Activation of the Aryl Hydrocarbon Receptor during Different Critical Windows in Pregnancy Alters Mammary Epithelial Cell Proliferation and Differentiation

Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Toxicological Sciences (Impact Factor: 3.85). 07/2009; 111(1):151-62. DOI: 10.1093/toxsci/kfp125
Source: PubMed


Exposure to the aryl hydrocarbon receptor (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. Although AhR activation throughout pregnancy did not cause early involution, there was a 50% decrease
in cell proliferation, which was observed as early as the sixth 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.

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Available from: Betina Lew, Apr 29, 2014
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    • "While it is recommended that infants are breastfed exclusively for at least the first six months of life [44], several million mothers are unable to breastfeed or have significant difficulty breastfeeding each year [45]. Research in rodents suggests that factors that interfere with MG growth and differentiation can negatively affect both the gland's ability to produce milk and the milk composition [45] [46]. Factors that accelerate MG development also make the gland less sensitive to ovarian and pituitary hormones. "
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    • "Prenatal TCDD treatment resulted in increased tumor incidence in rats [19]. Varying responses to TCDD exposure at different times during pregnancy have been reported [14]. Additional research is needed to determine if these diverse effects are a result of circulating estrogen levels or AhR protein levels. "
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    • "It is known that TCDD, a potent environmental pollutant ubiquitously present in our environment, has various toxic end-points, such as mammary glands (Lew et al., 2009), ovary (Petroff and Mizinga, 2003), uterus (Cummings et al., 1996), and placenta (Ishimura et al., 2002). We accordingly utilized five human cell lines which were derived from the above mentioned organs and investigated the effect of TCDD on their proliferation. "
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