With PZ, vinclozolin, and pro-cymidone exposures, male malformations were produced without the severe testicular lesions observed with phthalate exposure. Like PZ, procymidone and vinclo-zolin metabolites are AR antagonists, suggesting that AR antagonism may be a mechanism for malformation production through PZ exposure. Although further data are required before we can definitively determine what mechanisms of action are most responsible for the demasculin-ization of male pups, PZ antagonism of androgen in the Hershberger assay is consistent with in vivo AR antagonism by PZ.
As a rule, chemicals that disrupt the androgen signaling pathway during sexual differentiation disrupt the androgen-dependent tissue development in the fetal male without producing malformations in the female reproductive tract. This is true for phthalates that inhibit fetal Leydig cell hormone production, or the AR antagonists such as vinclozolin, procymidone, or flutamide Androgens are required for male-specific tissues to differentiate from an indifferent state to the male phenotype. Reducing the androgen levels in the fetus or blocking androgen action at the level of the AR in the tissue induces a female-like phenotype. Because the pathway for androgen-induced tissue development is not activated during differentiation of the female reproductive tract, inhibition of the androgen signaling pathway does not affect the female phenotype.