PPARα Activation-Mediated Testosterone Reduction as the Key Adverse Outcome Pathway for Cd-Induced Male Infertility: A Novel Integrated Approach
Bibliographic record
Abstract
Cadmium (Cd)-induced male infertility and its mechanisms have been widely studied, but systematic construction of an adverse outcome pathway (AOP) network and identification of key AOPs remained unknown. This study integrated network toxicology, single-cell sequencing, NHANES research, animal experiments, and molecular modeling to construct an AOP network and identify the key AOP for Cd-induced male infertility. We constructed an AOP network comprising 9 AOPs and confirmed that PPARα activation leading to testosterone reduction and subsequent male infertility is the key AOP. Single-cell sequencing analysis showed downregulation of testosterone synthesis genes ( Cyp11a1 ) in Cd-exposed Leydig cells, whereas NHANES data showed a threshold effect between blood Cd (about 1.17 μg/L) and serum testosterone, indicating that high Cd exposure can reduce serum testosterone levels. Subnetwork analysis prioritized PPARα activation and increased the number of reactive oxygen species as potential critical MIEs. In vivo experiments further validated that the PPARα inhibitor (GW6471) more effectively reversed Cd-evoked sperm count reduction than the antioxidant N -acetylcysteine. Taken together, these results validated PPARα activation-mediated testosterone reduction as the key pathway for Cd-induced male infertility and established a novel integrative paradigm for identifying key AOPs in environmental toxicology.
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How this classification was reachedexpand
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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".