Knotting nets: Molecular junctions of interconnecting endocrine axes identified by application of the adverse outcome pathway concept

Abstract

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 11b-hydroxysteroid dehydrogenase (11b-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.

Evaluating the toxic potential of agrochemicals on the hypothalamic‐pituitary‐thyroid axis in tilapia(Oreochromis mossambicus)

“…However, the awareness of the disruption of the thyroid hormone system by chemicals is on the increase. In common with the reproductive steroid hormones, the synthesis and release of thyroid hormones are governed by a central Hypothalamus‐pituitary‐thyroid (HPT) axis (Bruggemann et al, ; Cortes, LangloisV, & Fernandino, ). Thyroid hormones are important in growth, metabolism, and homeostasis.…”

Towards a holistic and solution-oriented monitoring of chemical status of European water bodies: how to support the EU strategy for a non-toxic environment?

“…A risk-based prioritization of groups of chemicals sharing common MoAs is required but also an increased understanding of processes along AOPs also for mixtures. It should be considered that different molecular initiating events may culminate in the same AOP [ 83 ]. As an example, endocrine disruption may be the result of nuclear receptor binding as a molecular initiating event but also of impacts on steroid synthesis [ 69 ].…”

A Molecular Image-Based Novel Quantitative Structure-Activity Relationship Approach, Deepsnap-Deep Learning and Machine Learning

“…The objective variables have various types and strengths, namely reactivity and affinity, of different chemical substances, including hormones and inhibitors that maintain homeostasis of biological functions, ligands act on energy metabolism, and agonist/antagonist for vitamins involved in signal transduction (Hsu et al, 2014;Santos et al, 2017;Nagamani et al, 2018;Sakkiah et al, 2018;Agrawal et al, 2019;Kato 2020). Moreover, these chemical substances are involved in a process called key event (KE), which explains an unexpected in this pathway, that induces the expression of physiological activity by interacting with target molecules, such as receptors (Bal-Price and Meek, 2017;Scotti et al, 2017;Brüggemann et at 2018;Ehlert, 2018;Naqvi et al, 2018). Further, the type of physiological activity depends on the type of target molecule, and the strength of the physiological activity is determined by the strength of interaction with the target molecule (Devidas and Ranawat, 2019).…”