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Spontaneous fetal loss caused by placental thrombosis in estrogen sulfotransferase—deficient mice

Abstract

Estrogen sulfotransferase (EST, encoded by SULT1E1) catalyzes the sulfoconjugation and inactivation of estrogens. Despite decades of biochemical study and the recognition that high levels of estrogen sulfates circulate in the blood of pregnant and nonpregnant women, the physiological role of estrogen sulfation remains poorly understood. Here we show that ablation of the mouse Sult1e1 gene caused placental thrombosis and spontaneous fetal loss. This phenotype was associated with elevated free estrogen levels systemically and in the amniotic fluid, increased tissue factor expression in the placenta and heightened platelet sensitivity to agonist-induced activation ex vivo. Treatment of pregnant Sult1e1-null mice with either an anticoagulant or antiestrogen prevented the fetal loss phenotype. Our results thus identify Est as a critical estrogen modulator in the placenta and suggest a link between estrogen excess and thrombotic fetal loss. These findings may have implications for understanding and treating human pregnancy failure and intrauterine growth retardation.

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Figure 1: Spontaneous fetal loss in Sult1e1−/− mice.
Figure 2: Placental thrombosis in Sult1e1−/− mice.
Figure 3: Expression of Sult1e1 in the mouse placenta.
Figure 4: Estrogen excess caused fetal death in Sult1e1−/− mice.
Figure 5: Induction of placental tissue factor expression in pregnant Sult1e1−/− mice.
Figure 6: Increased platelet sensitivity to agonist-induced activation in pregnant Sult1e1−/− mice.

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Acknowledgements

This work is supported by a grant from the US National Institutes of Health to W.-C. S. (HD-42767) and L.F.B. (HL-40387 and HL-45181). We thank L. Zhou, J. Epstein and M. Lu for help with the in situ experiments, L. Roy for providing tissue factor antibodies and B. Everson for help in manuscript preparation.

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Correspondence to Wen-Chao Song.

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Supplementary information

Supplementary Table 1

Mating experiments with wild-type (+/+) and Est knockout (−/−) mice to determine the influence of parental genotype on litter size. (PDF 13 kb)

Supplementary Methods (PDF 59 kb)

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Tong, M., Jiang, H., Liu, P. et al. Spontaneous fetal loss caused by placental thrombosis in estrogen sulfotransferase—deficient mice. Nat Med 11, 153–159 (2005). https://doi.org/10.1038/nm1184

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