Antiandrogens and Development of the Male Rat Reproductive Tract

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Title: Antiandrogens and Development of the Male Rat Reproductive Tract
Author: Barlow, Norman James
Advisors: C. Lee Robinette, Committee Member
Paul M.D. Foster, Committee Co-Chair
Talmage T. Brown, Committee Co-Chair
Philip L. Sannes, Committee Member
Abstract: Di(n-butyl) phthalate (DBP) is an antiandrogen with known human exposure. The objectives of this thesis were to investigate the development of male reproductive tract malformations secondary to in utero DBP exposure from the fetus to the adult, to characterize the effects of DBP on fetal testicular gene expression for the steroidogenic enzymes, and to further explore DBP's potential for inducing Leydig cell adenomas following gestational exposure. In utero DBP exposure led to a characteristic set of fetal testicular lesions including large aggregates of fetal Leydig cells, multinucleated gonocytes, and increased numbers of gonocytes. In addition to the testicular effects, DBP also caused maldevelopment of the epididymides. During the early postnatal period the fetal testicular lesions became less apparent while decreased numbers of spermatocytes were observed. Underdeveloped epididymides noted in fetuses remained small or failed to fully develop resulting in epididymides with missing components. Malformed epididymides were fully manifest in the adult with absent portions observed both unilaterally and bilaterally. Testicular atrophy with loss of spermatocytes became more severe as gestationally exposed animals matured. Gene expression for the steroidogenic enzymes was examined in testes exposed to DBP in utero. Gene expression was decreased for P450 side-chain cleavage enzyme, 3beta-hydroxysteroid dehydrogenase, and P450c17; while mRNA expression for 17beta-hydroxysteroid dehydrogenase, which catalyzes the final step in testosterone biosynthesis, was not altered. In utero exposure to DBP failed to induce an increased incidence of classical Leydig cell adenomas. However, a dysgenetic lesion composed of numerous poorly differentiated Leydig cells surrounding immature seminiferous tubules was identified. Testicular dysgenesis was observed with a similar incidence between age groups in mature rats, which supports in utero induction by DBP rather than development over time. Together these data provide insight into the molecular mechanisms underlying the induction of DBP-initiated male reproductive tract malformations.
Date: 2004-02-18
Degree: PhD
Discipline: Comparative Biomedical Sciences

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