Evaluation of the Aromatase Inhibitor Fadrozole in a Short-Term Reproduction Assay with the Fathead Minnow (Pimephales promelas)
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Bibliographic record
Abstract
Cytochrome P450 aromatase (CYP19) is a key enzyme in vertebrate steroidogenesis, catalyzing the conversion of C19 androgens to C18 estrogens such as beta-estradiol (E2). The objective of this study was to assess effects of the CYP19 inhibitor fadrozole on fathead minnow (Pimephales promelas) reproductive endocrinology and physiology in a short-term reproduction assay proposed for identifying specific classes of endocrine-disrupting chemicals. A concentration-dependent reduction in fecundity was observed in fish exposed for 21 days to water concentrations of fadrozole ranging from 2 to 50 microg/l. Consistent with the expected mechanism of action, there was a significant inhibition of brain aromatase activity in both male and female fathead minnows exposed to fadrozole. In females, this inhibition was accompanied by a concentration-dependent decrease in plasma E2 and vitellogenin concentrations; the latter observation is consistent with the fact that activation of the estrogen receptor by E2 initiates hepatic vitellogenin production in oviparous vertebrates. Histological assessment of ovaries from females exposed to fadrozole indicated a decrease in mature oocytes and an increase in preovulatory atretic follicles. Exposure of male fathead minnows to fadrozole significantly increased plasma concentrations of the androgens testosterone (T) and 11-ketotestosterone (KT) and resulted in a marked accumulation of sperm in the testes. Results of this study indicate that the proposed fathead minnow assay should effectively identify test chemicals as potential aromatase inhibitors, both in the context of their reproductive toxicity and the specific mechanism of action. These results also should be of utility in assessing the potential ecological risk of CYP19 inhibitors, in particular in the context of relating alterations in subcellular indicators of endocrine function (changes in steroids, proteins) to adverse consequences in the whole organism.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it