LESIONS OF ARYL-HYDROCARBON RECEPTOR-DEFICIENT MICE

We have analyzed the possible role of the aryl-hydrocarbon receptor (A HR) 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 w hich were apparent after only 9 months of age. Cardiovascular alterati ons included cardiomyopathy (100%) with hypertrophy and focal fibrosis . Vascular hypertrophy and mild fibrosis were found in the portal area s 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 m onths of age. Ahr-/- mice had T-cell deficiency in their spleens but n ot in other lymphoid organs. The immune system deficiency described pr eviously could be the ori,ain for the rectal prolapse found in 48% of the null mice, associated with Helicobacter hepaticus infection. In th e 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 h air follicles, were also evident. None of these lesions were found in 42 control (Ahr +/+ or +/-) mice of similar ages. These observations s uggest that the AHR protein, in the absence of an apparent exogenous ( xenobiotic) ligand, plays an important role in physiology and homeosta sis in major organs in mice, and further supports an evolutionary cons erved role for this transcription factor.