Knotting Nets: Molecular Junctions of Interconnecting Endocrine Axes Identified by Application of the Adverse Outcome Pathway Concept

To be defined as an endocrine disruptor, a substance has to meet several criteria, including the induction of specific adverse effects, a specific endocrine mode of action, and a plausible link between both. The latter criterion in particular might not always be unequivocally determined, especially because the endocrine system consists of diverse endocrine axes. The axes closely interact with each other, and manipulation of one triggers effects on the other. The present review aimed to identify some of the many interconnections between these axes. The focus was on fish, but data obtained in studies on amphibians and mammals were considered if they assisted in closing data gaps, because most of the endocrine mechanisms are evolutionarily conserved. The review includes data both from ecotoxicological studies and on physiological processes and gives information on hormone/hormone receptor interactions or gene transcription regulation. The key events and key event relationships identified 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 are identified, describing connections between the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) axes, the HPG and hypothalamic-pituitary-adrenal/interrenal (HPA/I) axes, and the HPT and HPA/I axes. Central key events identified across axes were altered aromatase activity as well as altered expression and function of the proteins 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) and steroidogenic acute regulatory (StAR) protein. Substance classes that act on more than one endocrine axis were, for example, goitrogens or aromatase inhibitors. Despite the wealth of information gathered, the present review only provides a few insights into the molecular nets of endocrine axes, demonstrating the complexity of their interconnections. (C) 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.