Epigenetic effects of prenatal estradiol-17β exposure on the reproductive system of pigs

Kradolfer, David; Flöter, Veronika L.; Bick, Jochen T.; Fürst, Rainer W.; Rode, Kristina; Brehm, Ralph; Henning, Heiko; Waberski, Dagmar; Bauersachs, Stefan; Ulbrich, Susanne E.

doi:10.1016/j.mce.2016.04.005

Cited by 11 publications

(15 citation statements)

References 75 publications

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“…Fürst et al () demonstrated that the two low doses of E2, corresponding to the ADI and close to the NOEL, administered during the entire length of gestation, affected body weight development and body composition, respectively, in the offspring. Further low‐dose effects in the offspring were observed by analyzing the bone (Flöter et al, ) and prostate (Kradolfer et al, ). These lasting effects may be due to the altered endocrine environment during pregnancy, particularly due to exposure effects already occurring during the time of preimplantation when still low endogenous estrogen concentrations prevail.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we might observe a habituation or programming with subtle, but not detrimental effects toward the presence of estrogens. Certain alterations were observed in the pre‐ and postpubertal offspring (Flöter et al, ; Fürst et al, ; Kradolfer et al, ), which might also result from exposure during this very early time of development. Additionally, this leads to the possibility that administering estrogens on days 9 and 10 of pregnancy, might lead to changes in miRNA expression particularly at days 12–15 possibly involved in the drastic outcome of abortion (Geisert et al, ; Pope et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…Suitably, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) announced an acceptable daily intake (ADI) of 0.05 μg E2/kg body weight (bw) for humans in 1999 (JECFA, ). Only recently, we demonstrated that orally administered low doses of E2 to pigs during the entire period of pregnancy affected body composition in male offspring (Fürst et al, ), bone parameters in male and female offspring (Flöter et al, ), as well as gene expression in the prostate (Kradolfer et al, ). Especially prenatal development, starting as early as the preimplantation phase, has been demonstrated to be a sensitive period, when disruptive stimuli may induce long‐term consequences (Amstislavsky et al, ; Amstislavsky, Kizilova, Golubitsa, Vasilkova, & Eroschenko, ; Diamanti‐Kandarakis et al, ; Hochberg et al, ; Ma, Song, Das, Paria, & Dey, ).…”

Section: Introductionmentioning

confidence: 99%

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

Flöter

Lorenz

Kirchner

et al. 2018

Molecular Reproduction Devel

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Porcine conceptuses synthesize estrogens between Day 11 and 12 as signal for maternal recognition of pregnancy. A preimplantational estrogen exposure to pregnant gilts has been associated with embryonic losses and changes in endometrial mRNA expression. MicroRNAs (miRNAs) play a key role in the mRNA regulation by modulating the expression. Effects of estrogens on endometrial miRNAs have not been investigated in this context so far. Thus, we studied the endometrial expression profile of miRNAs in the pig at gestational Day 10 after daily estradiol-17β (E2) application starting at fertilization using either 0, 0.05 (ADI-acceptable daily intake), 10 (NOEL-no-observed-effect level) and 1,000 (high dose) µg E2/kg body weight/day, respectively. In endometrial homogenates, E2 (p < 0.001) and total estrogen concentrations (p < 0.001) were significantly increased, namely 28- and 160-fold, respectively, in the high dose group as compared to the control. Additionally, total estrogens were sixfold elevated in the NOEL group. Interestingly, high-throughput sequencing of small non-coding RNA libraries did not indicate any differentially expressed miRNAs between the treatment groups and the control group. The expression of 12 potential E2 target miRNAs investigated by RT-qPCR were equally unaffected. Thus, preimplantational E2 exposure resulted in significantly higher endometrial estrogen concentrations, but did not perturb the expression profile of endometrial miRNAs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Flöter

Lorenz

Kirchner

et al. 2018

Molecular Reproduction Devel

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“…The 24 transcripts contained several genes that have previously been associated with genital development, sex hormone actions, and/or male reproduction (Table 1) [ [21][22][23][24][25][26][27][28]. In particular, APOD is known as an androgentarget gene in human genital fibroblasts, and Cyp1b1 has been implicated in genital development of mice.…”

Section: Putative Androgen-regulated Transcriptsmentioning

confidence: 99%

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity

et al. 2019

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Endogenous and exogenous androgens induce masculinization of external genitalia through binding to the androgen receptor (AR). The target genes of androgens in external genitalia remain to be determined, although previous studies have shown that the apolipoprotein D gene (APOD) was significantly upregulated by dihydrotestosterone (DHT), the most potent androgen in humans. In the present study, we performed microarray analysis for genital skin fibroblasts obtained from four boys with buried penis (the control individuals) and a patient with partial androgen insensitivity syndrome (PAIS) due to a hypomorphic mutation in AR (the PAIS patient). We identified 24 transcripts that were upregulated or downregulated by DHT in all samples of control individuals and, to a lesser extent, in the sample of the PAIS patient. Differences between DHT-treated and-untreated samples were small; the results of 24 transcripts did not reach statistical significance. The 24 transcripts included CYP1B1, a gene possibly involved in the development of genital tubercle in mice, and APOD, as well as several genes that have been reported as androgen targets in prostate or other tissues. The results of this study indicate that androgen-mediated masculinization of external genitalia is unlikely to depend on massive transcriptional changes in specific AR target genes. Rather, minor transcriptional changes of several genes, and/or a complex molecular network may play a major role in penile development. Importantly, our data suggest the possible involvement of CYP1B1 in human genital development and confirm the clinical importance of APOD as a biomarker for AR function.

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“…Thus, our continuous E2 treatment starting with insemination was less disruptive as treatments only directly before implantation [21][22][23][24][25]. Still, lasting consequences were observed in the offspring, namely a bone density phenotype, a shift in body composition as well as gene expression differences mainly in the prostate [10,39,82].…”

Section: Discussionmentioning

confidence: 99%

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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Epigenetic effects of prenatal estradiol-17β exposure on the reproductive system of pigs

Cited by 11 publications

References 75 publications

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

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

Dihydrotestosterone induces minor transcriptional alterations in genital skin fibroblasts of children with and without androgen insensitivity

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

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