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 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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| 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".