Substances that activate various liver receptors as endocrine disruptors

Why?

The current development of NAMs in the field of endocrine disruption (ED) is very active as the concept of ED is evolving in various areas of toxicology including liver toxicity/xenobiotic metabolism and metabolic disorders.

Currently, transactivation assays are being investigated, as ED relevant assays, for hepatic nuclear receptors that are responsible for inducing liver phase I & II enzymes that accelerate the metabolism of xenobiotics and may also affect the metabolism of some endogenous metabolites such as hormones.

A number of AOPs have described where activation by xenobiotics of hepatic Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) is eventually causing a decrease or an increase in circulating androgen or estrogen hormones in exposed organisms resulting in adverse effects. AOPs with other nuclear receptors such as the Aryl hydrocarbon Receptor (AhR) and the peroxisome proliferator activated receptor (PPAR) have also been described as potentially affecting the level of endogenous hormones. In addition, activation of some of these nuclear receptors are also believed to contribute to a number of metabolic disorders (such as obesity) and this field of investigation is currently being addressed in the US and in Europe (via some EU projects under the umbrella of EURION).

The Task Force work will first focus on hepatic clearance of sex steroid hormones in the context of adult exposure (in utero exposure not in scope). Adverse effects under consideration are uterine adenocarcinoma and effects on the male reproduction system.