Fernandez-Salguero P M, Ward J M, Sundberg J P, Gonzalez F J
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Vet Pathol. 1997 Nov;34(6):605-14. doi: 10.1177/030098589703400609.
We have analyzed the possible role of the aryl-hydrocarbon receptor (AHR) in the aging process of mice using a homozygous null mouse (Ahr-/-) line as a model. We studied 52 male and female Ahr-/- mice aged from 6-13 months. Forty-six percent died or were ill by 13 months of age. Ahr-/- mice developed age-related lesions in several organs, some of which were apparent after only 9 months of age. Cardiovascular alterations included cardiomyopathy (100%) with hypertrophy and focal fibrosis. Vascular hypertrophy and mild fibrosis were found in the portal areas of the liver (81%), and vascular hypertrophy and mineralization were common in the uterus (70%). Gastric hyperplasia that progressed with age into polyps was evident in the pylorus of 71% of the mice over 9 months of age. Ahr-/- mice had T-cell deficiency in their spleens but not in other lymphoid organs. The immune system deficiency described previously could be the origin for the rectal prolapse found in 48% of the null mice, associated with Helicobacter hepaticus infection. In the dorsal skin (53% incidence), severe, localized, interfollicular and follicular epidermal hyperplasia, with hyperkeratosis and acanthosis, and marked dermal fibrosis, associated with the presence of anagenic hair follicles, were also evident. None of these lesions were found in 42 control (Ahr +/+ or +/-) mice of similar ages. These observations suggest that the AHR protein, in the absence of an apparent exogenous (xenobiotic) ligand, plays an important role in physiology and homeostasis in major organs in mice, and further supports an evolutionary conserved role for this transcription factor.
我们以纯合缺失小鼠品系（Ahr-/-）为模型，分析了芳烃受体（AHR）在小鼠衰老过程中可能发挥的作用。我们研究了52只6至13个月大的雄性和雌性Ahr-/-小鼠。到13个月大时，46%的小鼠死亡或患病。Ahr-/-小鼠在多个器官出现了与年龄相关的病变，其中一些病变在仅9个月大时就已明显。心血管改变包括心肌病（100%）伴肥大和局灶性纤维化。在肝脏门区发现血管肥大和轻度纤维化（81%），子宫中血管肥大和矿化很常见（70%）。71%的9个月以上小鼠的幽门出现胃增生，且随年龄增长发展为息肉。Ahr-/-小鼠脾脏存在T细胞缺陷，但其他淋巴器官未出现。先前描述的免疫系统缺陷可能是48%的缺失小鼠出现直肠脱垂的原因，这与肝螺杆菌感染有关。在背部皮肤（发病率53%），还明显出现严重的、局限性的、滤泡间和滤泡性表皮增生，伴有角化过度和棘层肥厚，以及明显的真皮纤维化，并伴有生长期毛囊。在42只年龄相仿的对照（Ahr +/+或+/-）小鼠中未发现这些病变。这些观察结果表明，在没有明显外源性（异生素）配体的情况下，AHR蛋白在小鼠主要器官的生理和内环境稳定中发挥重要作用，并进一步支持了该转录因子具有进化保守作用。
