Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor

• Published in: Toxicological sciences 2015-01, Vol.143 (1), p.36-45
• Main Authors: Basham, Kaitlin J, Leonard, Christopher J, Kieffer, Collin, Shelton, Dawne N, McDowell, Maria E, Bhonde, Vasudev R, Looper, Ryan E, Welm, Bryan E
• Format: Article
• Language: English
• Subjects: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator - drug effects; Aryl Hydrocarbon Receptor Nuclear Translocator - genetics; Aryl Hydrocarbon Receptor Nuclear Translocator - metabolism; Basic Helix-Loop-Helix Transcription Factors - agonists; Basic Helix-Loop-Helix Transcription Factors - drug effects; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Caseins - genetics; Caseins - metabolism; Cells, Cultured; Dioxin Disrupts Lactation Via the AhR Repressor; Down-Regulation; Environmental Pollutants - toxicity; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; Female; Lactation - drug effects; Mammary Glands, Animal - drug effects; Mammary Glands, Animal - metabolism; Mammary Glands, Animal - pathology; Mammary Glands, Animal - physiopathology; Mice; Polychlorinated Dibenzodioxins - toxicity; Receptors, Aryl Hydrocarbon - agonists; Receptors, Aryl Hydrocarbon - genetics; Receptors, Aryl Hydrocarbon - metabolism; Repressor Proteins - drug effects; Repressor Proteins - metabolism; RNA Interference; Signal Transduction - drug effects; Transcription, Genetic - drug effects; Transfection
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfu203

In mammals, lactation is a rich source of nutrients and antibodies for newborn animals. However, millions of mothers each year experience an inability to breastfeed. Exposure to several environmental toxicants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), has been strongly implicated in impaired mammary differentiation and lactation. TCDD and related polyhalogenated aromatic hydrocarbons are widespread industrial pollutants that activate the aryl hydrocarbon receptor (AHR). Despite many epidemiological and animal studies, the molecular mechanism through which AHR signaling blocks lactation remains unclear. We employed in vitro models of mammary differentiation to recapitulate lactogenesis in the presence of toxicants. We demonstrate AHR agonists directly block milk production in isolated mammary epithelial cells. Moreover, we define a novel role for the aryl hydrocarbon receptor repressor (AHRR) in mediating this response. Our mechanistic studies suggest AHRR is sufficient to block transcription of the milk gene β-casein. As TCDD is a prevalent environmental pollutant that affects women worldwide, our results have important public health implications for newborn nutrition.