Ventolin Inhalers

- Late Gestational Exposure to the Fungicide Prochloraz: INTRODUCTION(2)

Neither PZ nor its metabolites 2,4,6-trich-lorophenoxyacetic acid and 2,4,6-trichlorophenol affect androgen receptor (AR)-dependent gene expression in transfected cells.

In the fetal male rat, maternal PZ treatment inhibits testosterone production and increases progesterone production, indicating an inhibition of P450 17,20 lyase activity.

Although the P450 effects observed are to be expected from a member of the imidazole family of fungicides, PZ has also recently been shown to act as an AR antagonist in vitro and in vivo. This is a novel mechanism of action for this class of antifungals, which until recently, have not been shown to bind the AR. In vitro, PZ inhibits AR-dependent gene expression in transiently transfected CHO cells. In vivo, in a Hershberger assay (using castrated adolescent male rats with administered replacement testosterone), PZ exhibited antiandrogenic activity by reducing weights of androgen-dependent tissues (ventral prostate, seminal vesicles, levator ani plus bulbocavernosus muscles, and bulbourethral glands). Together, these data suggest that PZ has multiple mechanisms of endocrine action mediated through both the AR and several P450 enzyme pathways.

In the current study, we re-evaluated key observations from the literature by testing the ability of PZ to bind the rat AR and to modulate human AR-mediated gene transcription. We also evaluated effects of prenatal PZ exposure in the pregnant dam, and whether in utero PZ exposure affected the development of androgen-regulated tissues in male pups. We hypothesized that these tissues would be the most likely to display in vivo effects of PZ antagonism to androgen or aromatase activities. We expected that PZ would delay parturition if aromatase inhibition altered estrogen synthesis in vivo. In addition, we expected PZ to demasculinize male offspring (as do other AR antagonists) if antiandrogenic activity was expressed in the fetal male rat.

February 16, 2014 Parturition
Tags: antiandrogen environment fungicide hypospadias male reproductive tract