Studies on the Inhibition of Fetal Androgen Formation. Inhibition of Testosterone Synthesis in Rat and Rabbit Fetal Testes with Observations on Reproductive Tract Development

Bloch, Eric D.; Lew, Michael J.; Klein, Milton D.

doi:10.1210/endo-89-1-16

Cited by 32 publications

(8 citation statements)

References 1 publication

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“…Bloch et al [3] have reported their studies of CTM on the rat fetus which substantially confiim our observations. In addition, they have shown that intra-amniotic injection of the analog into rat fetuses on day I Oof gestation inhi bits l4C progesterone conversion from uC-pregnenolone on day 11.…”

Section: Early Effectiveness O F Analogsupporting

confidence: 86%

“…[3] and observed by us (unpublished observations). Josso [30] has observ ed that the Wolffian ducts degenerate in organ culture unless the testis or testosterone is present.…”

Section: Target Organ Dehydrogenasesupporting

confidence: 66%

“…The C.2, 0 , and C2l0 5 steroids are 21-sulfurylated and are therefore cleaved by Helix pomatia enzymes. This technique has validated the production by CTM of the abnormal excretion o f the same 3/7-hydroxy-l5-androgens noted by Bloch et al to accumulate in in vitro incubations [3]. We have discovered three new candidates for ASDI inhibition of the dehydrogenase [27] (table I).…”

Section: Urinary Steroidal Excretion Patternsmentioning

confidence: 83%

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Inhibition of 3β-Hydroxy-Δ<sup>5</sup>-Steroid Dehydrogenase

Goldman¹

1971

Gynecol Obstet Invest

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Selective inhibition of rat fetal 3Β-Hydroxy-Δ⁵-steroid dehydrogenase with certain substrate analogs has produced a precise animal model of human congenital adrenal hyperplasia due to a genetic deficiency of this enzyme system. Inhibition of fetal testicular dehydrogenase dehydrogenase by the analog produces testosterone-reversible blockade of penis formation and of nipple anlagen resorption in male fetuses. These observations have been duplicated by maternal administration of rabbit antisera to testosterone-3-bovine serum albumin. Inhibition of the fetal adrenal dehydrogenase system leads to excess dehydroepiandrosterone (DHA) production which, in turn, produces corticosterone-reversible virilization of female fetal genitalia and nipple anlagen. Inhibition-induced excess DHA production may also explain the persistence of wolffian duct structures in male fetuses since recent studies indicate presence of a ductal dehydrogenase system capable of transforming DHA into testosterone and dihydrotestosterone. The striking properties of these analogs, e.g., tight binding to the enzymatic active sites, potency, specificity, prolonged duration of action and intrauterine effectiveness before differentiation of the fetal enzyme, can be ascribed to active site-directedirreversible (ASDI) inhibition. Application of principles of ASDI inhibition has led to the discovery of new ASDI inhibitors with a differing specificity of enzymatic inhibition and sites of action. Steroidal excretion patterns determined by gasliquid chromatography – mass spectrometry produced by these inhibitors support the sites of action determined in vitro. These ASDI inhibitors and hormone-antibodies give promise of highly specific and precise molecular probes of the chemical controls of sexual differentiation.

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Section: Early Effectiveness O F Analogsupporting

confidence: 86%

“…[3] and observed by us (unpublished observations). Josso [30] has observ ed that the Wolffian ducts degenerate in organ culture unless the testis or testosterone is present.…”

Section: Target Organ Dehydrogenasesupporting

confidence: 66%

Section: Urinary Steroidal Excretion Patternsmentioning

confidence: 83%

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Inhibition of 3β-Hydroxy-Δ<sup>5</sup>-Steroid Dehydrogenase

Goldman¹

1971

Gynecol Obstet Invest

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“…Indifferent supporting cells (future Sertoli cells) start to undergo morphological and biochemical changes indicative of endocrine activity approximately by GD 20 (Gondos et al 1973, Gondos 1974. Secretions of both cell types are involved in differentiation of the reproductive system (Bloch et al 1971, Klonisch et al 2004. In rabbits, testosterone concentration in fetal blood/tissue remains high until birth, when it drops and remains low until PND 40 (Veyssiere et al 1976, Berger et al 1982.…”

Section: Discussionmentioning

confidence: 99%

“…Also, perinatal developmental events are well documented for the rabbit (Bloch et al 1971, Gondos et al 1973, Bjerregaard et al 1974, Gondos 1974, Catt et al 1975. Furthermore, use of rabbits (in contrast to rodents) facilitates multiple evaluations of seminal quality and sexual capacity.…”

Section: Introductionmentioning

confidence: 99%

Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide

Veeramachaneni¹,

Palmer²,

Amann³

et al. 2006

Reproduction

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We studied sequelae of prenatal plus infantile exposure of male rabbits to vinclozolin, because it is ingested by women and children. Female Dutch-Belted rabbits (7 -10/group) were treated daily per orum from gestation day 15 through post-natal week 4 to provide 0, 7.2, or 72 mg vinclozolin/kg dam's body weight/day. Vinclozolin had no effect on maintenance of pregnancy, growth of pups, age at testicular descent or weight of organs. Concentrations of serum LH or testosterone at 6, 12, or 24 weeks of age were unaffected. However, FSH was lower (P < 0.05) in both vinclozolin groups at all three ages. Following injection of GnRH at 12 or 24 weeks, the increase in FSH was less (P < 0.05) in both vinclozolin groups, as was testosterone at 12 weeks of age. After full sexual maturity, 2 of 7 low dose rabbits were uninterested in female or male teasers and never achieved erection or ejaculation. Overall, rates of ejaculation failure were: control 0% (0/48), low dose 29% (12/42), and high dose 5% (3/60). Daily sperm production per gram of testis and total number of sperm per ejaculate in both vinclozolin groups were similar (P > 0.1) to controls. However, semen from vinclozolin rabbits contained over two times more (P < 0.05) morphologically abnormal spermatozoa, mostly nuclear and acrosomal defects, than semen from controls. Seminiferous tubules with degenerative changes were more frequent (P < 0.05) in vinclozolin rabbits than in controls. Lesions included syncytia of spherical spermatids and desquamation of germ cells. Hence, developmental exposure to vinclozolin caused presumably permanent changes in copulatory ability, secretion of FSH, and spermiogenesis.

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Developmental and Reproductive Toxicity Testing

2010

Drug Safety Evaluation

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Studies on the Inhibition of Fetal Androgen Formation. Inhibition of Testosterone Synthesis in Rat and Rabbit Fetal Testes with Observations on Reproductive Tract Development

Cited by 32 publications

References 1 publication

Inhibition of 3β-Hydroxy-Δ<sup>5</sup>-Steroid Dehydrogenase

Inhibition of 3β-Hydroxy-Δ<sup>5</sup>-Steroid Dehydrogenase

Disruption of sexual function, FSH secretion, and spermiogenesis in rabbits following developmental exposure to vinclozolin, a fungicide

Developmental and Reproductive Toxicity Testing

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