Thackaberry E A, Bedrick E J, Goens M B, Danielson L, Lund A K, Gabaldon D, Smith S M, Walker M K
Molecular and Environmental Toxicology Center, Department of Nutritional Sciences, University of Wisconsin, 1415 Linden Drive, Madison, Wisconsin 53706, USA.
Toxicol Sci. 2003 Dec;76(2):407-17. doi: 10.1093/toxsci/kfg229. Epub 2003 Sep 11.
The aryl hydrocarbon receptor (AhR) was originally characterized because of its high affinity binding of 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin. However, studies using AhR-null mice have demonstrated the importance of this protein in normal physiology and development. Here we demonstrate that AhR-null embryos develop cardiac enlargement, and that this phenotype is dependent, at least in part, on the maternal genotype. Neonates born to AhR-null females had increased heart weights regardless of the neonatal genotype, an outcome also observed in gestational diabetes. The cardiac hypertrophy markers, beta-myosin heavy chain and atrial natriuretic factor, and the cardiac proliferative index were increased in AhR-null embryos, indicating that the cardiac enlargement is associated with myocyte hypertrophy and hyperplasia, which begin prior to birth. Importantly, two- to three-month-old pregnant and seven-month-old nonpregnant females, but not nonpregnant three-month-old AhR-null females had significantly decreased fasting plasma insulin levels and a reduced ability to respond to exogenous insulin compared to controls. Despite these alterations in insulin regulation and responsiveness, pregnant AhR females did not have abnormal glucose tolerance tests and did not develop hyperglycemia, classic characteristics of gestational diabetes. However, twenty-three percent of seven-month-old AhR-null females did have altered glucose tolerance tests, but did not show hyperglycemia or increased hemoglobin A1C concentration under normal feeding conditions. While the ultimate cause of the neonatal phenotype remains unclear, these studies establish that the AhR is required for normal insulin regulation in pregnant and older mice and for cardiac development in embryonic mice.
芳烃受体（AhR）最初因其对2,3,7,8 - 四氯二苯并 - p - 二恶英具有高亲和力结合而被鉴定。然而，使用AhR基因敲除小鼠的研究已证明该蛋白在正常生理和发育中的重要性。在此我们证明，AhR基因敲除胚胎会出现心脏增大，并且这种表型至少部分取决于母体基因型。无论新生小鼠的基因型如何，AhR基因敲除雌性所生的新生儿心脏重量都会增加，这一结果在妊娠期糖尿病中也有观察到。AhR基因敲除胚胎中的心脏肥大标志物β - 肌球蛋白重链和心钠素以及心脏增殖指数均增加，表明心脏增大与出生前就开始的心肌细胞肥大和增生有关。重要的是，与对照组相比，两到三个月大的怀孕雌性和七个月大的未怀孕雌性（但不是三个月大的未怀孕AhR基因敲除雌性）空腹血浆胰岛素水平显著降低，对外源性胰岛素的反应能力也降低。尽管胰岛素调节和反应性有这些改变，但怀孕的AhR雌性葡萄糖耐量试验并无异常，也未发生高血糖，这是妊娠期糖尿病的典型特征。然而，23%的七个月大的AhR基因敲除雌性葡萄糖耐量试验确实有改变，但在正常喂养条件下未出现高血糖或血红蛋白A1C浓度升高。虽然新生儿表型的最终原因仍不清楚，但这些研究表明，AhR对于怀孕和成年小鼠的正常胰岛素调节以及胚胎小鼠的心脏发育是必需的。
