title: Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor.
abstract: 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.
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Kaitlin J
authors.initials: KJ
authors.lastname: Basham
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Leonard
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Collin
authors.initials: C
authors.lastname: Kieffer
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Dawne N
authors.initials: DN
authors.lastname: Shelton
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Maria E
authors.initials: ME
authors.lastname: McDowell
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Vasudev R
authors.initials: VR
authors.lastname: Bhonde
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Looper
authors.affiliation: *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112 *Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, Department of Chemistry, University of Utah, Salt Lake City, Utah 84112 and Department of Surgery, University of Utah, Salt Lake City, Utah 84112 bryan-welm@omrf.org.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Welm
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002364:Caseins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007774:Lactation / Q000187:drug effects*; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D034622:RNA Interference; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D002364:Caseins; D004785:Environmental Pollutants; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C484722:Ahr protein, mouse; C117300:Ahrr protein, mouse; C497397:Arnt protein, mouse
keywords: AHR; AHRR; ARNT; TCDD; lactation; mammary gland