Vinclozolin Treatment Induces Reproductive Malformations and Infertility in Male Rats When Administered During Sexual but Not Gonadal Differentiation; However, the Effects Are Not Transmitted to the Subsequent Generations.

Abstract

Administration of vinclozolin (V) during androgen-dependent sexual differentiation causes hypospadias, retained vaginal pouch, and undescended testes in F1 male rats, among other effects. Recently, it was reported that i.p. administration of 100 mg V/kg/d earlier in gestation (GD8-15) during gonadal differentiation induces epigenetic alterations in that were transmitted from the F1 to F2, F3 and F4 generations (severe testicular histopathology, reduced sperm counts, infertility and tumors; Anway et al., 2005). However, two recent studies could not replicate the effects of V on the testis or fertility in any generation using either i.p. or oral dosing. Our study was designed to determine if oral 100 mg V/kg/d induced epigenetic effects in the male rat offspring when administered during gonadal differentiation (GD8-15, n=10) or androgen-dependent differentiation of the reproductive tract (GD13-17, n=5). A vehicle control group (n=10) was dosed from GD8-17. GD13-17 V treatment demasculinized F1 SD male rat offspring; however none of the effects examined to date were transmitted to the F2 or F3 generations. In F1 males, GD13-17 V treatment reduced anogenital distance at birth, and induced female-like nipples, undescended testes, hypospadias, reduced fertility and reduced androgen-dependent tissue weights. The effects of V on AGD, nipple and fertility were not transmitted to the F2 generation. In contrast to the effects seen with GD13-17 treatment, GD8-15 V treatment did not reduce F1 or F2 fertility, induce reproductive tract malformations or reduce epididymal sperm numbers in the F1 generation. F2 and F3 males will be examined further at middle age and the histology of the testes and other organs will be examined in males from all generations to determine if vinclozolin treatment induced effects on these tissues. In summary, oral V treatment during gonadal differentiation did not affect reproductive morphology, sperm numbers or the fertility in the F1 generation. In contrast, clear adverse reproductive effects were seen in the group exposed to V during androgen-dependent sexual differentiation. This abstract does not necessarily reflect US EPA policy.