Conazole Pesticide Disruption of Testicular Steroidogenesis during Different Stages of Male Development.

Abstract

This work investigated conazole pesticide effects on rat gonadal steroidogenesis and related the observed changes in testosterone production to adverse effects on pubertal and fetal reproductive development. In the initial experiments, prochloraz (PCZ) exposure during male rat pubertal development was investigated to test the hypotheses that PCZ would inhibit testosterone production within the pubertal testis and delay pubertal development. Furthermore, PCZ antagonism of the androgen receptor (AR) in vivo was quantified to assess whether this mechanism contributed to delayed pubertal development. These studies showed that PCZ was a strong inhibitor of steroidogenesis relative to its AR antagonism and unexpectedly the large decrease in testosterone did not necessarily delay pubertal development.

Next, the sensitivity of fetal testosterone production to maternal PCZ exposure was investigated to support the hypothesis that PCZ inhibition of testosterone synthesis in the fetal testis contributes to the reported adverse effects in androgen-dependent tissues of male offspring. PCZ inhibited fetal testosterone production at doses that correspond to those which cause adverse reproductive malformations in the adult. The hormone data suggested that PCZ inhibits the conversion of progesterone to testosterone through the inhibition of CYP17. To test this hypothesis, the effects of PCZ on CYP17 gene expression and CYP17 hydroxylase activity were evaluated. PCZ did not affect gene expression, but did significantly inhibit CYP17 hydroxylase activity. Taken together, these observations support the hypotheses that PCZ inhibits CYP17 enzymatic activity resulting in reduced testosterone synthesis with adverse consequences to male development.

In the last chapter, two triazole conazoles, myclobutanil and triadimefon, were hypothesized to be steroidogenesis inhibitors similar to PCZ. Both compounds weakly inhibited steroidogenesis in vitro, and when myclobutanil was tested to inhibit fetal steroidogenesis ex vivo, there were no effects. Myclobutanil, triadimefon, and a third triazole, propiconazole, did increase serum testosterone in the adult rat after developmental exposure. Focusing on triadimefon, the elevated serum testosterone was hypothesized to be from increased testicular testosterone production. Triadimefon exposure to the adult rat increased intra-testicular testosterone levels suggesting the testis contributed to the increased serum testosterone.

In summary, PCZ was unique among the conazoles examined in its ability to reduce testicular testosterone production and alter male reproductive development.