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

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.