Development, Validation, and Application of a Human Reproductive Toxicity Prediction Model Based on Adverse Outcome Pathway

A growing number of environmental contaminants have been
proved
to have reproductive toxicity to males and females. However, the unclear
toxicological mechanism of reproductive toxicants limits the development
of virtual screening methods. By consolidating androgen (AR)-/estrogen
receptors (ERs)-mediated adverse outcome pathways (AOPs) with more
than 8000 chemical substances, we uncovered relationships between
chemical features, a series of pathway-related effects, and reproductive
apical outcomeschanges in sex organ weights. An AOP-based
computational model named RepTox was developed and evaluated to predict
and characterize chemicals’ reproductive toxicity for males
and females. Results showed that RepTox has three outstanding advantages.
(I) Compared with the traditional models (37 and 81% accuracy, respectively),
AOP significantly improved the predictive robustness of RepTox (96.3%
accuracy). (II) Compared with the application domain (AD) of models
based on small in vivo datasets, AOP expanded the
ADs of RepTox by 1.65-fold for male and 3.77-fold for female, respectively.
(III) RepTox implied that hydrophobicity, cyclopentanol substructure,
and several topological indices (e.g., hydrogen-bond
acceptors) were important, unbiased features associated with reproductive
toxicants. Finally, RepTox was applied to the inventory of existing
chemical substances of China and identified 2100 and 7281 potential
toxicants to the male and female reproductive systems, respectively.