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Effects of the fungicide imazalil on the fathead minnow (Pimephales promelas) reproductive axis a case study in 21st century toxicity testing
Citation:
Randolph, E., G. Ankley, B. Blackwell, J. Cavallin, W. Cheng, D. Feifarek, K. Jensen, M. Kahl, R. Milsk, S. Poole, T. Saari, AND Dan Villeneuve. Effects of the fungicide imazalil on the fathead minnow (Pimephales promelas) reproductive axis a case study in 21st century toxicity testing. SETAC North America, Orlando, FL, November 06 - 10, 2016.
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Description:
Since its introduction in 1983 imazalil has been used primarily as a fungicide on crops post-harvest, such as tubers and citrus fruits. Its effectiveness lies in the ability to inhibit the fungal enzyme, lanosterol 14 á-demethylase. However, like other azole fungicides, imazalil can inhibit a range of cytochrome p450 enzymes, including one or more involved in steroid biosynthesis. Previous in vitro and high throughput screening assays showed that imazalil can cause aromatase inhibition and reduce 17â-estradiol (E2) production by H295R cells. In the present study, we tested imazalil in a number of in vitro and in vivo bioassays with fathead minnows (Pimephales promelas) to evaluate whether it would elicit effects consistent with an adverse outcome pathway (AOP) linking inhibition of aromatase to reduced fecundity. Ex vivo ovarian E2 and testosterone (T) production by ovary tissue from reproductively mature female P. promelas exposed to imazalil for 24 h at concentrations of 100, 500 and 1580 µg/L were significantly lower (p<0.05) than controls. Plasma E2 concentrations of females exposed for 24 h were significantly lower at imazalil concentrations of 80 and 250 µg/L, but not 2.5, 8, and 25 µg/L. In a separate 60 h exposure, plasma E2 concentrations were significantly lower than controls in mature P. promelas exposed to 200 ìg imazalil/L, but not at 0.2, 2, or 20 ug/L. Real-time quantitative PCR analyses measuring relative abundance of mRNA transcripts for various CYPs in ovary indicated an upregulation of cyp19a1a, cyp17, and cyp11a in P. promelas exposed to 200 ìg imazalil/L. This induction is potentially due to compensatory/feedback responses along the hypothalamic-pituitary-gonadal axis. Overall, data collected to date support the hypothesis that imazalil causes endocrine disruption in exposed female fathead minnows in a manner consistent with an established AOP and supports the broader utility of that AOP in hazard assessment.