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Floeter, Veronika L.; Bauersachs, Stefan; Fuerst, Rainer W.; Krebs, Stefan; Blum, Helmut; Reichenbach, Myriam and Ulbrich, Susanne E. (2019): Exposure of pregnant sows to low doses of estradiol-17 beta impacts on the transcriptome of the endometrium and the female preimplantation embryos. In: Biology of Reproduction, Vol. 100, No. 3: pp. 624-640

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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 beta (E2) exposure 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 mu 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. Maternal oral low-dose estrogen exposure during the preimplantation period specifically targeted female embryos by inducing a male-like gene expression profile.

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