The use of traditional and alternative methods to study endocrine disruption in model avian species
Bibliographic record
Abstract
Toxicity testing of chemicals is integral to environmental hazard determination and risk assessment. Traditional whole animal (in vivo) testing methods are resource-intensive and raise ethical concerns pertaining to animal use. This has led to a surge in the development of alternative methods (cells and tissues) to screen and prioritize chemicals. Despite the promise shown by such methods, little is known about how they perform against whole animal tests. Overall, this thesis aimed to advance knowledge on A) traditional and alternative toxicity testing methods, and B) the effects of 17β-trenbolone (17βT- an endocrine disrupting chemical used in livestock as a growth promoter) in model avian species. The specific aims were to 1) use in vivo exposures and next-generation RNA-Sequencing to examine sex- and developmental stage-related differences in the hepatic transcriptome of Japanese quail (JQ, Coturnix japonica) exposed to 17βT; Aim 2) assess molecular and biochemical effects on the quail endocrine system during early stages of in vivo exposure to 17βT; Aim 3) compare effects of chemicals on gene expression in three alternative methods: hepatocytes, liver slice culture, and in ovo liver of white leghorn chicken (Gallus gallus domesticus); and Aim 4) outline key challenges, opportunities, and monetary costs, time and number of animals associated with traditional and alternative testing. In Aim 1, analysis of the quail hepatic transcriptome indicated that early life stages may be more vulnerable to endocrine disruption than adults. Differentially expressed genes were related to processes including cell proliferation, and transport and metabolism of lipids and proteins. In Aim 2, analyses of the JQ endocrine pathway revealed significant differences in plasma hormone levels in exposed males and females that fluctuated over the duration of exposure, but no changes in the expression of associated genes, implying that metabolic pathways and other receptors may be involved in the mechanisms by which 17βT impairs the endocrine system. In Aim 3, hierarchical clustering analysis of gene expression results across three alternative methods showed similarities between liver slice culture and in ovo liver, while hepatocytes were more different. In Aim 4, bibliometric searches of resource-related costs from various sources showed that, realistically, the status quo in toxicity testing will not be able to provide toxicity data for all existing and emerging chemicals. In summary, this work demonstrated the potential of liver slices as alternatives in toxicity testing; further, this work showed that even using traditional methods results may vary depending on factors such as sex, developmental stage, and exposure duration. This thesis advances knowledge on two fronts: A) the potential of alternative testing methods to aid in their future implementation and the reduction of traditional methods in chemical toxicity testing, and B) the importance of including aforementioned factors while examining molecular and biochemical endpoints in toxicity studies.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".