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ToxSci Advance Access originally published online on June 6, 2006
Toxicological Sciences 2006 93(2):357-368; 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

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

Anni R. Thomsen*,{dagger}, Kristian Almstrup{dagger},2, John E. Nielsen{dagger}, Ilona K. Sørensen*, Ole William Petersen{ddagger}, Henrik Leffers{dagger},1 and Vibeke M. Breinholt*,3

* Department of Toxicology and Risk Assessment, Danish Institute for Food and Veterinary Research, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark; {dagger} University Department of Growth and Reproduction, Section GR-5064, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark; and {ddagger} Structural Cell Biology Unit, Department of Medical Anatomy, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark

Received March 24, 2006; accepted May 23, 2006

We examined the effect of 17ß-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 postweaning period and E2 administered orally during the lactational period. Whole mounts 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 PNDs 42–43 the postweaning isoflavone and the E2 groups showed a transient reduction in the number of TEBs. A similar response after isoflavone and E2 exposure was further substantiated by changes in gene expression, since the same groups of genes were up- and downregulated, particularly in the E2 and postweaning 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.

Key Words: mammary gland; development; estradiol; phytoestrogens; isoflavones.


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