PARENT SESSION
Sex Determination

CHARACTERIZATION OF MALE MICE DEFICIENT IN STEROID 5 -REDUCTASE ISOZYMES.

Mahendroo, Mala¹, ¹

ABSTRACT- The conversion of testosterone to dihydrotestosterone(DHT) is catalyzed by steroid 5-reductase, a membrane bound enzyme that utilizes NADPH as a cofactor to reduce the ^4,5 bond in the substrate. Two 5-reductase genes exist and are designated type 1 and type 2. The contributions of each 5-reductase enzyme to sexual differentiation and reproductive biology have been elucidated in humans and mice. Mutations in the human 5-reductase 2 gene give rise to male pseudohermaphroditism in which the wolffian ducts virilize normally due to the actions of testosterone but the prostate and external genitalia fail to form in the absence of DHT. In mice, targeted mutation of the 5-reductase1 gene results in males that are indistinguishable from wild type counterparts, presumably due to the presence of the active type 2 enzyme. Female mice that lack the type 1 enzyme exhibit partially penetrant defects in parturition and fecundity. These results confirm the notion that the two 5-reductase enzymes have different endocrine roles and they suggest that the type 1 enzyme may be of greater importance in the female whereas the type 2 enzyme is more important in the male. In the current study we report the construction and analysis of mice that lack 5-reductase 2 and both 5-reductase type 1 and 2. The absence of the type 2 enzyme causes a mild virilization defect in the male marked by a reduction in the size of secondary sexual glands. Crossing the type 2 deficient mice with the previously constructed type 1 deficient mice resulted in mice with no 5-reductase activity. The modest virilization defect observed in type 2 deficient male mice is more pronounced in animals lacking both enzymes, however the prostate, penis, and scrotum differentiate in these mice and the animals are fertile. DHT administration increased seminal vesicle, coagulating gland and prostate weights in mice lacking 5-reductase 1 and 2 while administration of an inhibitor of 5-reductase (GI208335X) had no effect in mice lacking both enzymes. The unexpected virilization observed in the 5-reductase deficient male mice, suggest that unlike the situation in rats and humans, only a single androgen, testosterone, is required for formation of the male phenotype in mice.

KEY WORDS: 5alpha-reductase, prostate, gene knockout, male reproduction