Chemical activation of estrogen and aryl hydrocarbon receptor signaling pathways and their interaction in toxicology and metabolism

ABSTRACT

Introduction: Estrogen receptors (ERs) and the arylhydrocarbon receptor (AHR) are ligand-activated transcription factors that regulate the expression of genes involved in many physiological processes. With both receptors binding a broad range of natural and anthropogenic ligands, they are molecular targets for many substances, raising concerns for possible health effects.

Areas covered: This review shall give a brief overview on the physiological functions of both receptors including their underlying molecular mechanisms. It summarizes the interaction of the respective signaling pathways including impacts on metabolism of endogenous estrogens, transcriptional interference, inhibitory crosstalk, and proteasomal degradation. Also addressed are the AHR dependent formation of estrogenic metabolites from polycyclic aromatic hydrocarbons and the possible impact of the ER/AHR crosstalk in the context of drug metabolism.

Expert opinion: Despite decade-long research, the physiological role of the AHR and ER as well as the implications of their complex mutual crosstalk remain to be determined as do resulting potential impacts on human health. With more and more endogenous AHR ligands being discovered, future research should hence systematically address the potential impact of such substances on estrogen signaling. The intimate link between these two pathways and the genes regulated therein bears the potential for impacts on drug metabolism and human health.

KEYWORDS:

• AHR/ER signalling
• AHR/ER ligands
• AHR/ER crosstalk
• dioxin
• PAHs
• endogenous AHR ligands
• toxicology
• drug metabolism

Article highlights

• Both pathways, AHR, and ER signaling, are involved in mammalian reproduction.

• Complex interaction of both signaling pathways occurs on multiple levels, including modification of metabolism, transcriptional interference, and proteasomal degradation.

• Estrogenic metabolites can be formed from polycyclic hydrocarbons.

• AHR and ER are activated by a wide range of anthropogenic, plant-derived and endogenous compounds.

• The crosstalk of AHR/ER is likely to have consequences for toxicology, especially in the context of exposure to environmental mixtures.

• With possible detrimental effects of AHR ligands often being dependent on dose and the metabolic stability of the respective compound, the physiologic function of endogenous AHR agonists on the endocrine system are yet to be explored. The AHR/ER crosstalk’s effect on substance metabolism is likely to contribute to observe differences in drug metabolism.

This box summarizes key points contained in the article.

Declaration of interest

The authors have received intramural financial support by the German Federal Institute for Risk Assessment, Berlin, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.