Analysis of the Molecular Mechanisms of Human Estrogen Receptors α and β Reveals Differential Specificity in Target Promoter Regulation by Xenoestrogens
Bibliographic record
Abstract
Most of the currently available information on the transcriptional activities of endocrine-disrupting chemicals (xenoestrogens) through estrogen receptors alpha (ERalpha) and beta (ERbeta) has been derived from transactivation studies on synthetic estrogen-responsive reporters. Thus, the ability of the xenoestrogen-liganded ERs to regulate endogenous estrogen-responsive gene expression has not been well characterized. Here, we have evaluated the activities of xenoestrogens through ERalpha and ERbeta on the vitellogenin A2 estrogen-response element (ERE) and the human pS2, lactoferrin, and complement 3 physiological target gene promoters. Using mammalian cell transient transfection assays, we found that the activities of xenoestrogens were mediated in a promoter-specific manner. For example, when bound to all ligands examined, ERalpha displayed high levels of transcription on the vitellogenin ERE and the lactoferrin promoter, but substantially lower activity on the complement 3 and pS2 promoters. However, one of the most important observations was that there were significant differences in the relative transcriptional activities of xenoestrogen-bound ERalpha and ERbeta on different promoters, suggesting that ERalpha and ERbeta make unique contributions to xenoestrogen action in target cells. When probing the molecular mechanism of the promoter-specific activities observed, we found that the transcriptional activity of the ERs correlated with the ability of each receptor to assume an active conformation on specific promoters. Taken together, the results indicate that the transcriptional activities of xenoestrogens are mediated in a promoter-specific manner and that estrogen-responsive promoters communicate differently with ERalpha and ERbeta by influencing their structures in a distinct manner that leads to diversity in their transcriptional responses.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".