Although the only effect observed herein in PZ-treated female offspring was a transient increase in neonatal anogenital distance, it is important to note that our evaluation of the female reproductive system was limited to an examination of a few developmental landmarks and organ weights, as the female offspring were not the focus of the current study, and it is possible that the reproducible, high-dose effect of PZ on neonatal anogenital distance is associated with adverse developmental reproductive toxicity on fertility, estrous cyclicity, behavior, or histopathology (or a combination of these) of the female rat.
Together, transcriptional activation, enzyme induction, and tissue incubation data suggest that PZ displays three distinct mechanisms of endocrine disruption, including AR antagonism, inhibition of aromatase activity, and inhibition of androgen synthesis.
Potential effects of the current study on PZ regulation have yet to be determined regarding human health, or fish and wildlife populations. That PZ causes malformations in the reproductive tract of male offspring at dosage levels that are not maternally toxic could have an effect on the acute dietary risk assessment of this chemical if a regulatory agency determined that these effects were displayed at dosage levels that were low enough to raise their level of concern about potential effects in humans. In addition, the observation that other pesticides such as vinclozolin and procymidone share a common mechanism of toxicity with PZ indicates that cumulative exposures to PZ with other pesticides might be important in an estimation of the risk of PZ or other antiandrogens to human health.
In summary, PZ is an androgen antagonist in vitro and in vivo. In the current study, we confirmed the original findings that PZ binds to mammalian androgen receptors and inhibits AR-dependent gene expression in vitro. We also demonstrated that gestational exposure delayed parturition in the dam (consistent with previous unpublished reports), and showed for the first time that PZ causes reproductive malformations in androgen-dependent tissues of male offspring of exposed rats. PZ is the first imidazole fungicide shown to induce reproductive tract malformations.