Abstract
The vertebrate hypothalamic-pituitary-gonadal (HPG) axis is controlled through various feedback mechanisms that maintain a dynamic homeostasis in the face of changing environmental conditions, including exposure to chemicals. We assessed the effects of prochloraz on HPG axis function in adult fathead minnows (Pimephales promelas) at multiple sampling times during 8-day exposure and 8-day depuration/recovery phases. Consistent with one mechanism of action of prochloraz, inhibition of cytochrome P450 (CYP) 19 aromatase activity, the fungicide depressed ex vivo ovarian production and plasma concentrations of 17beta-estradiol (E2) in female fish. At a prochloraz water concentration of 30 microg/l, inhibitory effects on E2 production were transitory and did not persist during the 8-day exposure phase. At 300 microg/l prochloraz, inhibition of E2 production was evident throughout the 8-day exposure but steroid titers recovered within 1 day of cessation of exposure. Compensation or recovery of steroid production in prochloraz-exposed females was accompanied by upregulation of several ovarian genes associated with steroidogenesis, including cyp19a1a, cyp17 (hydroxylase/lyase), cyp11a (cholesterol side-chain cleavage), and follicle-stimulating hormone receptor. In male fathead minnows, the 8-day prochloraz exposure decreased testosterone (T) production, possibly through inhibition of CYP17. However, as for E2 in females, ex vivo testicular production and plasma concentrations of T recovered within 1 day of stopping exposure. Steroidogenic genes upregulated in testis included cyp17 and cyp11a. These studies demonstrate the adaptability of the HPG axis to chemical stress and highlight the need to consider the dynamic nature of the system when developing approaches to assess potential risks of endocrine-active chemicals.
Highlights
Prochloraz is an imidazole fungicide registered for various agricultural uses throughout the world
By the day, prochloraz in the high treatment tanks had diminished to 7.2 lg/l (0.75, 4), a concentration just above the analytical detection limit, and by day 4 of the recovery phase, no prochloraz was detected in any tank
The ar and cyp17 transcripts were significantly elevated in the 300-lg/l treatment group on day 8 of the exposure (Figs. 4a and 4b), and cyp17 was significantly increased in this treatment group compared to controls when data from the exposure phase of the test were pooled for analysis
Summary
Prochloraz is an imidazole fungicide registered for various agricultural uses throughout the world (http://pubchem. ncbi.nlm.nih.gov/summary/summary.cgi?cid1⁄473665). Ankley et al (2009) describe a research effort focused on a systems-based approach for studying reproductive effects of HPG-active chemicals with differing mechanisms of action in fish. Because prochloraz affects other targets in addition to aromatase, it provides a useful comparison to fadrozole in terms of revealing commonalities and differences in effects of the two chemicals on steroid synthesis and HPG function. The type of temporally intensive design employed for this work, while challenging to implement, is necessary for generation of the robust data sets needed for (1) identifying linkages between events occurring at differing biological levels of organization and (2) the development of dynamic modeling approaches for prediction of chemical effects on the reproductive system of fish (Ankley et al, 2009)
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