guzewska

et al. 2020

IJMS

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“…The increasing concentrations of E2 and/or its metabolites reaching the uterus as depicted in this manuscript and elsewhere [64], respectively, are one possible explanation for the expression differences found in the NOEL and the high dose group compared to the control animals. Despite a 160-fold increase in unconjugated total estrogens in the endometrium, there was no difference in the number of offspring at birth after treatment over the entire pregnancy [10].…”

Section: Discussionsupporting

confidence: 50%

“…In addition, the continuous E2 exposure did not lead to embryonic losses [10]. Interestingly, our preimplantation E2 exposure did not affect the endometrial miRNA expression profile [64].…”

Section: Discussionmentioning

confidence: 92%

“…Single embryos as well as tissue samples (from endometrium, skeletal muscle and heart) were shock frozen in liquid nitrogen and stored at -80 °C. As published earlier [64], all embryos were hatched spherical blastocysts according to the expected stage and contained an embryonic disc. There was neither significant difference in number (overall n = 230, p = 0.33) nor in size (2.2 mm ± 0.1 mm (mean ± SEM); p = 0.08) of the embryos.…”

Section: Study 2: Direct Maternal E2 Exposurementioning

confidence: 90%

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

Flöter

Bauersachs

Fürst

et al. 2018

Biology of Reproduction

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Maternal exposure to estrogens can induce long-term adverse effects in the offspring. The epigenetic programming may start as early as the period of preimplantation development. We analyzed the effects of gestational estradiol-17 (E2) exposure on blastocysts with two distinct low doses, corresponding to the acceptable daily intake "ADI" and close to the no-observed-effect level "NOEL," and a high dose (0.05, 10 and 1000 g E2/kg body weight daily, respectively). The E2 doses were orally applied to sows from insemination until sampling at day 10 of pregnancy and compared to carrier-treated controls leading to a significant increase in E2 in plasma, bile and selected somatic tissues including the endometrium in the high dose group. Conjugated and unconjugated E2 metabolites were as well elevated in the NOEL group. Although RNA-sequencing revealed a dose-dependent effect of 14, 17 and 27 differentially expressed genes (DEG) in the endometrium, single embryos were much more affected with 982 DEG in female blastocysts of the high dose group, while none were present in the corresponding male embryos. Moreover, the NOEL treatment caused 62 and 3 DEG in female and male embryos, respectively. Thus, we detected a perturbed sex-specific gene expression profile leading to a leveling of the transcriptome profiles of female and male embryos. The preimplantation period therefore demonstrates a vulnerable time window for estrogen exposure, potentially constituting the cause for lasting consequences. The molecular fingerprint of low-dose estrogen exposure on developing embryos warrants a careful revisit of effect level thresholds.

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“…A previous study has shown that highly expressed miRNAs may play vital roles in the regulation of embryo implantation [30]. The expression of top 20 most highly expressed known miRNAs in ULF exosomes was compared with that in endometrium [31] and embryo [29] collected on D10. Among these miRNAs, ssc-miR-21-5p was the most abundant in all libraries.…”

Section: Discussionmentioning

confidence: 99%

Small RNA-seq analysis of exosomes from porcine uterine luminal fluid during peri-implantation

Hua

Wang

Lian

et al. 2019

Preprint

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Background The exosomes of uterine luminal fluid (ULF) mediate intrauterine communication between conceptus and uterus in pigs. The small RNAs of ULF exosomes are widely recognized as important factors that influence embryonic implantation in humans, mice, cattle and sheep. Therefore, it can be hypothesized that small RNAs of ULF exosomes are essential for implantation in pigs. Results Cupshaped exosomes (diameters: 40-160 nm) of porcine ULF were isolated and characterized, and then PKH67 stained exosomes were taken up by endometrial epithelial cells and porcine trophectoderm cells. The expression of small RNAs in these exosomes on days 10 (D10), 13 (D13) and 18 (D18) of pregnancy was comprehensively profiled through sequencing. From nine libraries, a total of 152 known microRNAs (miRNAs), 43 novel miRNAs and 145 novel Piwi-interacting RNAs (piRNAs) were identified. Among these small RNAs, ssc-miR-21-5p, ssc-let-7a, ssc-let-7i-5p and ssc-let-7g were differentially and highly expressed during the three stages. Hierarchical cluster analysis and principal component analysis suggested that the expression profiles of small RNAs in D13 group were different from those in D10 and D18 groups. Bioinformatics analysis showed that the miRNAs differentially expressed in the comparisons between D10 and D13, D13 and D18, and D10 and D18 groups were involved in important molecular functions and pathways such as "G-protein coupled receptor activity" and "Insulin signaling pathway". Conclusions Our results reveal that porcine ULF exosomes contain various small RNAs with potentially vital effects on implantation. This research also provides resources for studies of miRNAs and piRNAs in the cross-talk between embryo and endometrium. BackgroundPrevious studies have indicated that the majority of pre-natal losses occur during the periimplantation period in pigs [1,2]. During this period, the porcine blastocyst expands from 0.5-1 mm in diameter at hatching to 2-mm spheres on day 10 of pregnancy (D10) and begins to rapidly elongate into tubular and filamentous shapes on day 11 or 12 [3,4]. The conceptus starts to attach to the surface of maternal endometrium at day 13 of pregnancy (D13) and the attachment is usually completed between days 18 (D18) and 24 of pregnancy [5,6]. The synchronous communication between conceptus and uterus exerts strong influence on embryo implantation [7]. Furthermore, the

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Impact of preimplantational oral low‐dose estradiol‐17β exposure on the endometrium: The role of miRNA

Cited by 10 publications

References 56 publications

MiRNAs in the Peri-Implantation Period: Contribution to Embryo–Maternal Communication in Pigs

MiRNAs in the Peri-Implantation Period: Contribution to Embryo–Maternal Communication in Pigs

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

Small RNA-seq analysis of exosomes from porcine uterine luminal fluid during peri-implantation

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