Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.
Disruption of Ah Receptor Signaling during Mouse Development Leads to Abnormal Cardiac Structure and Function in the Adult.
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DOI：
10.1371/journal.pone.0142440
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Puga A
中科院分区：
文献类型：
--
作者：
Carreira VS;Fan Y;Kurita H;Wang Q;Ko CI;Naticchioni M;Jiang M;Koch S;Zhang X;Biesiada J;Medvedovic M;Xia Y;Rubinstein J;Puga A
健康与疾病的发育起源(DOHAD)理论认为，胎儿生命和婴儿期所遇到的环境永久地塑造了组织生理学和动态平衡，因此母亲应激、营养不良或暴露于环境因素造成的损害可能是成人发病的核心。干扰芳香烃受体(AHR)的内源性发育功能，无论是通过基因切除还是在子宫内暴露于2，3，7，8-四氯二苯并-对二恶英(TCDD)，都会导致小鼠胚胎心脏结构、分子和功能的异常以及心脏生理的改变。为了测试胚胎效应是否演变为成年表型，我们调查了AHR消融或TCDD暴露在子宫内是否会导致成年小鼠在去除药物后很长时间内出现心脏异常。10个月大的成年Ahr-/-和在子宫中暴露于TCDD的Ahr+/+小鼠表现出性别二态异常的心血管表型，其特征是超声心动图表现为肥大、心室扩张和心脏重量增加、静息心率、收缩压和平均血压，以及运动耐量下降。在这些效应的基础上，与心肌肥大和线粒体功能相关的信号网络中的基因表达存在差异。由AHR信号干扰引起的小鼠胚胎心脏功能障碍似乎进展为心脏结构和功能异常，使成年鼠易患心脏病，但尽管胚胎功能障碍在雄性和雌性中同样强烈，但成年异常在雌性中更普遍，在Ahr-/-雌性中严重程度最高。这些研究结果强调了心脏发育中的AHR信号是与心血管疾病相关的环境因素的一个潜在靶点的结论。
The Developmental Origins of Health and Disease (DOHaD) Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease. Interference with endogenous developmental functions of the aryl hydrocarbon receptor (AHR), either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent. Ten-months old adult Ahr -/- and in utero TCDD-exposed Ahr +/+ mice showed sexually dimorphic abnormal cardiovascular phenotypes characterized by echocardiographic findings of hypertrophy, ventricular dilation and increased heart weight, resting heart rate and systolic and mean blood pressure, and decreased exercise tolerance. Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. Cardiac dysfunction in mouse embryos resulting from AHR signaling disruption seems to progress into abnormal cardiac structure and function that predispose adults to cardiac disease, but while embryonic dysfunction is equally robust in males and females, the adult abnormalities are more prevalent in females, with the highest severity in Ahr -/- females. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease.