Bibliographic record
Abstract
The phasing out of polybrominated diphenyl ether (PBDE) flame retardants has resulted in their replacement with organophosphate esters (OPEs); these are now present ubiquitously in the environment and human matrices. Data from previous studies suggest that OPEs are endocrine active and thus may have detrimental effects on female fertility. In this thesis, my goal was to elucidate the effects of commonly used OPEs on granulosa cells, endocrine cells that surround the oocyte and play key roles in ovarian physiology. First, I assessed the effects of nine individual OPEs on the phenotypes of immortalized KGN human granulosa cells using a high-content imaging approach. At non-cytotoxic concentrations, several OPEs increased total mitochondria, decreased lysosomes, increased the total area of lipid droplets, and induced oxidative stress in KGN cells. Potency ranking, using benchmark modelling and Toxicological Prioritization Index analyses, revealed that while most of the individual OPEs tested were more potent than a predominant PBDE congener, BDE-47, others showed little to no effect. Second, I showed that the ability of OPEs to perturb the production of progesterone and estradiol in KGN cells was higher than that of BDE-47. These effects on hormone production were related to alterations in the expression of transcripts that are key in steroidogenesis and cholesterol biosynthesis. Third, I used a high- throughput transcriptomic approach, TempO-seq, to query the effects of OPEs on the expression of ~3000 environmentally responsive genes. The results indicated that the cholesterol biosynthesis pathway was a sensitive pathway in response to OPE exposures. Follow-up assays showed that the inhibition in cholesterol biosynthesis was likely a consequence of negative feedback elicited by excessive free cholesterol. I also observed effects on pathways related to cell cycle regulation and stress-responses, including inflammation. Lastly, I exposed the cells to environmentally relevant mixtures of OPEs, reconstituting the profiles of OPEs found in Canadian house dust. Exposure to OPE mixtures altered the phenotype, function, transcriptome, and lipidome of KGN cells. These OPE mixtures induced significant effects at concentrations at which individual OPEs had low or no activity, suggesting that investigations of single compounds may underestimate the risk of exposure to OPEs. Together, these studies are the first to compare the effects of OPEs to those of legacy compounds in ovarian cells. Exposure to OPEs may impair female reproductive health by altering the structure and function of ovarian granulosa cells. The combination of high-content imaging and omics analyses is a powerful screening strategy to identify potential endocrine and reproductive toxicants and provide information on the mechanism(s) underlying the effects of data-poor compounds
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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".