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ToxSci Advance Access published online on June 5, 2009
Toxicological Sciences, doi:10.1093/toxsci/kfp125
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© The Author 2009. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Activation of the aryl hydrocarbon receptor (AhR) during different critical windows in pregnancy alters mammary epithelial cell proliferation and differentiation

Betina J. Lew1, Loretta L. Collins1, Michael A. O'Reilly2 and B. Paige Lawrence1

1 Dept. of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 2 Dept. of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, NY

Corresponding author: B. Paige Lawrence; Address: Box 850, University of Rochester Medical Center, Rochester, NY 14642; E-mail address: Paige_Lawrence{at}urmc.rochester.edu; Tel.: 585 275-1974; fax: 585 276-0239

Received March 23, 2009; revision received May 18, 2009; accepted May 27, 2009


  Abstract

Exposure to the AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) during pregnancy causes severe defects in mammary gland development and function; however, the underlying mechanism remains unclear. Alterations in epithelial cell proliferation, differentiation, and apoptosis during pregnancy-related mammary development can lead to failed lactogenesis. To determine which of these processes are affected and at what time periods, we examined proliferation, differentiation and apoptosis in mammary glands following exposure to TCDD during early, mid or throughout pregnancy. While AhR activation throughout pregnancy did not cause early involution, there was a 50% decrease in cell proliferation, which was observed as early as the 6th day of pregnancy (DP). TCDD treatment on the day of impregnation only reduced development and proliferation in early and mid-pregnancy, followed by partial recovery by DP17. However, when AhR activation was delayed to DP7, developmental impairment was not observed in mid-pregnancy, but became evident by DP17, whereas proliferation was reduced at all times. Thus, early exposure to TCDD was neither necessary nor sufficient to cause persistent defects in lactogenesis. These varying outcomes in mammary development due to exposure at different times in pregnancy suggest there are critical windows during which AhR activation impairs mammary epithelial cell proliferation and differentiation.

Key Words: TCDD; mammary gland development; lactogenesis; ductal branching; alveologenesis.


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