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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    ABSTRACT: Although understanding the environmental factors that contribute to breast cancer could improve disease prevention, standard chemical testing protocols do not adequately evaluate chemicals' effects on breast development. Evidence suggests: (1) Mammary gland (MG) development is a complex process that extends from gestation through fetal and neonatal growth, puberty, and pregnancy; (2) altered MG development can increase the risk of breast cancer and other adverse outcomes; and (3) chemical exposures during susceptible windows of development may alter the MG in ways that increase risk for later disease. Together, these highlight the need to better understand the complex relationship between exposure to endocrine disrupting compounds (EDCs) and the alterations in MG morphology and gene expression that ultimately increase disease risk. Changing guideline toxicity testing studies to incorporate perinatal exposures and MG whole mounts would generate critical knowledge about the effects of EDCs on the MG and could ultimately inform disease prevention.
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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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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates a battery of genes in re- sponse to exposure to a broad class of environmental poly aromatic hydrocarbons (PAH). AhR is historically character- ized for its role in mediating the toxicity and adaptive responses to these chemicals, however mounting evidence has established a role for it in ligand-independent physiological processes and pathological conditions, including cancer. The AhR is overexpressed and constitutively activated in advanced breast cancer cases and was shown to drive the pro- gression of breast cancer. In this article we will review the current state of knowledge on the possible role of AhR in breast cancer and how it will be exploited in targeting AhR for breast cancer therapy.
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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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