Ah receptor-mediated deregulation of lactogenesis

Ah 受体介导的泌乳失调

• 批准号: 7345016
• 负责人: B Paige Lawrence
• 金额: $ 33.73万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7345016
• 关键词: apoptosis; aromatic hydrocarbon receptor; breast feeding; cell proliferation; dioxins; environmental exposure; gene expression profiling; genetically modified animals; immunocytochemistry; infant mortality; laboratory mouse; lactation; ligands; mammary disorder; mammary epithelium; pregnancy

DESCRIPTION (provided by applicant): Background: We have recently discovered a new toxic effect of the aryl hydrocarbon receptor (AhR) ligand 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD or dioxin). Specifically, exposure during pregnancy impairs mammary gland development and suppresses the coordinated induction of milk proteins, resulting in impaired lactation and neonatal mortality. Objectives/Hypothesis: The objectives of the proposed studies are (1) to further characterize this novel finding and (2) to identify the lactogenic regulatory pathways adversely affected by exposure to dioxin. The hypothesis for these studies is that AhR activation during pregnancy disrupts the normal signaling that directs pregnancy-associated mammary development and milk protein gene expression, resulting in impaired epithelial cell differentiation and lactation. Specific Aims: 1).To determine whether defects in lactogenesis result from direct effects on mammary tissue, we will cross-transplant mammary tissue from wild-type and AhR-null mice. 2) To identify the mechanism underlying impaired milk production, we will determine whether exposure to TCDD deregulates the activation of NF-kappaB-, STATSa- and C/EBbeta-mediated signalling pathways in mammary epithelial cells. 3) To determine whether stunted glandular development during pregnancy results from deregulation of proliferation, differentiation, apoptosis or defects in multiple pathways, we will further characterize the effects of exposure to TCDD on these processes in mammary cells during pregnancy. 4) To identify additional molecular pathways that are deregulated following exposure to TCDD, we will compare the expression of factors known to regulate to glandular differentiation and lactogenesis in glands derived from vehicle- and TCDD-treated pregnant mice using a combination of gene expression profiling and immunocytochemical methods. Mammary tissue from AhR-null mice will be used to distinguish defects that are directly AhR-mediated from defects that arise due to an upstream lesion. Significance: The proposed studies address an area that is clinically-relevant but has received very little attention. An estimated 3-6 million mothers of live infants annually are either unable to or have significant difficulty initiating breastfeeding. The causes of this problem are not clear, and very little is known about the effects of exposure to environmental contaminants on lactogenesis. Furthermore, since the mechanisms that control lactogenesis also regulate proliferation and differentiation in other organs, and exposure to AhR ligands disrupts the proliferation and differentiation of epithelial cells in other tissues, findings from these studies will have broad biological significance, and will help us better understand the mechanisms by which dioxin-like chemicals adversely affect epithelial cells throughout the body.

描述（由申请人提供）：背景：我们最近发现了芳基烃受体（AHR）配体2,3,7,8- tetrachlorodibenzo-p-dioxin（TCDD或二恶英）的新毒性作用。具体而言，怀孕期间的暴露会损害乳腺发育并抑制牛奶蛋白的协调诱导，从而导致泌乳和新生儿死亡率受损。 目标/假设：拟议研究的目标是（1）进一步表征这一新发现，（2）识别受到暴露于二恶英的不利影响的乳酸调节途径。这些研究的假设是，妊娠期间的AHR激活破坏了指导与妊娠相关的乳腺发育和牛奶蛋白基因表达的正常信号传导，从而导致上皮细胞分化和泌乳受损。具体目的：1）。为了确定泌尿解构缺陷是否是对乳腺组织的直接影响导致的，我们将从野生型和AHR-null小鼠中交叉移植乳腺组织。 2）为了确定牛奶产生受损的机制，我们将确定暴露于TCDD的暴露是否会消除乳腺上皮细胞中NF-kappab-，statsa-和c/ebbeta介导的信号通路的激活。 3）确定怀孕期间的腺体发育是否导致多种途径的扩散，分化，凋亡或缺陷导致，我们将进一步表征TCDD暴露于妊娠期间乳腺细胞中这些过程的影响。 4）为了鉴定暴露于TCDD后消失管制的其他分子途径，我们将比较已知的调节因子的表达，与源自基因和TCDD治疗的怀孕小鼠的腺体分化和泌乳作用，使用基因表达分析和免疫细胞化学方法的组合。来自AHR无效小鼠的乳腺组织将用于区分直接AHR介导的缺陷与由于上游病变引起的缺陷。意义：拟议的研究涉及临床上与临床相关但很少关注的领域。估计每年有3-6万个活生生的母亲无法发起母乳喂养或巨大困难。这个问题的原因尚不清楚，对暴露于环境污染物对泌乳发生的影响知之甚少。此外，由于控制乳酸作用的机制还调节其他器官的增殖和差异，并且暴露于AHR配体会破坏其他组织中上皮细胞的增殖和分化，因此，这些研究的发现将具有广泛的生物学意义，并将帮助我们更好地理解二氧蛋白型细胞的机制。