Propiconazole Inhibits Steroidogenesis and Reproduction in the Fathead Minnow (Pimephales promelas)

Abstract

Conazoles are designed to inhibit cytochrome P450 (CYP) 14α-demethylase, an enzyme key to fungal cell wall formation. In vertebrates, conazoles may inhibit other CYPs, potentially disrupting processes like sex steroid synthesis. Propiconazole is a current-use pesticide that is among the first chemicals being tested in the U.S. Environmental Protection Agency endocrine disruptor screening program. Fathead minnows (Pimephales promelas) were exposed to 0, 5, 50, 500, or 1000 µg propiconazole/l in a 21-day study that evaluated apical reproductive endpoints (fecundity, fertility, hatch); measures of endocrine function and steroid synthesis, such as cholesterol, vitellogenin (VTG), and sex steroid (testosterone [T], 17β-estradiol [E2]) concentrations in the plasma; and changes in gonadal expression of steroidogenic genes. Plasma E2 and VTG concentrations in females were reduced by exposure to propiconazole, and egg production was decreased in the 500 and 1000 µg/l treatment groups. These in vivo effects coincided with inhibition of E2 synthesis by ovary explants exposed to propiconazole in vitro. We also observed a compensatory response in females exposed to propiconazole, manifested as increased gonad weight and upregulation of genes coding for key steriodogenic proteins, including CYP19 (aromatase), CYP17 (hydroxylase/lyase), CYP11A (cholesterol side-chain-cleavage), and steroidogenic acute regulatory protein. Other than an increase in relative testis weight, effects on endocrine function in males were less pronounced than in females. This study provides important data relative to the potential endocrine activity of propiconazole in fish and, more generally, to the further delineation of pathways for the reproductive effects of steroid synthesis inhibitors in fish.

Sex specific response in cholesterol level in zebrafish ( Danio rerio ) after long-term exposure of difenoconazole

“…CYP51 catalyse the demethylation of lanosterol in the cholesterogenic process which is also the target of triazole compounds. Previous research documented that cholesterol level in plasma decrease associated with inhibition of hepatic expression of CYP51 and HMGCR in propiconazole treated fathead minnow (Skolness et al, 2013). In this work, similar with the results of Skolness et al (2013), the reduction of gene expression of CYP51 and HMGCRa, were observed with the decreased TCHO level in male zebrafish liver.…”

Occurrence and origin of sensitivity toward difenoconazole in zebrafish (Danio reio) during different life stages

“…Both these two genes play important parts in cholesterol synthesis. Previous research has shown that a decrease in the cholesterol level in plasma occurred with the down-regulation of hepatic CYP51 and HMGCR in fathead minnow (P. promelas) treated with propiconazole (Skolness et al, 2013). Therefore difenoconazole may also cause a decrease in the level of total cholesterol because its mode of action and gene expression effects are similar to propiconazole.…”

“…Morrison et al (2014) found that ketoconazole has the potential to inhibit zebrafish CYP51, based on the results of a docking experiment. Skolness et al (2013) demonstrated that propiconazole could inhibit steroidogenesis in the fathead minnow (Pimephales promelas) and down-regulated the expression of some key genes, such as CYP51, HMGCR and FDPS, in the hepatic synthesis process. In the present study, a significant decrease in the hepatic expression of cyp51, hmgcra, and fas was observed in the groups exposed to a high difenoconazole concentration, which is in good agreement with previously reported results.…”

Evaluating the credibility of histopathology data in environmental endocrine toxicity studies

“…Therefore, 1 benefit of including this type of table in reports is that it may compel authors to more methodically analyze their histologic specimens and data interpretations prior to publication. As a positive example, Table 8 is a reprint from 1 of the reviewed manuscripts [13] of a simple data table that elegantly portrays the histopathologic prevalence and severity results. In terms of data credibility, a third example of a weakness was dependence on transmission electron microscopy (TEM) data as the sole or primary means of identifying morphologic effects of chemical exposure.…”

“…a From Skolness et al [13]; reprinted by permission. were published 11 to 15 yr ago (62%; n ¼ 47); in contrast, the lowest percentages involved articles that were published either within the past 5 yr (50%; n ¼ 54) or more than 15 yr ago (50%; n ¼ 16).…”