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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Strott, C.A. Steroid sulfotransferases. Endocr. Rev. 17, 670–697 (1996).
Kakuta, Y. et al. Mouse steroid sulfotransferases: substrate specificity and preliminary X-ray crystallographic analysis. Biochem. Pharmacol. 55, 313–317 (1998).
Qian, Y., Deng, C. & Song, W.C. Expression of estrogen sulfotransferase in MCF-7 cells by cDNA transfection suppresses the estrogen response: potential role of the enzyme in regulating estrogen-dependent growth of breast epithelial cells. J. Pharmacol. Exp. Ther. 286, 555–560 (1998).
Falany, J.L. & Falany, C.N. Regulation of estrogen activity by sulfation in human MCF-7 breast cancer cells. Oncol. Res. 9, 589–596 (1997).
Falany, J.L. & Falany, C.N. Expression of cytosolic sulfotransferases in normal mammary epithelial cells and breast cancer cell lines. Cancer Res. 56, 1551–1555 (1996).
Suzuki, T. et al. Estrogen sulfotransferase and steroid sulfatase in human breast carcinoma. Cancer Res. 63, 2762–2770 (2003).
Moore, S.S., Thompson, E.O. & Nash, A.R. Oestrogen sulfotransferase: isolation of a high specific activity species from bovine placenta. Aust. J. Biol. Sci. 41, 333–341 (1988).
Hobkirk, R., Cardy, C.A., Saidi, F., Kennedy, T.G. & Girard, L.R. Development and characteristics of an oestrogen sulphotransferase in placenta and uterus of the pregnant mouse. Comparison between mouse and rat. Biochem. J. 216, 451–457 (1983).
Tseng, L., Lee, L.Y. & Mazella, J. Estrogen sulfotransferase in human placenta. J. Steroid Biochem. 22, 611–615 (1985).
Song, W.C., Moore, R., McLachlan, J.A. & Negishi, M. Molecular characterization of a testis-specific estrogen sulfotransferase and aberrant liver expression in obese and diabetogenic C57BL/KsJ-db/db mice. Endocrinology 136, 2477–2484 (1995).
Song, W.C., Qian, Y., Sun, X. & Negishi, M. Cellular localization and regulation of expression of testicular estrogen sulfotransferase. Endocrinology 138, 5006–5012 (1997).
Tong, M.H. & Song, W.C. Estrogen sulfotransferase: discrete and androgen-dependent expression in the male reproductive tract and demonstration of an in vivo function in the mouse epididymis. Endocrinology 143, 3144–3151 (2002).
Stone, R. Environmental estrogens stir debate.[comment]. Science 265, 308–310 (1994).
Safe, S.H. Endocrine disruptors and human health--is there a problem? An update. Environ. Health Perspect. 108, 487–493 (2000).
Kester, M.H. et al. Potent inhibition of estrogen sulfotransferase by hydroxylated PCB metabolites: a novel pathway explaining the estrogenic activity of PCBs.[comment]. Endocrinology 141, 1897–1900 (2000).
Shevtsov S, P.E., Pedersen LC, Negishi M. Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic estrogen binding site of human estrogen sulfotransferase. Environ. Health Perspect. 111, 884–888 (2003).
Kakuta, Y., Pedersen, L.G., Carter, C.W., Negishi, M. & Pedersen, L.C. Crystal structure of estrogen sulphotransferase. Nat. Struct. Biol. 4, 904–908 (1997).
Qian, Y.M. et al. Targeted disruption of the mouse estrogen sulfotransferase gene reveals a role of estrogen metabolism in intracrine and paracrine estrogen regulation. Endocrinology 142, 5342–5350 (2001).
Oates, J.A. et al. Clinical implications of prostaglandin and thromboxane A2 formation. N. Engl. J. Med. 319, 689–698 (1988).
Rocca, B. et al. Directed vascular expression of the thromboxane A2 receptor results in intrauterine growth retardation. Nat. Med. 6, 219–221 (2000).
Constancia, M. et al. Placental-specific IGF-II is a major modulator of placental and fetal growth.[see comment]. Nature 417, 945–948 (2002).
Miozzo, M. & Simoni, G. The role of imprinted genes in fetal growth. Biol. Neonate 81, 217–228 (2002).
Franklin, G.C., Adam, G.I. & Ohlsson, R. Genomic imprinting and mammalian development. Placenta 17, 3–14 (1996).
Adamson, S.L. et al. Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta. Dev. Biol. 250, 358–373 (2002).
Georgiades, P., Watkins, M., Burton, G.J. & Ferguson-Smith, A.C. Roles for genomic imprinting and the zygotic genome in placental development. Proc. Natl. Acad. Sci. USA 98, 4522–4527 (2001).
Mahendroo, M.S., Cala, K.M., Landrum, D.P. & Russell, D.W. Fetal death in mice lacking 5alpha-reductase type 1 caused by estrogen excess. Mol. Endocrinol. 11, 917–927 (1997).
Jayachandran, M. & Miller, V.M. Human platelets contain estrogen receptor alpha, caveolin-1 and estrogen receptor associated proteins. Platelets 14, 75–81 (2003).
Khetawat, G. et al. Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression. Blood 95, 2289–2296 (2000).
Nealen, M.L., Vijayan, K.V., Bolton, E. & Bray, P.F. Human platelets contain a glycosylated estrogen receptor beta. Circ. Res. 88, 438–442 (2001).
Moro, L. et al. Nongenomic effects of 17{beta}-estradiol in human platelets: potentiation of thrombin-induced aggregation through estrogen receptor beta and Src kinase. Blood 105, 115–121 (2005).
Henrikson, K.P., Greenwood, J.A., Pentecost, B.T., Jazin, E.E. & Dickerman, H.W. Estrogen control of uterine tissue factor messenger ribonucleic acid levels. Endocrinology 130, 2669–2674 (1992).
Quirk, S.M. et al. The regulation of uterine tissue factor by estrogen. Endocrine 3, 177–184. (1995).
Rosendaal, F.R., Helmerhorst, F.M. & Vandenbroucke, J.P. Female hormones and thrombosis. Arterioscler. Thromb. Vasc. Biol. 22, 201–210 (2002).
Scarabin, P.Y. et al. Changes in haemostatic variables induced by oral contraceptives containing 50 micrograms or 30 micrograms oestrogen: absence of dose-dependent effect on PAI-1 activity. Thromb. Haemost. 74, 928–932 (1995).
Koh, K.K., Horne, M.K., 3rd & Cannon, R.O., 3rd . Effects of hormone replacement therapy on coagulation, fibrinolysis, and thrombosis risk in postmenopausal women. Thromb. Haemost. 82, 626–633 (1999).
Acute myocardial infarction and combined oral contraceptives: results of an international multicentre case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.[comment]. Lancet 349, 1202–1209 (1997).
Daly, E. et al. Risk of venous thromboembolism in users of hormone replacement therapy.[comment]. Lancet 348, 977–980 (1996).
Hobkirk, R. Steroid sulfotransferases and steroid sulfate sulfatases: characteristics and biological roles. Can. J. Biochem. Cell Biol. 63, 1127–1144 (1985).
Stanley, E.L., Hume, R., Visser, T.J. & Coughtrie, M.W. Differential expression of sulfotransferase enzymes involved in thyroid hormone metabolism during human placental development. J. Clin. Endocrinol. Metab. 86, 5944–5955 (2001).
Buchner, V. Environmental endocrine disrupting chemicals.[comment]. Rev. Environ. Health 17, 249–252 (2002).
Backlin, B.M., Persson, E., Jones, C.J. & Dantzer, V. Polychlorinated biphenyl (PCB) exposure produces placental vascular and trophoblastic lesions in the mink (Mustela vison): a light and electron microscopic study. APMIS 106, 785–799 (1998).
Lutz, B. et al. Developmental regulation of the orphan receptor COUP-TF II gene in spinal motor neurons. Development 120, 25–36 (1994).
Qian, Y. & Song, W.C. Correlation between PAP-dependent steroid binding activity and substrate specificity of mouse and human estrogen sulfotransferases. J. Steroid Biochem. Mol. Biol. 71, 123–131 (1999).
Hartzell, S., Ryder, K., Lanahan, A., Lau, L.F. & Nathan, D. A growth factor-responsive gene of murine BALB/c 3T3 cells encodes a protein homologous to human tissue factor. Mol. Cell. Biol. 9, 2567–2573 (1989).
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1184
This article is cited by
-
Genome-wide detection of genetic structure and runs of homozygosity analysis in Anhui indigenous and Western commercial pig breeds using PorcineSNP80k data
BMC Genomics (2022)
-
Filgotinib: A Clinical Pharmacology Review
Clinical Pharmacokinetics (2022)
-
Triclosan causes spontaneous abortion accompanied by decline of estrogen sulfotransferase activity in humans and mice
Scientific Reports (2015)
-
Oestrogen sulfotransferase ablation sensitizes mice to sepsis
Nature Communications (2015)
-
Molecular and biochemical characterization of two brassinosteroid sulfotransferases from Arabidopsis, AtST4a (At2g14920) and AtST1 (At2g03760)
Planta (2007)