CHARACTERIZATION OF MICE DEFICIENT IN AROMATASE (ARKO) BECAUSE OF TARGETED DISRUPTION OF THE CYP19 GENE

The formation of estrogens from C-19 steroids is catalyzed by aromatas e cytochrome P450 (P350arom), the product of the cyp19 gene. The actio ns of estrogen include dimorphic anatomical, functional, and behaviora l effects on the development of both males and females, considerations that prompted us to examine the consequences of deficiency of aromata se activity in mice, Mice lacking a functional aromatase enzyme (ArKO) were generated by targeted disruption of the cyp19 gene. Male and fem ale ArKO mice were born with the expected Mendelian frequency from F-1 parents and grew to adulthood. Female ArKO mice at 9 weeks of age dis played underdeveloped external genitalia and uteri. Ovaries contained numerous follicles with abundant granulosa cells and evidence of antru m formation that appeared arrested before ovulation. No corpora lutea were present. Additionally the stroma were hyperplastic with structure s that appeared to be atretic follicles, Development of the mammary gl ands approximated that of a prepubertal female. Examination of male Ar KO mite of the same age revealed essentially normal internal anatomy b ut with enlargement of the male accessory sex glands because of increa sed content of secreted material. The testes appeared normal. Male ArK O mice are capable of breeding and produce litters of approximately av erage size. Whereas serum estradiol levels were at the limit of detect ion, testosterone levels were elevated, as were the levels of follicle -stimulating hormone and luteinizing hormone, The phenotype of these a nimals differs markedly from that of the previously reported ERKO mice , in which the estrogen receptor alpha is deleted bp targeted disrupti on.