Fig. 2.

Proposed Adverse Outcome Pathway (AOP) network for disrupted Hedgehog (HH) signaling during development leading to reproductive disease. From what is currently known about the involvement of HH signaling in gonadal development, testes and ovaries, it is possible to extract putative AOPs for further elaboration. The numbers (purple circles) in the developmental pathway correspond to events that are believed to be essential to progress the cause-effect pathway towards the adverse outcome (AO), but the upper developmental pathway is far from a complete description of the HH signaling pathway as it takes place in cells and tissues. Being pragmatic descriptions of pathways between initial molecular perturbation to an AO in an intact organisms, the AOP serve as reference points for predicting toxic effects from effects on upstream events only; meaning, molecular initiating events (MIE) and key events (KE) should be measurable and applicable for chemical risk assessment. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)