Knotting nets. Molecular junctions of interconnecting endocrine axes identified by application of the adverse outcome pathway (AOP) concept

In order to be defined as endocrine disruptor, a substance has to meet several criteria, including the induction of specific adverse effects, specific endocrine mode-of-action and a plausible link between both. Especially the latter criterion might not always be unequivocally determined, particularly as the endocrine system consists of diverse endocrine axes. The axes closely interact with each other, and manipulation of one triggers effects on the other. This review aimed at identifying some of the many interconnections between these axes. This study focusses on fish, but also considers data obtained in studies on amphibians and mammals if these assist in closing data gaps, as most of the endocrine mechanisms are evolutionary conserved. The review comprises data of ecotoxicological studies, as well as data on physiological processes. The gathered information delivers data on hormone/hormone receptor interactions or gene transcription regulation. The identified key events (KE) and KE relationships (KER) provide explanations for unexpected effects on one axis, exerted by substances suspected to act specifically on another axis. Based on these data, several adverse outcome pathway (AOP) segments were identified, describing connections between the HPG- and HPT-axes, the HPG- and HPA/I-axes, and the HPT- and HPA/I-axes. Central KEs identified across axes were altered aromatase activity, and altered expression and function of the proteins 11beta-hydroxysteroid dehydrogenase (11beta-HSD) and steroidogenic acute regulatory (StAR) protein. Substance classes, which act on more than one endocrine axis were for example goitrogens or aromatase inhibitors. Despite the wealth of gathered information, it only provides a small insight into the molecular nets of endocrine axes, demonstrating the complexity of the interconnections between endocrine axes.