Changes In Androgen-Mediated Reproductive Development In Male Rat Offspring Following Exposure To A Single Oral Dose Of Flutamide At Different Gestational Ages. Running Title: In utero flutamide time course

Changes In Androgen-Mediated Development In Adult Male Rat Offspring Following Exposure To A Single Oral Dose Of Flutamide At Different Gestational Ages. Paul M. D. Foster and Martha W. Harris. Toxicological Sciences Previous studies have indicated that the androgen receptor antagonist, flutamide, can produce a suite of reproductive malformations in the male rat when orally administered daily on gestation days (GD) 12-21. The objective of this study was to investigate the gestation time dependence for the induction of these malformations to establish a robust animal model for future studies of gene expression related to specific malformations. Groups of timed-pregnant Sprague-Dawley rats (GD 0 = day of mating) were administered flutamide as a single gavage dose (50 mg/kg) on GD 16, 17, 18, or 19 with 10 dams per group. Control animals (5 dams per time per group) were administered corn oil vehicle (2 ml/kg). Dams were allowed to litter and their adult male offspring were killed at postnatal day (PND) 100±10. Anogenital distance was measured at PND 1 and 100. Areolae were scored at PND 13 and permanent nipples evaluated at PND 100. No reproductive tract malformations were found in control male offspring. In the treated groups, malformations were noted following exposure at every GD, although the incidence of specific malformations varied by GD. At GD 16, the highest incidence was noted for permanent nipples (46% pups, 60% litters), epispadias (12% pups, 30% litters), and missing epididymal components (5% pups , 20% litters). The highest incidences for hypospadias (58% pups , 80% litters), vaginal pouch (49% pups, 70% litters), cleft prepuce (29% pups, 60% litters) and missing prostate lobes (12% pups, 60% litters) were