US EPA

3102781 

Journal Article 

Production of hypospadias in the rat by selective inhibition of fetal testicular 17 alpha-hydroxylase and C17-20-lyase 

Goldman, AS 

1971 

Yes 

Endocrinology
ISSN: 0013-7227
EISSN: 1945-7170 

88 

2 

527-531 

English 

5540068 

10.1210/endo-88-2-527 

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0015008399&doi=10.1210%2fendo-88-2-527&partnerID=40&md5=136a8cc77201db9fa25e9ddbdb67931f
Exit
 

Although congenital adrenal hyperplasia due to a deficiency of 17α-hydroxylation has been described only in genetic women, one would expect genetic males with this defect to fail to masculinize in utero due to inadequate fetal testosteronogenesis. To test this hypothesis 2 drugs, Su-10, 603 [7-Cl-3, 4-dihydro-2-(3-pyridyl)- 1(2H)-naphthalenone] and Su-8000 [3-(6- chloro-3-methyl-2-indenyl)pyridine], which inhibit 17α-hydroxylase and C17-20-lyase selectively in rat testes, have been administered to pregnant rats. Neither drug affects maternal adrenal or fetal adrenal weights or female fetal urethral distance, presumably because 17α-hydroxylation is not involved in corticoidogenesis in this species. At maximal sublethal doses each drug produces a significant degree of hypospadias in male fetuses. Incubates of experimental testes with appropriate cofactors have more residual labeled progesterone and 17α-hydroxyprogesterone but less androstenedione, testosterone and 5α-androstan-3α, 17β-diol than those of control testes, indicating that the experimental testes have a considerable reduction in activity of 17 α hydroxylase and C17-20-lyase but about the same degree of activity of NADPH-dependent 17- ketosteroid reductase and testosterone-5α-reductase and 3-ketosteroid reductase compared to control testes. Although the changes in testicular enzymatic activities are apparent in incubations of 100 μl total volume, they only become statistically significant when the volume is reduced to 20 μl, indicating dissociation of endogenous inhibitor from enzyme occurs at higher dilutions. The present results have shown that reduction of fetal testosteronogenesis by inhibition of 17αhydroxylation and Cn_2o side chain cleavage in addition to the previously demonstrated inhibition of 2 other testosteronogenic enzymes, Δ5, 3β- hydroxysteroid dehydrogenase and cholesterol desmolase, results in failure of masculinization of male fetuses as manifested by hypospadias. © 1971 by The Endocrine Society.