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ToxSci Advance Access published online on June 6, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfl029
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 24, 2006
Accepted May 23, 2006

Reproductive and Developmental Toxicology

Estrogenic Effect of Soy Isoflavones on Mammary Gland Morphogenesis and Gene Expression Profile

Anni R. Thomsen 1, Kristian Almstrup 2, John E. Nielsen 3, Ilona K. Sørensen 4, Ole William Petersen 5, Henrik Leffers 3 *, and Vibeke M. Breinholt 6

1 Danish Institute for Food and Veterinary Research, Department of Toxicology and Risk Assessment, Mørkhøj Bygade 19, DK-2860 Søborg; University Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen
2 University Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen; Present address: Molecular Genetics, Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark
3 University Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen
4 Danish Institute for Food and Veterinary Research, Department of Toxicology and Risk Assessment, Mørkhøj Bygade 19, DK-2860 Søborg
5 Structurel Cell Biology Unit, Department of Medical Anatomy, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark
6 Danish Institute for Food and Veterinary Research, Department of Toxicology and Risk Assessment, Mørkhøj Bygade 19, DK-2860 Søborg; Present address: Maxygen Aps, Agern Alle 1, DK-2970 Hørsholm, Denmark

* To whom correspondence should be addressed.
Henrik Leffers, E-mail: henrik.leffers{at}biobase.dk


  Abstract

We examined the effect of 17{beta}-estradiol (E2) and soy isoflavones exposure on morphogenesis and global gene expression in the murine mammary gland. Three exposure regimens were applied: isoflavones added to the diet throughout either the lactational period (via the dams) or the post-weaning period, and E2 administered orally during the lactational period. Wholemounts of mammary glands were evaluated both in juvenile and adult animals with respect to branching morphogenesis and terminal end bud (TEB) formation. At postnatal day (PND) 28 we observed a significant increase in branching morphogenesis in all treated groups with the most pronounced effect after E2 exposure. For the E2 treated animals there was also a significant increase in TEB formation. At PND 42-43 the post-weaning isoflavone and the E2 groups showed a transient reduction in the number of TEBs. The similar response after isoflavone and E2 exposure was further substantiated by changes in gene expression, since the same groups of genes were up and down regulated, particularly in the E2 and post-weaning isoflavone regimen. All changes in gene expression correlated with changes in the cellular composition of the gland, i.e. more and larger TEBs and ducts. The results suggest an estrogenic response of physiological doses of isoflavones on mammary gland development at both the morphological and molecular level, which resembled that induced by puberty.

Keywords: Mammary gland; development; estradiol; phytoestrogens; isoflavones.
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